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Itch

Basic Mechanisms and Therapy


edited by

Gil Yosipovitch
Wake Forest University School o f Medicine Winston-Salem, North Carolina, U.S.A.

Malcolm W. Greaves
University of London London, England and Singapore General Hospital Singapore, Republic of Singapore

Alan 6. Fleischer, Jr.


Wake Forest University School of Medicine Winston-Salem, North Carolina, U.S.A.

Francis McGlone
Unilever Research and Development Wirral, England and University of Wales Bangor, Wales

a%
MARCEL DEKKER

MARCEL DEKKER, INC.

NEWYORK BASEL

Although great care has been taken to provide accurate and current information, neither the author(s) nor the publisher, nor anyone else associated with this publication, shall be liable for any loss, damage, or liability directly or indirectly caused or alleged to be caused by this book. The material contained herein is not intended to provide specic advice or recommendations for any specic situation. Trademark notice: Product or corporate names may be trademarks or registered trademarks and are used only for identication and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress. ISBN: 0-8247-4747-X This book is printed on acid-free paper. Headquarters Marcel Dekker, Inc., 270 Madison Avenue, New York, NY 10016, U.S.A. tel: 212-696-9000; fax: 212-685-4540 Distribution and Customer Service Marcel Dekker, Inc., Cimarron Road, Monticello, New York 12701, U.S.A. tel: 800-228-1160; fax: 845-796-1772 Eastern Hemisphere Distribution Marcel Dekker AG, Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland tel: 41-61-260-6300; fax: 41-61-260-6333 World Wide Web http://www.dekker.com The publisher oers discounts on this book when ordered in bulk quantities. For more information, write to Special Sales/Professional Marketing at the headquarters address above. Copyright n 2004 by Marcel Dekker, Inc. All Rights Reserved.

Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microlming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher. Current printing (last digit): 10 9 8 7 6 5 4 3 2 1 PRINTED IN THE UNITED STATES OF AMERICA

BASIC AND CLINICAL DERMATOLOGY


Series Editors
ALANR. SHALITA, M.D. Distinguished Teaching Professor and Chairman Department of Dermatology State University of New York Health Science Center at Brooklyn Brooklyn, New York

DAVID A. NORRIS, M.D. Director of Research Professor of Dermatology The University of Colorado Health Sciences Center Denver, Colorado

1. Cutaneous Investigation in Health and Disease: Noninvasive Methods and Instrumentation,edited by Jean-Luc Leveque 2. Irritant Contact Dermatitis, edited by Edward M. Jackson and Ronald Goldner 3. Fundamentalsof Dermatology: A Study Guide, Franklin S. Glickman and Alan R. Shalita 4. Aging Skin: Properties and Functional Changes, edited by Jean-Luc Leveque and Pierre G. Agache 5. Retinoids: Progress in Research and Clinical Applications, edited by Maria A. Livrea and Lester Packer 6. Clinical Photomedicine,edited by Henry W. Lim and Nicholas A. Soter 7. Cutaneous Antifungal Agents: Selected Compounds in Clinical Practice and Development, edited by John W. Rippon and Robert A. Fromtling 8. Oxidative Stress in Dermatology, edited by Jurgen Fuchs and Lester Packer 9. Connective Tissue Diseases of the Skin, edited by Charles M. Lapiere and Thomas Krieg 10. Epidermal Growth Factors and Cytokines, edited by Thomas A. Luger and Thomas Schwarz 11. Skin Changes and Diseases in Pregnancy, edited by Marwali Harahap and Robert C. Wallach 12. Fungal Disease: Biology, Immunology, and Diagnosis, edited by Paul H. Jacobs and Lexie Nall 13. lmmunomodulatory and Cytotoxic Agents in Dermatology, edited by Charles J. McDonald

14. Cutaneous Infection and Therapy, edited by Raza Aly, Kart R. Beutner, and Howard 1. Maibach 15. Tissue Augmentation in Clinical Practice: Procedures and Techniques, edited by Arnold William Klein 16. Psoriasis: Third Edition, Revised and Expanded, edited by Henry H. Roenigk, Jr., and Howard 1. Maibach ,l7. Surgical Techniques for Cutaneous Scar Revision, edited by Mamali Harahap 18. Drug Therapy in Dermatology, edited by Lany E. Millikan 19. Scarless Wound Healing, edited by Hari G. Garg and Michael T. Longaker 20. Cosmetic Surgery: An Interdisciplinary Approach, edited by Rhoda S. Narins 21. Topical Absorption of Dermatological Products, edited by Robert L. Bronaugh and Howard 1. Maibach 22. Glycolic Acid Peels, edited by Ronald Moy, Debra Luffman, and Lenore S. Kakita 23. InnovativeTechniques in Skin Surgery, edited by Marwali Harahap 24. Safe Liposuction, edited by Rhoda S. Narins 25. Psychocutaneous Medicine, edited by John Y. M. Koo and Chai Sue Lee 26. Skin, Hair, and Nails: Structure and Function, edited by Bo Forslind and Magnus Lindberg 27. Itch: Basic Mechanisms and Therapy, edited by Gil Yosipovitch,Malcolm W. Greaves, Alan 8. Fleischer, Jr., and Francis McGlone

ADDITIONAL VOLUMES IN PREPARA TION

Vitiligo: Problems and Solutions, edited by Torello Loffi and Jana Hercogova Photoaging, edited by Darrel S. Rigel, Robert A. Weiss, Henry W. Lim, and Jeffrey S. Dover

To my wife, Galit, my children, Dan and Natalie, and my devoted parents, Shifra and Zvi. Without their continuous support, love, and understanding, this book would not have been possible. G. Y. To all my itchy patients who taught me that there is more to pruritus than scratching the surface. M. W. G. To my wonderful and patient wife, Anne. A. B. F. For all those who suer still, in the hope that our growing knowledge of the mechanisms will enhance our therapies. F. M.

Series Introduction

Over the past decade, there has been a vast explosion in new information relating to the art and science of dermatology as well as fundamental cutaneous biology. Furthermore, this information is no longer of interest only to the small but growing specialty of dermatology. Scientists from a wide variety of disciplines have come to recognize both the importance of skin in fundamental biological processes and the broad implications of understanding the pathogenesis of skin disease. As a result, there is now a multidisciplinary and worldwide interest in the progress of dermatology. With these factors in mind, we have undertaken to develop this series of books specically oriented to dermatology. The scope of the series is purposely broad, with books ranging from pure basic science to practical, applied clinical dermatology. Thus, while there is something for everyone, all volumes in the series will ultimately prove to be valuable additions to the dermatologists library. The latest addition to the series, edited by Gil Yosipovitch, Malcolm Greaves, Alan Fleischer, and Francis McGlone, is both timely and pertinent. The authors are well-known authorities in the eld. We trust that this volume will be of broad interest to scientists and clinicians alike. Alan R. Shalita SUNY Health Science Center Brooklyn, New York

Foreword

You know that I would cut o My hands to help you But if I did I wouldnt have Anything to scratch with And then Id be of No use at all. Don McGonigal, The Itch, 1991 Itch is one of the most distressing sensations that substantially impair the quality of life, and in some cases it may even cause psychological disorders. It is a symptom of many skin diseases and may be caused by a variety of systemic diseases. The enormous developments in biotechnology of the past ve years have enabled major progress in neurophysiological research, allowing us to
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Foreword

dene novel pathways for itch. Improved understanding of the pathophysiology and molecular basis of itching ultimately has stimulated the search for and development of novel therapeutic strategies. In the current book Drs. Yosipovitch, Greaves, Fleischer, and McGlone were able to motivate outstanding scientists and clinicians to provide, in a multidisciplinary approach, the most current knowledge of the complex experimental, clinical, and therapeutic aspects of itching. This includes recent research concerning basic mechanisms of itching such as central nervous aspects, animal and human models, and neuropeptides as well as their respective receptors. Furthermore, emphasis is put on new techniques of itch evaluation such as microdialysis and questionnaires. Another important topic is the symptom of itch in dermatological as well as systemic diseases. Finally, as a result of our improved understanding of the pathophysiology of itching, several chapters address the most up-to-date therapeutic developments, including new drugs and psychological approaches. In summary, the important insights provided by the expertise of these outstanding contributors will be of major interest to clinicians managing this challenging symptom as well as to researchers interested in the pathogenesis of itching. Thomas A. Luger, M.D. Professor and Chairman Department of Dermatology University Clinics Munster Munster, Germany

Preface

For many years progress in understanding the neuropathophysiology and molecular basis of itch has been handicapped by a lack of specic and sensitive investigational methodologies for human subjects and the unsuitability of animal models. Researchers have nally begun to overcome these diculties, with important clinical implications. Recent neurophysiological research has made possible a more accurate description of neural pathways of itch and has conrmed the distinctiveness of itch pathways in comparison with pain pathways. We were motivated to work on this book by consideration of patients aicted by chronic and intractable itch and our desire to contribute to a better understanding of this common, bothersome symptom. The idea was proposed in October 2001 at the International Workshop for the Study of Itch in Singapore. This was the rst multidisciplinary meeting that brought clinicians and scientists together to address problems related to itch. This book presents a concise discussion of the basic aspects of itch, various diseases in which itch constitutes a major problem, and methods employed in its diagnosis and management. It is designed to be a source of
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Preface

information for both dermatologists and nondermatologists who treat itch, as well as for researchers in the eld of neurophysiology and pharmacology. The organization of the chapters reects our views as to how the reader can best utilize these materials. The book has six parts. Part I contains a proposed clinical classication of itch, based on an improved understanding of its neurophysiology. Part II reviews the basic mechanisms of itch. Part III addresses the evaluation of the patient with itch. Part IV focuses on epidemiology and characteristics of itch in skin and systemic diseases. Part V provides an overview of the dierent methods for the treatment of itch currently in use or in clinical trials. The last part consists of three chapters addressing the social and psychological aspects of itch. The authors were selected for their expertise and interest in this eld. While eorts were made to avoid repetition, each author was free to present his or her own concepts and thoughts. The progress documented in this book is encouraging and is a direct result of expanded interest in the problem of itch in both the scientic and clinical communities. Gil Yosipovitch Malcolm W. Greaves Alan B. Fleischer, Jr. Francis McGlone

Contents

Foreword Thomas A. Luger Preface Contributors Part I. Clinical Classication of Itch

vii ix xv

1. Denitions of Itch Gil Yosipovitch and Malcolm W. Greaves Part II. Basic Mechanisms of Itch

2. Neurophysiologic Basis of Itch Martin Schmelz and Hermann O. Handwerker 3. Pain and Itch Martin Schmelz and Hermann O. Handwerker 4. Central Neural Mechanisms of Itch David Andrew and A. D. Craig 5. Animal Models of Itch: Scratching Away at the Problem Earl Carstens and Yasushi Kuraishi

13

21

35

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Contents

6.

Histamine-Induced Discriminative and Aective Responses Revealed by Functional MRI Francis McGlone, Roman Rukwied, Matt Howard, and David Hitchcock Central Nervous System Imaging of Itch with PET Ulf Darsow, Alexander Drzezga, and Johannes Ring Skin Nerve Anatomy: Neuropeptide Distribution and Its Relationship to Itch Dieter Metze Substance P and Itch Tsugunobu Andoh and Yasushi Kuraishi Peripheral Opiate Receptor System in Human Epidermis and Itch Paul Lorenz Bigliardi and Mei Bigliardi-Qi Antipruritic Activity of a Novel K-Opioid Receptor Agonist, TRK-820 Jun Utsumi, Yuko Togashi, Hideo Umeuchi, Kiyoshi Okano, Toshiaki Tanaka, and Hiroshi Nagase Putative Role of Cannabinoids in Experimentally Induced Itch and Inammation in Human Skin Roman Rukwied, Melita Dvorak, Allan Watkinson, and Francis McGlone Itch Models in Animals, with Special Emphasis on the Serotonin Model in Rats Jens Schiersing Thomsen Human Itch Models, with Special Emphasis on Itch in SLS-Inamed and Normal Skin Jens Schiersing Thomsen Evaluation of Patients with Itch

51

7.

63

8.

71

9.

87

10.

97

11.

107

12.

115

13.

131

14.

139

Part III. 15.

Microdialysis in Itch Research Martin Schmelz

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Contents

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16.

Measuring Nocturnal Scratching in Atopic Dermatitits Toshiya Ebata Itch Questionnaires as Tools for Itch Evaluation Gil Yosipovitch Epidemiology and Characteristics of Itch

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17.

169

Part IV. 18.

Epidemiology of Itching in Skin and Systemic Diseases Gil Yosipovitch Uremic Pruritus: New Perspectives and Insights from Recent Trials Thomas Mettang, Dominik Mark Alscher, and Christiane Pauli-Magnus Pruritus Complicating Liver Disease Nora V. Bergasa and E. Anthony Jones Itch in HIV-Infected Patients Maria I. Duque, Gil Yosipovitch, and P. Samuel Pegram Neuropathic Pruritus Gil Yosipovitch, Rashel Goodkin, Ellen Mary Wingard, and Jerey D. Bernhard Clinical Features of Itch in Atopic Eczema Ulf Darsow and Johannes Ring Postburn Itch Robert D. Nelson Pruritus in Lichen Simplex Chronicus and Lichen Amyloidosis Yung-Hian Leow and Gil Yosipovitch Treatment of Itch

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19.

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20.

205

21.

219

22.

231

23.

241

24.

247

25.

255

Part V. 26.

Treatment of Pruritus in Internal and Dermatological Diseases with Opioid Receptor Antagonists Sonja Stander and Dieter Metze

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Contents

27.

Prospects for a Novel K-Opioid Receptor Agonist, TRK-820, in Uremic Pruritus Hiroo Kumagai, Shigeaki Matsukawa, Jun Utsumi, and Takao Saruta Treatment of Pruritic Skin Diseases with Topical Capsaicin Sonja Stander and Dieter Metze Mechanistic and Clinical Assessment of ZangradoR , an Extract of the Amazonian Ethnomedicine Sangre de Grado, for the Treatment of Itch Mark J. S. Miller, Brian K. Reuter, John L. Wallace, Keith A. Sharkey, and Paul Bobrowski Reduction in Itch Severity with Topical Immunomodulators: A New Approach for Patients with Inammatory Disease Alan B. Fleischer, Jr. 5-HT3 Receptor Antagonists as Antipruritics Elke Weisshaar Cutaneous Nerve Stimulation in Treatment of Localized Itch Joanna Wallengren Social and Psychological Aspects

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28.

287

29.

305

30.

315

31.

325

32.

335

Part VI. 33.

Psychosomatic Aspects of Pruritus Uwe Gieler, Volker Niemeier, Burkhard Brosig, and Jorg Kupfer On Psychological Factors Aecting Reports of Itch Perception Elia E. Psouni Itching as a Focus of Mental Disturbance Yuval Melamed and Gil Yosipovitch

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34.

351

35.

369

Index

377

Contributors

Dominik Mark Alscher, M.D. Vice Medical Director, Department of General Internal Medicine and Nephrology, Robert-Bosch Hospital, Stuttgart, Germany Tsugunobu Andoh, Ph.D. Department of Applied Pharmacology, Toyama Medical and Pharmaceutical University, Toyama, Japan David Andrew, B.D.S., Ph.D. Research Fellow, Department of Neuroscience and Biomedical Systems, University of Glasgow, Glasgow, Scotland Nora V. Bergasa, M.D. Associate Professor, Division of Digestive and Liver Diseases, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, U.S.A. Jerey D. Bernhard, M.D. Professor, Department of Dermatology, University of Massachusetts Medical School, Worcester, Massachusetts, U.S.A. Paul Lorenz Bigliardi, M.D. Department of Dermatology and Research, Basel University Hospital, Basel, Switzerland Mei Bigliardi-Qi, Ph.D. Head, Department of Research and Dermatology, Basel University Hospital, Basel, Switzerland Paul Bobrowski, B.S. Rainforest Pharmaceuticals, LLC, Scottsdale, Arizona, U.S.A.
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Contributors

Burkhard Brosig, M.D., Ph.D. Clinic for Psychosomatics and Psychotherapy, Clinic for Psychosomatic Medicine, University Hospital of Giessen, Giessen, Germany Earl Carstens, Ph.D. Professor, Section of Neurobiology, Physiology, and Behavior, University of California, Davis, Davis, California, U.S.A. A. D. Craig, Ph.D. Atkinson Pain Research Scientist, Department of Neurosurgery, Barrow Neurological Institute, Phoenix, Arizona, U.S.A. Ulf Darsow, M.D. Department of Dermatology and Allergy Biederstein, Technical University of Munich, Munich, Germany Alexander Drzezga, M.D. Senior Nuclear Medicine Physician, Department of Nuclear Medicine, Technical University of Munich, Munich, Germany Maria I. Duque, M.D. Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, U.S.A. Melita Dvorak, Ph.D. School of Biological Sciences, University of Manchester, Manchester, England Toshiya Ebata, M.D. Assistant Professor, Department of Dermatology, Jikei University School of Medicine, Tokyo, Japan Alan B. Fleischer, Jr., M.D. Professor and Chair, Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, U.S.A. Uwe Gieler, M.D. Department of Psychosomatic Dermatology, Clinic for Psychosomatics and Psychotherapy, Justus-Liebig University, Giessen, Germany Rashel Goodkin, M.D. Department of Dermatology, Lahey Clinic, Burlington, Massachusetts, U.S.A. Malcolm W. Greaves, M.D., Ph.D., F.R.C.P. Professor Emeritus, Department of Dermatology, University of London, London, England, and Singapore General Hospital, Singapore, Republic of Singapore

Contributors

xvii

Hermann O. Handwerker, M.D., Ph.D. Professor and Chair, Department of Physiology and Experimental Pathophysiology, University of Erlangen, Erlangen, Germany David Hitchcock, Ph.D. Unilever Research and Development, Wirral, England Matt Howard, Ph.D. University of Liverpool, Liverpool, England E. Anthony Jones, M.D., D.Sc., F.R.C.P. Department of Gastrointestinal and Liver Diseases, Academic Medical Center, Amsterdam, The Netherlands Hiroo Kumagai, M.D. Assistant Professor, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan rg Kupfer, Ph.D. Department of Medical Psychology, Justus-Liebig UniJo versity, Giessen, Germany Yasushi Kuraishi, Ph.D. Professor, Department of Applied Pharmacology, Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Toyama, Japan Yung-Hian Leow, M.D., M.Med., F.A.M.S. Senior Consultant Dermatologist, National Skin Centre, Singapore, Republic of Singapore Shigeaki Matsukawa, M.D. Director, Department of Internal Medicine, Inagi Municipal Hospital, Tokyo, Japan Francis McGlone, Ph.D. Head and Professor, Cognitive Neuroscience, Unilever Research and Development, Wirral, England, and Associate Director of the Center for Cognitive Neuroscience, University of Wales, Bangor, Wales Yuval Melamed, M.D. Deputy Director and Lecturer in Psychiatry, Tel Aviv Faculty of Medicine, Lev-Hasharon Mental Health Center, Natania, Israel Thomas Mettang, M.D., P.D. Vice Medical Director, Department of General Internal Medicine and Nephrology, Robert-Bosch Hospital, Stuttgart, Germany Dieter Metze, M.D. Professor, Department of Dermatology, University of Mu nster, Mu nster, Germany

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Contributors

Mark J. S. Miller, Ph.D. Professor, Center for Cardiovascular Sciences, Albany Medical College, Albany, New York, U.S.A. Hiroshi Nagase, D.Sc. Director, Pharmaceutical Research Laboratories, Toray Industries, Inc., Kamakura, Kanagawa, Japan Robert D. Nelson, Ph.D. Director, Surgery Research Laboratory, Department of Surgery, Regions Hospital, St. Paul, Minnesota, U.S.A. Volker Niemeier, M.D. Department of Psychosomatic Dermatology, Clinic for Psychosomatics and Psychotherapy, Justus-Liebig University, Giessen, Germany Kiyoshi Okano, Ph.D. Head, First Laboratory of Drug Development, Pharmaceutical Research Laboratories, Toray Industries, Inc., Kamakura, Kanagawa, Japan Christiane Pauli-Magnus, M.D. Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland P. Samuel Pegram, M.D. Professor, Department of Infectious Diseases, Wake Forest University School of Medicine, Winston-Salem, North Carolina, U.S.A. Elia E. Psouni, B.Sc., M.Sc., Ph.D. Division of Neurophysiology, Department of Physiological Sciences, Lund University, Lund, Sweden Brian K. Reuter, Ph.D. Postdoctoral Fellow, Center for Cardiovascular Sciences, Albany Medical College, Albany, New York, U.S.A. Johannes Ring, Prof.Dr.med., Dr.phil. Professor and Director, Department of Dermatology and Allergy Biederstein, Technical University of Munich, Munich, Germany Roman Rukwied, Ph.D. Unilever Research and Development, Wirral, England Takao Saruta, M.D. Professor, Department of Internal Medicine, Nephrology and Hypertension, Keio University School of Medicine, Tokyo, Japan Martin Schmelz, M.D., Ph.D. Department of Anesthesiology Mannheim, University of Heidelberg, Mannheim, Germany

Contributors

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Keith A. Sharkey, Ph.D. Professor, Neurosciences Research Group, University of Calgary, Calgary, Alberta, Canada nder, M.D. Department of Dermatology, University of Mu Sonja Sta nster, Mu nster, Germany Toshiaki Tanaka, Ph.D. Head, Drug Discovery Laboratory, Pharmaceutical Research Laboratories, Toray Industries, Inc., Kamakura, Kanagawa, Japan Jens Schiersing Thomsen, M.D., Ph.D. Department of Dermatology, Gentofte University Hospital, Copenhagen, Denmark Yuko Togashi, M.Sc. Pharmaceutical Research Laboratories, Toray Industries, Inc., Kamakura, Kanagawa, Japan Hideo Umeuchi, M.S. First Laboratory of Drug Development, Pharmaceutical Research Laboratories, Toray Industries, Inc., Kamakura, Kanagawa, Japan Jun Utsumi, V.M.D., D.Sc. General Manager, Corporate Research Planning Department, Toray Industries, Inc., Tokyo, Japan John L. Wallace, Ph.D. Professor, Departments of Pharmacology and Medicine, University of Calgary, Calgary, Alberta, Canada Joanna Wallengren, M.D., Ph.D. Associate Professor, Department of Dermatology, University Hospital, Lund, Sweden Allan Watkinson, Ph.D. Unilever Research and Development, Wirral, England Elke Weisshaar, M.D. Consultant, Occupational and Environmental Dermatology, Department of Social Medicine, University of Heidelberg, Heidelberg, Germany Ellen Mary Wingard, M.D. Department of Dermatology, University of Massachusetts Medical School, Worcester, Massachusetts, U.S.A. Gil Yosipovitch, M.D. Associate Professor of Dermatology and Neuroscience, Department of Dermatology, and Neuroscience Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina, U.S.A.

1
Definitions of Itch
Gil Yosipovitch
Wake Forest University School of Medicine, Winston-Salem, North Carolina, U.S.A.

Malcolm W. Greaves
University of London, London, England, and Singapore General Hospital, Singapore, Republic of Singapore

The simple denition of itch rst proposed by Samuel Hafenreer (1) 340 years ago as an unpleasant sensation provoking the desire to scratch is still widely used; however, as indicated by Savin (2), it is unsatisfactory because unpleasant is a subjective adjective and is not a descriptor capable of precise denition. We also wish to point out that many subjects rub but do not scratch in response to itch. The well-known sign of polished ngernails bears witness to this fact, as does the familiar observation that patients with urticaria, a severely pruritic disorder, almost never have scratch marks. Although a satisfactory denition of itch remains elusive, at least to us, it is worth attempting operational denitions of dierent types of itch for the assistance of those working in this dicult eld. As with any other subjective symptom, denitions pose problems. They serve as an operational framework and we do not intend to constrain updates in the future. The terms and denitions are not meant to be a comprehensive glossary but rather a standard glossary for people who work in the eld of itch.
1

Yosipovitch and Greaves

Acute itch. An unpleasant sensation which provokes the desire to scratch for a limited period of time ranging from seconds to a week. It is elicited by substantial inammation or injury of body tissue and activation of pruritoceptive bers at the site of local tissue damage. This alters the response of pruritoceptives, their central connections, and the autonomic nervous system in the region. The report of itch can stop long before healing has completed. The patient can still have erythema and eczema even though the itch has subsided. This type of itch is seen after insect bites, acute dermatitis, and some skin diseases. Itch that persists for weeks, months, or years is not classied under this category. Chronic itch. Chronic itch diers from acute itch because therapies that provide transient itch relief do not resolve the underlying pathological process. Chronic itch will continue when treatment stops. Chronic itch corrodes the spirit and the quality of life. It may totally destroy a patients social life and even lead to suicide as in patients with chronic pain. Because chronic itch is unrelenting, aective and environmental stress factors, such as heat and dryness, may exacerbate the intensity and persistence of itch. Medical treatment would be helpful to prevent or reduce the itch and to shorten the duration of inammation and thereby shorten itch. Intractable itch. This itch cannot be treated in the generally accepted course of medical practice. A more detailed denition for intractable itch is a chronic itch state in which the cause cannot be removed or otherwise treated, and in the generally accepted course of medical practice no relief or cure of the cause of itch is possible or none has been found after reasonable eorts. This denition communicates a message of hopelessness, especially when we state that chronic itch is treatable. It is important to acknowledge that such patients are encountered weekly in dermatology clinics, and they do suer. In these cases, a more holistic approach is required by an interdisciplinary team, with the involvement of both patients and their families. It integrates pharmacologic and nonpharmacologic treatment with needed psychotherapy and rehabilitation. Alloknesis. This type of itch is due to an innocuous stimulus which does not normally provoke itch (3). This term is derived from the term allodynia, which is pain due to a stimulus which does not normally invoke pain. It is important to recognize that alloknesis involves a change in the quality of a sensation, whether tactile, mechanical, or of any other sort. The original modality is normally nonitchy, but the response is itchy. It has been described in atopic eczema after slight mechanical stimulation with wool bers in a noninvolved area surrounding an itching lesion. Another common

Definitions of Itch

clinical example in patients with atopic eczema is sweat, which prompts intense itching, especially in front of the neck and exural areas. Alloknesis has also been demonstrated in experimental itch models in humans by intracutaneous and subcutaneous injections of histamine (3, 4). Most probably, it can be demonstrated in other itchy dermatosis and in neuropathic itch, but there are as yet no reported instances of such demonstrations.

I.

CLASSIFICATION OF DIFFERENT TYPES OF ITCH

Recently, a denition of dierent types of itch was provided (5,6). This may help us to evaluate and treat itch in a more meaningful way both for the individual patient and for the comparison of potential therapies in studies. Pruritoceptive itch. Itch originating in the skin due to inammation, dryness, or other skin damage. Examples include itch due to xerosis, urticaria, insect bite reactions, and scabies, to name a few. Neuropathic itch. Itch due to pathology located at any point along the aerent pathway. Examples include postherpetic neuralgic itch, brachioradial itch, itch associated with cerebral vascular events in the CNS, itch associated with multiple sclerosis and brain tumors (see Chapter 22). Neurogenic itch. Itch that originates centrally but without evidence of neural pathology, exemplied by itch of cholestasis due to the action of opioid neuropeptides on opioid receptors (see Chapter 10). Psychogenic itch. Itch associated with psychological abnormalities, e.g., itch in a delusional state of parasitophobia or itch in a compulsive disorder (7). Of course, there is no reason why one type of itch may not coexist concurrently with another in a given patient, e.g., itch in a patient with prurigo nodularis, where there could be both a pruritoceptive itch as well as a neurogenic itch involved. REFERENCES
1. Hafenreer S. Nosodochium, in quo cutis, eique adaerentium partium, aectus omnes, singulari methodo, et cognoscendi e curandi delisime traduntur. Ulm: Ku hnen, 1660:98102. Savin J. How should we dene itching? J Am Acad Dermatol 1998; 39:268269. Simone DA, Alreja M, LaMotte RH. Psychophysical studies of the itch sensation

2. 3.

Yosipovitch and Greaves and itchy skin (alloknesis) produced by intracutaneous injection of histamine. Somatosens Mot Res 1991; 8:271279. Heyer G, Groene D, Martus P. Ecacy of naltrexone on acetylcholine-induced alloknesis in atopic eczema. Exp Dermatol 2002; 11:448455. Twycross R, Greaves MW, Handwerker H, et al. Itch: scratching more than the surface. Q J Med 2003; 96:726. Yosipovitch G, Greaves M, Schmelz M. Itch. Lancet 2003; 361:690694. Bernhard JD. Neurogenic pruritus and strange sensations. In: Bernhrad JD, ed. Itch Mechanisms and Management of Pruritus. New York: McGraw Hill, 1994:185202.

4. 5. 6. 7.

2
Neurophysiologic Basis of Itch
Martin Schmelz
University of Heidelberg, Mannheim, Germany

Hermann O. Handwerker
University of Erlangen, Erlangen, Germany

I.

ITCH PATHWAYS

Low-level activation in nociceptors has been proposed to initiate the itch sensation, whereas upon higher discharge frequency, the sensation switches to pain (intensity theory). In line with this theory, the application of high concentrations of pruritics, e.g., histamine, may be painful. However, low concentrations of algogens do not generally cause itch, but less intense pain. The most convincing argument against the intensity theory was generated using intraneural microstimulation in aerent nerves in humans: electrical stimulation via a microelectrode implanted in an aerent nerve of volunteers induced either the threshold sensation of pain or, more rarely, the sensation of itch. Increasing the stimulation frequency increased the magnitude of pain or of itch. No switch of the sensation from itch to pain was observed. Likewise, the decrease of stimulation frequency at a painful site decreased the magnitude of pain, but did not induce the sensation of itch (1). According to these results, ring frequency in nociceptors cannot account for the dierentiation between pain and itch. Thus, it has to be assumed that pruritics preferentially excite a certain subgroup of nociceptors which give rise to the itch sensation. However, the most common type of C-bers, the mechanoheat
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nociceptors (CMH or polymodal nociceptors), which have been extensively investigated in animal (2) and human (3) skin, are either insensitive to histamine or only very weakly activated. Thus, they cannot account for the lasting itch sensation observed, for example, following histamine application in the skin. Recently, C-nociceptors have been discovered among mechanoinsensitive C-nociceptors (4), which respond to histamine iontophoresis in parallel to the itch ratings of the subjects (Fig. 1) as postulated before (5). Characteristics of itch bers comprise low conduction velocity, large innervation territories, mechanical unresponsiveness, and high transcutaneous electrical thresholds. It is interesting to note that corresponding to the large innervation territories of these bers, two-point discrimination for histamine-induced itch is poor (15 cm in the upper arm) (6). In the group of unmyelinated nociceptors, about 80% respond to mechanical, heat, and

Figure 1 The upper panel shows instantaneous discharge frequency of a mechanoand heat-insensitive C-ber (CMiHi) in the supercial peroneal nerve following histamine iontophoresis (marked as open circles in the diagram). The unit was not spontaneously active before histamine application, but continued to re for about 15 min further (not shown in the diagram).The lower panel shows average itch magnitude ratings of a group of 21 healthy volunteers after an identical histamine stimulus. Ratings at 10 s intervals on a visual analog scale (VAS) with the end points no itch and unbearable itch. Bars: standard error of means. (From Ref. 4.)

Neurophysiologic Basis of Itch

Figure 2 Relative proportion of mechano-responsive and mechano-insensitive unmyelinated nociceptors in human skin nerves. About 20% of the nociceptors are mechano-insensitive. Itch units are found only among these mechano-insensitive bers and comprise about 5% of all nociceptors.

chemical stimuli. They have been termed polymodal nociceptors (7). The remaining 20% do not respond to mechanical stimulation. These bers have been classied as silent or sleeping nociceptors (811). They can be readily activated by chemical stimuli (12) and can also be sensitized to mechanical stimulation under inammatory conditions (12,13). Units with a strong and lasting histamine response are found only in the group of mechano-insensitive nociceptors. They comprise about 20% of the mechanoinsensitive class of nociceptors (Fig. 2).

II.

CHEMICAL RESPONSIVENESS OF ITCH FIBERS

There are only a few mediators which can induce histamine-independent pruritus. Prostaglandins were found to enhance histamine-induced itch in the skin (14,15), but also act directly as pruritogens in conjunctiva (16) and in human skin when applied via microdialysis bers (17). Upon intradermal injection, serotonin has been found to elicit pain and a weak itch sensation (18). Recent results suggest that the peripheral eect of serotonin may partly be due to the release of histamine from mast cells (19). There are also some reports on pruritic eects of mast cell mediators other than histamine like mast cell chymase (20) and other proteinases (21) in human skin. However, no

Schmelz and Handwerker

nal decision about the role of these macromolecules in itch induction can be made. Acetylcholine has been identied as a pruritic in AD, whereas it induces pain in normal subjects (22). This mechanism could easily explain the itch which many AD patients experience when sweating. The role of serotonin in the pathogenesis of itch is unclear. It might be involved in pruritus seen in polycythemia vera. The potency of the main known pruritics can be dened as histamineprostaglandin E2 > acetylcholine, serotonin; in contrast, bradykinin and capsaicin application basically induce a pure pain sensation. Neurons being responsible for the itch sensation would thus be expected to exhibit a graded response according to the pruritic potency of the mediators. In Figure 3, responses of dierent types of C-nociceptors to stimulation with histamine, prostaglandin E2, acetylcholine, serotonin, bradykinin, and capsaicin are depicted. Only the units showing lasting activation following histamine application were also excited by prostaglandin E2. In contrast, we did not observe any lasting activation of mechanoresponsive nociceptors by histamine or by prostaglandin E2. Similarly, all the mechano-insensitive bers,

Figure 3 Intensity of chemically induced activation of dierent classes of C-nociceptors. The units were stimulated with histamine (iontophoresis; 20 mC), prostaglandin E2 (PGE2; 105 M, 20-Al injection), acetylcholine (iontophoresis; 60 mC), serotonin (105 M, 20-Al injection), bradykinin (105 M, 20-Al injection), and capsaicin (0.1%, 20Al injection). (From Ref. 22a.)

Neurophysiologic Basis of Itch

which were unresponsive to histamine, were not activated by prostaglandin E2 application. Thus, the response pattern of the histamine-responsive itch units corresponds to the psychophysically observed pruritic eect of PGE2. Taking into account the histamine sensitivity of these units, indirect activation via histamine released from mast cells has to be considered. Intradermal injection of PGE2 has been reported to induce only marginal whealing (23,24); however, it provoked a small, albeit signicant, protein extravasation in other studies (25,26). Recently, dermal application of PGE2 via microdialysis has been combined with the measurement of local protein extravasation and local blood ow (17). In this study, PGE2 did not increase protein extravasation, even at a concentration of 104 M, but provoked a weak itch sensation and pronounced vasodilation. In contrast, histamine provokes protein extravasation at lower concentrations as compared to the induction of itch (27). Thus, rather than being mediated by histamine release, the pruritic eect of PGE2 is most probably due to the direct excitation of histamine-positive itch units. Specic activation of histamine-positive chemonociceptors by PGE2 in combination with the pruritogenic eects of prostaglandins provides a strong argument for a specic neuronal system for the itch sensation, which is separate from the pain pathway. However, the histamine-positive bers might not be classied as itch-specic because they are also excited by pure algogens. The reason why psychophysical algogens provoke pure pain, although they activate itch bers, is most probably a spinal inhibition of itch by pain (Fig. 4).

Figure 4 Schematic view of response intensity of nociceptors involved in itch processing (itch channel) and in pain processing (pain channel). Activation of the itch channel by algogens like capsaicin is not felt as itch because the pain sensation inhibits itch on a spinal cord level.

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The itch neurons might therefore be termed itch-selective (28) rather than itch-specic. Further support for the specicity, or rather selectivity theory, comes from the second-order neurons in the cat that have recently been recorded. These neurons cannot be excited by mechanical stimulation, but are activated by histamine iontophoresis with a similar time course as compared to the primary aerents (29). In summary, the pruritic potency of inammatory mediators is characterized by their ability to activate histamine-positive mechano-insensitive C-nociceptors. However, concomitant activation of mechanosensitive and mechano-insensitive histamine-negative nociceptors will decrease the itch. Therefore, the itch sensation is based on both activity in the itch channel and absence of activity in the pain channel.

REFERENCES
1. 2. 3. Torebjo rk HE, Ochoa J. Pain and itch from C ber stimulation. Soc Neurosci Abstr 1981; 7:228. Bessou P, Perl ER. Responses of cutaneous sensory units with unmyelinated bers to noxious stimuli. J Neurophysiol 1969; 32:10251043. Torebjo rk HE. Aerent C units responding to mechanical, thermal and chemical stimuli in human non-glabrous skin. Acta Physiol Scand 1974; 92:374 390. Schmelz M, Schmidt R, Bickel A, Handwerker HO, Torebjo rk HE. Specic Creceptors for itch in human skin. J Neurosci 1997; 17:80038008. LaMotte RH, Simone DA, Baumann TK, Shain CN, Alreja M. Hypothesis for novel classes of chemoreceptors mediating chemogenic pain and itch. In: Dubner R, Gebhart GF, Bond M, eds. Proceedings of the Vth World Congress on Pain. Amsterdam, New York: Elsevier, 1988:529535. Wahlgren CF, Ekblom A. Two-point discrimination of itch in patients with atopic dermatitis and healthy subjects. Acta Derm-Venereol (Stockh) 1996; 76: 4851. Perl ER. Cutaneous polymodal receptors: characteristics and plasticity. Prog Brain Res 1996; 113:2137. Lynn B. Silent nociceptors in the skin. Trends Neurosci 1991; 14:95. Meyer RA, Campbell JN. A novel electrophysiological technique for locating cutaneous nociceptive and chemospecic receptors. Brain Res 1988; 441:8186. Meyer RA, Davis KD, Cohen RH, Treede RD, Campbell JN. Mechanically insensitive aerents (MIAs) in cutaneous nerves of monkey. Brain Res 1991; 561: 252261. Schmidt RF, Schaible HG, Messlinger K, Hanesch U, Pawlak M. Silent and active nociceptors: structure, functions and clinical implications. In: Gebhart GF, Hammind DL, Jensen TS, eds. Seattle: IASP Press, 1994:213250.

4. 5.

6.

7. 8. 9. 10.

11.

Neurophysiologic Basis of Itch

11

12. Schmelz M, Schmidt R, Handwerker HO, Torebjo rk HE. Encoding of burning pain from capsaicin-treated human skin in two categories of unmyelinated nerve bres. Brain 2000; 123:560571. 13. Schmidt R, Schmelz M, Forster C, Ringkamp M, Torebjo rk HE, Handwerker HO. Novel classes of responsive and unresponsive C nociceptors in human skin. J Neurosci 1995; 15:333341. 14. Ha germark O, Strandberg K. Pruritogenic activity of prostaglandin E2. Acta Derm-Venereol 1977; 57:3743. 15. Ha germark O, Strandberg K, Hamberg M. Potentiation of itch and are responses in human skin by prostaglandins E2 and H2 and a prostaglandin endoperoxide analog. J Invest Dermatol 1977; 69:527530. 16. Woodward DF, Nieves AL, Hawley SB, Joseph R, Merlino GF, Spada CS. The pruritogenic and inammatory eects of prostanoids in the conjunctiva. J Ocul Pharmacol Ther 1995; 11:339347. 17. Neisius U, Olsson R, Rukwied R, Lischetzki G, Schmelz M. Prostaglandin E2 induces vasodilation and pruritus, but no protein extravasation in atopic dermatitis and controls. J Am Acad Dermatol 2002; 47:2832. 18. Ha germark O. Peripheral and central mediators of itch. Skin Pharmacol 1992; 5:18. 19. Weisshaar E, Ziethen B, Rohl FW, Gollnick H. The antipruritic eect of a 5HT3 receptor antagonist (tropisetron) is dependent on mast cell depletionan experimental study. Exp Dermatol 1999; 8:254260. 20. Ha germark O, Rajka G, Bergvist U. Experimental itch in human skin elicited by rat mast cell chymase. Acta Derm-Venereol 1972; 52:125128. 21. Rajka G. Latency and duration of pruritus elicited by trypsin in aged patients with itching eczema and psoriasis. Acta Derm-Venereol 1969; 49: 401 403. 22. Vogelgsang M, Heyer G, Hornstein OP. Acetylcholine induces dierent cutaneous sensations in atopic and non-atopic subjects. Acta Derm-Venereol 1995; 75:434436. 22a. Schmelz M, Schmidt R, Weidner C, Hilliges M, Torebjo rk HE, Handwerker HO. Chemical response pattern of dierent classes of C-nociceptors to pruritogens and algogens. J Neurophysiol 2003; 89:24412448. 23. Juhlin L, Michaelsson G. Cutaneous vascular reactions to prostaglandins in healthy subjects and in patients with urticaria and atopic dermatitis. Acta Derm-Venereol 1969; 49:251261. 24. Kingston WP, Greaves MW. Actions of prostaglandin E2 metabolites on skin microcirculation. Agents Actions 1985; 16:1314. 25. Sabroe RA, Kennedy CT, Archer CB. The eects of topical doxepin on responses to histamine, substance P and prostaglandin E2 in human skin. Br J Dermatol 1997; 137:386390. 26. Sciberras DG, Goldenberg MM, Bolognese JA, James I, Baber NS. Inammatory responses to intradermal injection of platelet activating factor, histamine and prostaglandin E2 in healthy volunteers: a double blind investigation. Br J Clin Pharmacol 1987; 24:753761.

12 27.

Schmelz and Handwerker Lischetzki G, Rukwied R, Handwerker HO, Schmelz M. Nociceptor activation and protein extravasation induced by inammatory mediators in human skin. Eur J Pain 2001; 5:4957. McMahon SB, Koltzenburg M. Itching for an explanation. Trends Neurosci 1992; 15:497501. Andrew D, Craig AD. Spinothalamic lamina 1 neurons selectively sensitive to histamine: a central neural pathway for itch. Nat Neurosci 2001; 4:7277.

28. 29.

3
Pain and Itch
Martin Schmelz
University of Heidelberg, Mannheim, Germany

Hermann O. Handwerker
University of Erlangen, Erlangen, Germany

It is a common experience that the itch sensation can be reduced by the pain induced by scratching. Moreover, the itch sensation is intimately linked to the desire to scratch, which has recently been visualized as an activation of the premotor cortical areas in positron emission tomography investigations (1 3). The inhibition of itch by painful stimuli has been shown experimentally using various painful thermal, mechanical, and chemical stimuli. Recently, also electrical stimulation via an array of pointed electrodes, cutaneous eld stimulation, has been successfully used to inhibit itch for several hours in an area of more than 10 cm around the stimulated site suggesting a central mode of action (4). In line with these results, itch is suppressed inside the secondary zone of capsaicin-induced mechanical hyperalgesia (5). This central eect of capsaicin should be clearly separated from the neurotoxic eect it exerts locally on the nerve bers (6), with both mechanisms inhibiting itch. The inhibition of itch by pain is not relevant only in a situation with enhanced painful input. The mirror image of this inhibition has signicant implications: inhibition of pain processing may reduce its inhibitory eect, and thus enhance itch (7). This is of particular relevance for spinally applied A-opioids which are widely used in pain states and typically cause pruritus.
13

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I.

INTERACTION OF PAIN AND ITCHPRIMARY AFFERENTS

Although the responses in itch units reect the pruritic potency of pruritic mediators as shown in an earlier chapter, the strong activation of these units by capsaicin and bradykinin seems to contradict a specic role of these units in itch, since both substances are mainly algogenic and not pruritogenic. An explanation for their ambiguous role in exciting itch and pain-mediating nociceptors may be that their strong excitatory eect on nociceptors involved in pain processing inhibits the neurons of the itch pathway in the course of central nervous processing. It is common knowledge that scratching relieves itch. Thus, it can be assumed that activity in mechanosensitive nociceptors suppresses itch. There are, to date, many reports on itch suppression exerted by painful stimuli. These stimuli include electrical stimulation (4) or treatment with capsaicin (5). Recently, also the opposite eect, i.e., increasing of itch sensation by pain reduction, has been clearly shown (7). On a spinal level, opioids inhibit pain processing and thereby may provoke itch (8). This mechanism is probably the basis for the antipruritic action of opioid antagonists like naloxone or naltrexone (9,10). The inhibition of itch by painful stimuli has to be taken into consideration when activity in itch units is correlated to the pruritic potency of the tested mediator (8). As shown in Chapter 2, prostaglandin E2 exclusively excites itch nociceptors, whereas acetylcholine activated a considerable number of nonitch nociceptors. Thus, the pruritic eect of PGE2 can be explained by the activation of itch units and simultaneously the absence of activity in itch-suppressing nociceptors. Conversely, the activation of itch units by acetylcholine does not provoke itch because the simultaneously activated nonitch nociceptors suppress the itch and the perceived sensation is pain. Accordingly, capsaicin that readily activates itch and nonitch units provokes strong pain and no-itch sensation. Although our data support this concept, experimental proof for it can only be obtained in recordings from second-order neurons.

II.

CENTRAL MECHANISMS

Many mechanisms interact with the itch sensation. Temperature changes can either enhance or suppress itch. Cooling can inhibit itch on a central level (11). In addition, histamine-induced activation of nociceptors has been shown to be temperature-dependent (12), and thus cooling of itching skin sites can reduce the activity of the primary aerents. Note that heating the

Pain and Itch Table 1 Environmental Factors and Drugs Attenuating Itch Perception Eects on peripheral endings Temperature Cold Warmth Noxious heat A-Opioids n-Opioids Capsaicin Inhibition Facilitation Nociceptor activation Histamine release Histamine release Neurotoxic Spinal eects Inhibition ? Inhibition Disinhibition Inhibition Inhibition

15

Psychophysical result Antipruritic Pruritic Antipruritic Pruritic Antipruritic Antipruritic

skin would consequently lead to exacerbation of itch; however, as soon as the heating becomes painful, central inhibition of pruritus will counteract this eect. A summary of peripheral and central eects is given in Table 1 (13).

III.

CENTRAL SENSITIZATION IN THE PAIN AND ITCH SYSTEM

Beyond the direct interaction of pain and itch, a remarkable similarity of central sensitization phenomena exists for the two perceptions. Activity in chemonociceptors subserving the pain sensation will not only lead to an acute pain sensation, but also can sensitize second-order neurons in the dorsal horn leading to increased pain sensitivity (hyperalgesia). Two dierent types of hyperalgesia can be dierentiated: normally painless touch sensations in the uninjured surroundings of the trauma can be felt as painful stroke-evoked allodynia (see Fig. 1). This type of sensitization requires ongoing activity of primary aerent nociceptors. In addition, slightly painful pinprick-like stimulation is felt as more painful in the secondary zone punctuate hyperalgesia. Punctate hyperalgesia does not require ongoing activity in primary nociceptors, but can persist for hours following a trauma (1420). In itch processing, similar phenomena have been described: touchevoked pruritus around an itching site has been termed itchy skin or alloknesis (21,22). Like allodynia, it requires ongoing activity in primary aerents and is elicited by low threshold mechanoreceptors (Ah bers). Also, more intense prick-induced itch sensations hyperknesis have been reported following histamine iontophoresis in healthy volunteers (7) (see Table 2).

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Figure 1 Schematic view of central sensitization mechanisms in the pain system (upper panel) and in the itch system (lower panel). Under physiological conditions, touch stimuli activate low threshold mechanoreceptive Ah bers resulting in the sensation of touch. Noxious input by histamine-negative chemonociceptors can sensitize the second-order neurons in the spinal cord. If sensitized, they will also be activated by low threshold mechanoreceptorsthus, touching the skin will not only provoke the sensation of touch, but also pain (touch-evoked hyperalgesia or allodynia). Similarly, input from Ay nociceptors, which is normally felt as pricking, is felt more intensely under the condition of central sensitization punctate hyperalgesia. In the lower panel, the corresponding mechanisms are depicted for the itch system. Ongoing activity of itch units (histamine-positive chemonociceptors) can sensitize second-order itch neurons in the spinal cord. In the sensitized state, they can be activated by the input from low threshold mechanoreceptors alloknesis or by the input from Ay bers punctate hyperknesis. DRG=dorsal root ganglion; CNS=central nervous system.

Pain and Itch

17

Table 2 Comparison Between Pain and Itch Characteristics Channel Pain Acute pain Allodynia touch-evoked pain Characteristics Activity in chemonociceptors (histamine-negative) . Requires ongoing activity of histamine-negative chemonociceptors . Stimulated by Ah bers . Does not require ongoing activity of primary aerents . Stimulated by Ay bers Activity in chemonociceptors (histamine-positive) . Requires ongoing activity of itch bers . Stimulated by Ah bers . Does not require ongoing activity of primary aerents . Stimulated by Ay bers?

Punctate hyperalgesia prick-evoked pain Itch Acute itch Alloknesis touch-evoked itch Punctate hyperknesis prick-evoked pain

While these considerations appear to be mainly of theoretical relevance, they have an enormous impact on the understanding of clinical itch conditions. Under the condition of central sensitization leading to punctuate hyperknesis, normally painful stimuli are felt as itching. This phenomenon has already been described before for painful electrical stimulation in atopic dermatitis patients (23). Noteworthy also is the fact that acetylcholine provokes itch instead of pain in patients suering from atopic dermatitis (24,25), indicating that pain-induced inhibition of itch might be compromised in these patients. As there are a multitude of mediators and mechanisms which are potentially algogenic in an inamed skin site (26) and thus could produce itch in a sensitized patient, a therapeutical approach targeting single pruritic mediators does not appear to be promising under this condition. In contrast, the main therapeutical implication of this phenomenon is that a combination of centrally acting drugs counteracting the sensitization and topically acting drugs counteracting the inammation should provide the optimum way for antipruritic treatment. While the exact mechanism and role of central sensitization for itch under clinical condition still have to be explored, a major role of central

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sensitization in chronic pain patients is generally accepted. It should be noted that in addition to the similarities between itch and pain in experimentally induced secondary sensitization phenomena, there is emerging evidence that a corresponding interaction also exists in chronic pain and chronic itch patients: recently, Baron and colleagues have described that in neuropathic pain patients, histamine iontophoresis, which normally provokes a pure itch sensation, is felt as burning pain (27). Conversely, cutaneous stimulation with acidied solution, which provokes a purely painful sensation in normal subjects, is felt as itching in atopic dermatitis patients when applied in or close to their eczematous skin (Ikoma and Schmelz, work in progress). In summary, the latest progress in the understanding of the interaction of pain and pruritus has led to new ideas about central mechanisms of the itch sensation. New therapeutical options are provided especially by the emerging role of spinal opioids for the central itch processing. Further clarication of central sensitization phenomena in chronic itch patients will provide a better understanding of their disease for the patients and will also provide new therapeutical targets for the inhibition of itch.

REFERENCES
1. Hsieh JC, Ha germark O, Stahle Backdahl M, Ericson K, Eriksson L, Stone Elander S, Ingvar M. Urge to scratch represented in the human cerebral cortex during itch. J Neurophysiol 1994; 72:30043008. Drzezga A, Darsow U, Treede R, Siebner H, Frisch M, Munz F, Weilke F, Ring J, Schwaiger M, Bartenstein P. Central activation by histamine-induced itch: analogies to pain processing: a correlational analysis of O-15 H(2)O positron emission tomography studies. Pain 2001; 92:295305. Darsow U, Drzezga A, Frisch M, Munz F, Weilke F, Bartenstein P, Schwaiger M, Ring J. Processing of histamine-induced itch in the human cerebral cortex: a correlation analysis with dermal reactions. J Invest Dermatol 2000; 115:1029 1033. HJ Nilsson. Levinsson A, Schouenborg J. Cutaneous eld stimulation (CFS): a new powerful method to combat itch. Pain 1997; 71:4955. Brull SJ, Atanasso PG, Silverman DG, Zhang J, LaMotte RH. Attenuation of experimental pruritus and mechanically evoked dysesthesiae in an area of cutaneous allodynia. Somatosens Motor Res 1999; 16:299303. Simone DA, Nolano M, Johnson T, Wendelschafer-Crabb G, Kennedy WR. Intradermal injection of capsaicin in humans produces degeneration and subsequent reinnervation of epidermal nerve bers: correlation with sensory function. J Neurosci 1998; 18:89478954. Atanasso PG, Brull SJ, Zhang J, Greenquist K, Silverman DG, LaMotte RH.

2.

3.

4. 5.

6.

7.

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8. 9.

10.

11.

12.

13. 14. 15.

16.

17. 18. 19.

20. 21.

22.

23.

24.

Enhancement of experimental pruritus and mechanically evoked dysesthesiae with local anesthesia. Somatosens Motor Res 1999; 16:291298. Schmelz M. A neural pathway for itch. Nat Neurosci 2001; 4:910. Wolfhagen FH, Sternieri E, Hop WC, Vitale G, Bertolotti M, Van Buuren HR. Oral naltrexone treatment for cholestatic pruritus: a double-blind, placebocontrolled study. Gastroenterology 1997; 113:12641269. Odou P, Azar R, Luyckx M, Brunet C, Dine T. A hypothesis for endogenous opioid peptides in uraemic pruritus: role of enkephalin. Nephrol Dial Transplant 2001; 16:19531954. Bromm B, Scharein E, Darsow U, Ring J. Eects of menthol and cold on histamine-induced itch and skin reactions in man. Neurosci Lett 1995; 187:157 160. Mizumura K, Koda H. Potentiation and suppression of the histamine response by raising and lowering the temperature in canine visceral polymodal receptors in vitro. Neurosci Lett 1999; 266:912. Schmelz M. Itchmediators and mechanisms. J Dermatol Sci 2002; 28:9196. LaMotte RH, Shain CN, Simone DA, Tsai EFP. Neurogenic hyperalgesia psychophysical studies of underlying mechanisms. J Neurophysiol 1991; 66:190211. Simone DA, Sorkin LS, Oh U, Chung JM, Owens C, LaMotte RH, Willis WD. Neurogenic hyperalgesia central neural correlates in responses of spinothalamic tract neurons. J Neurophysiol 1991b; 66:228246. Simone DA, Baumann TK, LaMotte RH. Dose-dependent pain and mechanical hyperalgesia in humans after intradermal injection of capsaicin. Pain 1989; 38:99107. LaMotte RH. James Daniel Hardy (19041985). Tribute to a pioneer in pain psychophysics. Pain, 1986; 27:127130. Koltzenburg M, Torebjo rk HE. Pain and hyperalgesia in acute inammatory and chronic neuropathic conditions. Lancet 1995; 345:1111. Kilo S, Schmelz M, Koltzenburg M, Handwerker HO. Dierent patterns of hyperalgesia induced by experimental inammations in human skin. Brain 1994; 117:385396. Koltzenburg M, Lundberg LE, Torebjo rk HE. Dynamic and static components of mechanical hyperalgesia in human hairy skin. Pain 1992; 51:207219. Heyer G, Ulmer FJ, Schmitz J, Handwerker HO. Histamine-induced itch and alloknesis (itchy skin) in atopic eczema patients and controls. Acta DermVenereol (Stockh) 1995; 75:348352. Simone DA, Alreja M, LaMotte RH. Psychophysical studies of the itch sensation and itchy skin (alloknesis) produced by intracutaneous injection of histamine. Somatosens Motor Res 1991a; 8:271279. HJ Nilsson. Itch and pain inhibitory mechanisms in humans. Thesis/dissertation, Dept. Physiological Sciences, Section for Neurophysiology, University Lund, 1999:113. Vogelgsang M, Heyer G, Hornstein OP. Acetylcholine induces dierent cutaneous sensations in atopic and non-atopic subjects. Acta Derm-Venereol 1995; 75:434436.

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25. Groene D, Martus P, Heyer G. Doxepin aects acetylcholine induced cutaneous reactions in atopic eczema. Exp Dermatol 2001; 10:110117. 26. Reeh PW, Kress M. Eects of classical algogens. Semin Neurosci 1995; 7:221 226. 27. Baron R, Schwarz K, Kleinert A, Schattschneider J, Wasner G. Histamineinduced itch converts into pain in neuropathic hyperalgesia. NeuroReport 2001; 12:34753478.

4
Central Neural Mechanisms of Itch
David Andrew
University of Glasgow, Glasgow, Scotland

A. D. Craig
Barrow Neurological Institute, Phoenix, Arizona, U.S.A.

I.

INTRODUCTION

The specicity of the sensation of itch has been debated continuously since Johannes Mu ller formulated his theory of specic nerve energies in the 19th century. Initial investigations ignored itch, but von Frey (1) identied itch spots in the skin using punctate mechanical stimuli. As these itch spots seemed to coincide with pain spots, some considered that itch was a subliminal version of pain. The question of whether itch is a specic sensation or whether it arises from weak activation of pain pathways might seem trivial to those whose experience of itch is conned to the minor annoyance of a mosquito bite, but severe, intractable itching that is resistant to conventional drugs is a symptom of several systemic diseases including biliary cholestasis, renal failure, HIV infection, and immune disorders. A. Itch and Pain in Human Studies

Clinical evidence implicating the spinothalamic tract in itch was rst described by Bickford (2). He observed that spinal lesions in humans (either as a consequence of disease or cordotomy) that abolished pain and temperature
21

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sensations also abolished itch. Similar observations were made by Hyndman and Wolkin (3), Taren and Kahn (4), and Nathan (5). Pain and itch were considered by some to be related sensations because the sensory dysesthesia produced by noxious and pruritic stimuli were similar. After the initial pain has subsided following an injection of capsaicin into the skin, the injection site is surrounded by an area of allodynia, where pain is evoked by light touch, and an area of hyperalgesia to probing (6). After an intracutaneous injection of histamine, the injection site is surrounded by an area of alloknesis, where stroking the skin produces itching. Surrounding this zone is an area of punctate hyperknesis, where itch can be evoked with von Frey laments (2,7,8). The early experiments suggested that itch and pain were also transmitted by common neural structures, as itch could not be evoked in skin areas that were rendered hyperalgesic by injury (2,7). This observation does not conrm that itch and pain share common neural substrates; it does, however, demonstrate that itch and pain are sensations that interact (9,10), similar to pain and temperature (11). More recent studies (12,13) have shown that itch can indeed be demonstrated in hyperalgesic skin area as long as the hyperalgesia is mild, but not when the hyperalgesia is intense. Nonetheless, a specic itch pathway could not be excluded, and several independent lines of evidence suggested its existence. Firstly, opiates relieve pain, but they often cause itch rather than inhibit it (14); this is particularly true when they are given as part of a spinal anesthetic. Secondly, microneurography experiments in humans identied nerve fascicles which evoked the sensation of itch when they were electrically stimulated. Increasing the stimulus frequency increased the intensity of the itching, but did not produce pain (15); conversely, reducing the stimulus frequency at fascicles that produced pain when stimulated reduced the intensity of the pain, but did not produce itch. Thirdly, although some human C-ber polymodal nociceptors do respond to histamine (16), the time course and pattern of their activity do not match the well-dened psychophysical judgments of itch (4,17). B. Physiological Investigation of Itch-Related Neurons

Single-unit recordings from primary aerent bers have been made after the application of either histamine or cowhage spicules (Mucuna pruriens) to investigate the peripheral neural basis of itch. These reports that have been covered in Chapter 2 will only be mentioned briey here. An initial study investigated low threshold mechanoreceptive bers and thermoreceptors (18) to gain evidence for the existence of nociceptors as a distinct class of bers, and therefore itch was not investigated. Other studies sought itch-specic bers; however, in essence, all of them failed to provide evidence of elements specically excited by itchy substances, and alternative mechanisms involving

Central Neural Mechanisms of Itch

23

graded intensity encoding (16,19), unique patterns of activity (20), or dierential central sorting (21) were suggested. However, many of these studies suered from the drawback that the search stimuli used would not have identied itch-specic units. Interest in the existence of a specic pathway for itch was revived following the report by Schmelz et al. (22) describing cutaneous C-bers in humans that were insensitive to mechanical stimuli, but which showed longduration excitation that paralleled the psychophysical reports of itch following the application of histamine into their innervation territories. This was a highly signicant nding for several reasons. Firstly, the method of iontophoretic histamine delivery avoided direct injection, which was known to produce a mixed sensation of itch and pain (23). Secondly, bers were identied by electrical stimulation of the skin, whereas previous studies had used natural (usually mechanical) stimulation, eectively biasing against identifying units that were not excited by the search stimulus. Finally, methods were used that allowed the authors to record from the slowest conducting bers (<1 m/sec) which are traditionally dicult to isolate. The histamine-sensitive C-bers were considered to be a distinct subgroup of units as their conduction velocities were signicantly slower (f0.5 m/sec) and their electrical thresholds were considerably higher than other classes of C-bers. They were also mechanically insensitive and some were also heat-insensitive. We hypothesized that if itch was a specic sensation, then the selectivity of the histamine-specic C-bers would be maintained centrally. We made recordings from single spinothalamic neurons in lamina I of the cats spinal cord, where physiologically and morphologically distinct neurons are located (24), and we tested their responses to iontophoretically applied histamine (25).

II. A.

HISTAMINE-SENSITIVE LAMINA I SPINOTHALAMIC NEURONS Methods

Experiments were performed on 33 adult cats that were anesthetized with sodium pentobarbital (Nembutal 42 mg/kg I.P. then 5 mg/kg/hr I.V.) throughout the procedure. They were injected with the neuromuscular blocker Pancuronium (400 Ag I.V.) and articially ventilated to maintain end-tidal CO2 levels of 3.84.2%. Single lamina I spinothalamic tract (STT) neurons in the lumbosacral enlargement were recorded extracellularly with glass-insulated tungsten microelectrodes. Cells were identied as STT neurons by antidromic activation from an array of stimulating electrodes that was inserted into the contralateral thalamus under electrophysiological guidance (26). Each unit was conrmed as an STT neuron if it displayed high-

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frequency following (ve antidromic shocks at 250 Hz) and if collision occurred between antidromic and orthodromic impulses. The recording sites of lamina I STT neurons were marked with electrolytic lesions that were recovered in histological sections stained with thionin, as were the stimulating sites in the thalamus. The receptive properties of each unit that was isolated were tested with the following stimuli: innocuous brushing, blunt pressure, pinching with forceps, cooling with a beaker of wet ice for up to 30 sec, innocuous warming, and heating to noxious levels for 5 sec. Neuronal responses to these qualitative stimuli, and also their responses to quantitative stimuli (26), were used to classify units as one of three functional types: thermoreceptive-specic (COOL or WARM; 2), polymodal nociceptive (HPC, responsive to heat, pinch, and cold), and nociceptive-specic (NS, responsive to pinch and/or heat but not cold). Units that could not be excited by a mechanical or thermal stimulus were provisionally classied as insensitive, and their responses to histamine were investigated. Histamine was also applied to the receptive elds of NS and HPC neurons for comparison. Because the receptive elds of insensitive cells could not be located using conventional stimuli, histamine (1% in 2.5% methylcellulose gel) was applied to the area of the skin where background activity in nearby neurons could be elicited. Iontophoresis was used to apply the histamine as this method produces a pure sensation of itch without any pain (17). To test for nonspecic eects, iontophoresis of the vehicle was performed rst (+1 mA DC for 3060 sec, area 4 mm2) followed by histamine using identical parameters. Histamine was usually applied at several nonoverlapping sites to test for response reproducibility and in an attempt to gauge the extent of a neurons receptive eld. To test the chemical specicity of neurons, some cells were also investigated by applying mustard oil topically to their receptive eld (50% in ethanol) for 30 sec. B. Results

Single-unit recordings were made from 190 antidromically identied lamina I STT neurons with distal hind limb receptive elds. Using natural thermal and mechanical stimuli, we categorized 173 of them (91%) as COOL, WARM, HPC, or NS (26,27). The remaining 17 neurons could not be categorized; of these, 14 had no responses at all to any of the thermal or mechanical stimuli used, and 3 showed weak responses to noxious heat stimuli (<10 impulses in 30 sec). None of these neurons exhibited any background activity in the absence of stimulation (not a single action potential in a 2-min recording period), and thus the use of antidromic stimulation to isolate them was of critical importance.

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We tested each of these 17 insensitive neurons with iontophoretically applied histamine, and we also applied the same current using the vehicle that did not contain histamine as a control for each cell. Ten of the neurons were excited by histamine and not by the vehicle, with a discharge pattern that matched the temporal prole of histamine-sensitive C-ber activity in humans and the accompanying sensations of itch (22): units began to respond after a delay of 13 min, the response peaked within 5 min, and persisted for up to 30 min. The response of one histamine-sensitive lamina I STT neuron is shown in Fig. 1a, and mean responses to both histamine and vehicle are shown in Fig. 1b and c. We used electrical stimulation with intracutaneous needle electrodes to determine the conduction velocities of the peripheral bers that provided inputs to the histamine-sensitive lamina I STT neurons in four cases. Intense stimuli (>5 mA, duration up to 10 msec) were required to activate these cells, and they showed only long-latency responses that were time-locked. This observation indicates that the histamine-sensitive neurons were monosynaptically excited by peripheral C-bers but not by A-bers. The conduction velocities of the C-ber aerents were very slow (0.50.7 m/sec), slower than the velocities of C-bers that drive nociceptive lamina I STT neurons (28). These velocities are consistent with those of the histamine-selective C-bers identied in humans (22). For comparison, we tested 16 nociceptive lamina I STT neurons (9 NS, 7 HPC) with iontophoretically applied histamine and vehicle. Four units (2 NS, 2 HPC) were not excited at all by either histamine or vehicle. The remaining 12 neurons showed phasic excitation from the current applied by iontophoresis. Their ongoing activity typically increased slightly (12 impulses/sec) for a short time (12 min) following current application with either histamine or vehicle (Fig. 2). These results are consistent with the previous microneurographic observations in humans (16,22). The novel chemical sensitivity of the histamine-sensitive lamina I STT neurons distinguished them from other types of lamina I STT neurons, but they were also dierentiated by additional physiological properties, indicating that the histamine-sensitive neurons constitute a unique class of lamina I STT neurons. The neurons central conduction velocities were signicantly slower ( p<0.03, ANOVA) than those of NS, HPC, and COOL neurons (Fig. 3a). The conduction velocities of these latter three cell groups also dier from each other ( p<0.01, ANOVA), and they are also morphologically and physiologically distinct (24,26). In addition, none of the histamine-sensitive neurons showed any spontaneous activity when rst isolated (Fig. 3b), and this also diers signicantly from each of the other classes of lamina I STT neurons ( p<0.05 or better, KruskalWallis ANOVA). Finally, the pattern of thalamic projections of the histamine-sensitive neurons diered from those

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Figure 1 Histamine- and vehicle-evoked responses from histamine-sensitive lamina I STT neurons. (a) The response of a single neuron to histamine. Top histogram: binned ring rate of the neuron (1-sec bins). The middle trace shows the analog record of neuronal activity; the thickening of the baseline in this record during the iontophoresis (indicated by the lower trace) is due to the current-evoked activation of several neighboring neurons. (b) Mean response of all 10 histamine-sensitive lamina I STT neurons to histamine application. (c) Mean responses of the same 10 neurons to vehicle application. Error bars indicate 1 SD. Bin size is 20 sec. (Reproduced from Nature Neuroscience with permission.)

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Figure 2 The eects of histamine and vehicle on a nociceptive lamina I STT neuron. (a) Response of a polymodal nociceptive (HPC) lamina I STT neuron to iontophoretic application of histamine. (b) Response of the same neuron to iontophoresis using vehicle at an adjacent site. For each pair of traces, the upper histogram shows the binned rate of impulse activity (1-sec bins) of the single neuron shown in the middle trace, and the lower record shows the duration of the current application. (Reproduced from Nature Neuroscience with permission.)

of nociceptive neurons. The histamine-sensitive neurons were predominately activated from lateral thalamus (the ventral posterior inferior n. and the ventral posterior lateral n.), in contrast to NS and HPC neurons, which projected signicantly more often to medial thalamus (n. submedius; p<0.002, v2 test) (Fig. 3c). Thus, taken together, the data support the conclusion that histamine-sensitive cells are distinct anatomically and physiologically, and therefore form a unique group of STT neurons. The response characteristics of 4 of the 10 histamine-sensitive lamina I STT neurons were altered following stimulation. After activation by histamine, one cell became weakly responsive to noxious mechanical stimulation (pinching with forceps), and another responded to a slow-moving brush swept across its receptive eld and to punctate stimulation with a ne wire probe. Two neurons developed ongoing discharge (f0.10.5 Hz) after repeated

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Figure 3 Distinguishing features of histamine-sensitive lamina I STT neurons. (a) Median (horizontal line inside box), 25th and 75th percentiles (box boundaries), and range (bars) of the central conduction velocities of dierent functional classes of lamina I STT neurons. Figures in parentheses are numbers of neurons. (b) Background (ongoing) activity recorded over a 2-min period for dierent classes of lamina I STT neurons plotted as in (a). None of the histamine-sensitive neurons had ongoing activity when rst isolated. (c) Comparison of the incidence of histamine-sensitive and nociceptive (NS and HPC) lamina I STT neurons that could be antidromically activated from medial (n. submedius, Med) or lateral (the ventral posterior inferior and ventral posterior lateral nuclei, Lat) thalamus. Histamine-sensitive neurons projected signicantly less frequently to medial thalamus than nociceptive neurons ( p<0.002, v2 test). (Reproduced from Nature Neuroscience with permission.)

noxious heat stimulation. These changes in receptive properties could underlie the sensory phenomena of alloknesis and punctate hyperknesis. We did not apply noxious stimuli during a histamine-evoked discharge to test for inhibition of these histamine-sensitive neurons. We further investigated the chemosensitivity of seven neurons that had previously been tested with histamine by applying topical mustard oil to the cells innervation territory. This chemical algogen produces a sensation of burning pain, and excites most, if not all, C-ber nociceptors in the skin (29,30). Of these seven neurons, four were excited by histamine and the remaining three were not. All three of the histamine unresponsive neurons were excited by mustard oil for up to 15 min. These units were probably specic chemonociceptive neurons. Of the four histamine-sensitive lamina I STT neurons, two were not excited at all by mustard oil and they were clearly histamine-selective. Of the other two cells, one was excited briey by mustard oil, in contrast to its sustained excitation by histamine, and the other was excited for >20 min, better than all other cells studied, and its histamine response was weak. This neuron might have been a chemonociceptive neuron that was sensitized by prior noxious heat stimulation of the skin during the

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examination of other cells in that experiment. Thus its weak histamine response was in all likelihood an eect of the sensitization.

III.

OTHER SPINAL NEURONS EXCITED BY HISTAMINE

The eects of histamine, and also other irritant and noxious chemicals, on the activity of single rat spinal neurons with unidentied projections have been studied by Carstens (31) and Jinks and Carstens (32). The appropriateness of intracutaneous injection of histamine in rats as a model for itching has been discussed in Chapter 5. Initial studies examined cells in the deep dorsal horn that responded to both innocuous and noxious stimulithe classical wide dynamic range neurons. Almost all of the units studied (84%) were activated by injected histamine. The discharge prole of all of the neurons activated by histamine showed an adapting time course [time constant f60 sec; (31)], which does not match the time course of itch sensation in humans. Most of the cells were also excited by other chemical stimuli including capsaicin, mustard oil, ethanol, serotonin, and nicotine, although not every neuron responded to every chemical tested, implying some degree of selectivity. However, the responses to dierent chemicals were usually similar, in particular, the capsaicin-evoked responses were of a magnitude equal to the histamine-evoked responses. These wide dynamic range neurons are considered by many to be important in pain, as they increase their discharge as stimulus intensity increases from innocuous to noxious. A role in itch for these neurons might have been suggested if the histamine-evoked discharges were within a range of ring rates that spanned the innocuous to noxious range. However, their responses did not dierentiate a noxious chemical from a pruritic one when the sensations produced by them are very dierent (itching vs. burning pain). The failure to observe any evidence of coding of noxious and pruritic stimuli in the discharge of the neurons suggests that these modality ambiguous neurons are unlikely to be involved in the sensory-discriminative aspects of itching. A later study addressed the responses of supercial dorsal horn neurons (32) to histamine and other chemicals. Neurons were identied by the presence of ongoing (background) activity, classied using mechanical and heat stimuli, and their chemical sensitivity was investigated by injecting histamine and other irritant chemicals (capsaicin, mustard oil, and nicotine) intracutaneously into their receptive elds. Relying on background activity to identify cells will have automatically excluded the possibility of recording from neurons without spontaneous activity, which would have included the histamine-sensitive lamina I STT neurons identied in the cat. Like the deep dorsal horn neurons, the typical response of supercial dorsal horn neurons to histamine was adaptive, but the time constant of the supercial neurons was

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slightly longer than that of the deep cells (meanf92 sec). Additionally, almost all of the cells that responded to histamine were also activated by the other chemicals, as well as being responsive to nociceptive and/or non-nociceptive physical stimuli. Thus, like the deep dorsal horn neurons, supercial nociceptive neurons with unidentied projections do not distinguish a pruritic stimulus from a nociceptive stimulus. The eects of injected histamine on supercial and deep dorsal horn neurons in the rat are similar to those of iontophoretic histamine on nociceptive lamina I STT neurons in the cat, i.e., a brief phasic excitation that quickly declines to background levels. This is to be expected based on the weak histamine sensitivity of primary aerent nociceptors (see Chapters 2 and 3). Injected histamine is known to cause a mixed sensation of itch and pain (22), and the histamine-evoked excitation of nociceptive neurons likely reects the role of these cells in pain rather than in itch.

IV.

THALAMO-CORTICAL PATHWAYS FOR ITCH

Functional brain imaging studies have identied cortical regions activated by itch in humans. The rst investigation (33) used intracutaneously injected histamine to evoke itch, which can produce both pain and itch (see previous text). Notwithstanding this, the contralateral anterior cingulate cortex (area 24) was the most strongly activated brain region. Other motor-related structures activated included the ipsilateral inferior parietal cortex of the posterior parietal cortex, the supplemental motor area bilaterally, and the ipsilateral dorsolateral prefrontal cortex. Activation of the anterior cingulate (limbic motor cortex) was interpreted as being the representation of the urge to scratch, whereas the other cortical areas are involved in the integration and execution of target-orientated voluntary movements. A later study where histamine was pricked into the skin (34) conrmed the activation in many of the same motor regions, and also described correlations between itch unpleasantness/intensity and activation in the contralateral insula, primary somatosensory cortex, and supplemental motor areas bilaterally. The activation of these cortical regions, particularly anterior cingulate cortex and insular cortex, corresponds with the functional anatomy of ascending lamina I axons (35). In primates, there is a dedicated pain-andtemperature (and presumably itch) nucleus in the posterior thalamus (VMpo) (3638) that receives modality-specic information only from lamina I neurons. This nucleus projects topographically to insular cortex, but it also projects collaterals to area 3a in primary somatosensory cortex (S I). Other diencephalic targets of ascending lamina I axons are the ventrocaudal aspect of the mediodorsal nucleus (MDvc) and the ventral posterior inferior

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nucleus (VPI) (35,36). Neurons in MDvc project to area 24 in the anterior cingulate cortex, whereas those in VPI project to secondary somatosensory cortex (S II). Thus the activation of the insula and the anterior cingulate cortex in human imaging studies of itch is likely relayed by lamina I STT neurons that terminate in VMpo and MDvc, consistent with the proposed interoceptive role of this pathway. Substantial species dierences exist between cat and monkey as the lamina I projection to anterior cingulate in cats is probably relayed through neurons in the ventral periphery of the ventral posterior nucleus (VPI and VPL) (39,40), rather than MDvc. Nonetheless, the combination of results from physiological studies in cats, tracing studies in monkeys, and imaging studies in humans supports the concept of a dedicated lamina I spino-thalamo-cortical pathway for itch. Further experiments in nonhuman primates will be needed to conrm this prediction.

V.

NOVEL THERAPIES FOR ITCH

Our ndings provide strong evidence supporting the specic nature of the sensation of itch. Previous physiological data were insucient to exclude competing hypotheses of graded intensity, unique temporal patterns, or dierential sorting (16,21,41) until the demonstration of itch-specic primary aerent C-bers (22). Our observations conrm that the response prole of these bers is maintained in a distinct population of lamina I STT neurons, which have unique physiological properties. Another group of neurons was selectively excited by mustard oil, and these cells are likely to be important in chemogenic pain. Both results conrm theoretical predictions based on human psychophysical studies (6,41,42). The identication of a dedicated central neural pathway for itch oers the opportunity to identify novel targets for the development of new antipruritic agents. Nociceptive and thermoreceptive lamina I neurons are physiologically and anatomically unique. That is, the shape of a neurons soma and its proximal dendrites is a characteristic of its function (24). Thus pyramidalshaped cells are cooling-specic thermoreceptive neurons, fusiform-shaped cells are usually nociceptive-specic neurons, and multipolar cells are typically polymodal nociceptive neurons. Thermoreceptive and nociceptive lamina I STT neurons also have dierent patterns of termination in the thalamus (43). We hypothesize that because the histamine-sensitive lamina I STT neurons we identied were dierentiated by their distinct physiological characteristics, they will also have dening anatomical characteristics. Although histamine-sensitive neurons have not yet been intracellularly labeled, their incidence (f5%, 10/190) coincides with the incidence of lamina I STT neurons that have shapes categorized as unclassied, that is, neither pyramidal,

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fusiform, nor multipolar (44). The ability to determine histologically which lamina I STT neurons were histamine-sensitive could lead to, using DNA microarray techniques, the identication of novel genes and proteins expressed by those neurons alone. These markers could be used as targets for drug discovery.

ACKNOWLEDGMENTS This chapter is supported by the Royal Society of Edinburgh, the National Institutes of Health (NS 25616), and the Atkinson Pain Research Fund administered by the Barrow Neurological Foundation.

REFERENCES
von Frey M. Zur Physiologie der Juckempndung. Arch Neerl Physiol 1922; 7:142145. 2. Bickford RG. Experiments relating to the itch sensation, its peripheral mechanism, and central pathways. Clin Sci 1938; 3:377386. 3. Hyndman OR, Wolkin J. Anterior cordotomy. Further observations on physiologic results and optimum manner of performance. Arch Neurol Psychiat Arch Neurol Psychiat 50:129148. 4. Taren JA, Kahn EA. Thoracic anterolateral cordotomy. Operative Techniques for the Relief of Pain Arising in the Body. London: JA Churchill Ltd, 1966: 299310. 5. Nathan PW. Touch and surgical division of the anterior quadrant of the spinal cord. J Neurol Neurosurg Psychiatry 1990; 53:935939. 6. LaMotte RH, Shain CN, Simone DA, Tsai E. Neurogenic hyperalgesia: psychophysical studies on underlying mechanisms. J Neurophysiol 1991; 66:190 211. 7. Graham DT, Goodell H, Wol HG. Neural mechanisms involved in itch, itchy skin, and tickle sensations. J Clin Invest 1951; 30:3749. 8. Simone DA, Alreja M, LaMotte RH. Psychophysical studies of the itch sensation and itchy skin (alloknesis) produced by intracutaneous injection of histamine. Somatosens Motor Res 1991; 8:271279. 9. Ward L, Wright E, McMahon SB. A comparison of the eects of noxious and innocuous counterstimuli on experimentally induced itch and pain. Pain 1996; 64:129138. 10. Nilsson HJ, Levinsson A, Schouenborg J. Cutaneous eld stimulation (CFS): a new powerful method to combat itch. Pain 1997; 71:4955. 11. Craig AD, Reiman EM, Evans A, Bushnell MC. Functional imaging of an illusion of pain. Nature 1996; 384:258260. 1.

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12. Atanasso PG, Brull SJ, Zhang J-M, Greenquist K, Silverman DG, LaMotte RH. Enhancement of experimental pruritus and mechanically evoked dysesthesias with local anesthesia. Somatosens Motor Res 1999; 16:299303. 13. Brull SJ, Atanasso PG, Silverman DG, Zhang J-M, LaMotte RH. Attenuation of experimental pruritus and mechanically evoked dysesthesias in an area of cutaneous allodynia. Somatosens Motor Res 1999; 16:291298. 14. Ballantyne JC, Loach AB, Carr DB. Itching after epidural and spinal opiates. Pain 1988; 33:149160. 15. Torebjo rk HE, Ochoa JL. Pain and itch from C-ber stimulation. Soc Neurosci Abstr 1981; 7:228. 16. Handwerker HO, Forster C, Kircho C. Discharge patterns of human C-bers induced by itching and burning stimuli. J Neurophysiol 1991; 66:307315. 17. Magerl W, Westerman RA, Mo hner B, Handwerker HO. Properties of transdermal histamine iontophoresis: dierential eects of season, gender and body region. J Invest Dermatol 1990; 94:347352. llbrant N, Iggo A. The eect of histamine, 5-hydoxytryptamine and acetyl18. Fja choline on cutaneous aerent bres. J Physiol (Lond) 1961; 156:578590. 19. Tuckett RP, Wei JY. Response to an itch-producing substance in cat. II. Cutaneous receptor populations with unmyelinated axons. Brain Res 1987; 413: 95103. 20. Wall PD, Cronly-Dillon JR. Pain, itch and vibration. Arch Neurol 1960; 2:355 375. 21. McMahon SB, Koltzenburg M. Itching for an explanation. Trends Neurosci 1992; 15:497501. 22. Schmelz M, Schmidt R, Bickel A, Handwerker HO, Torebjo rk HE. Specic Creceptors for itch in human skin. J Neurosci 1997; 17:80038005. 23. Keele CA, Armstrong D. Substances Producing Itch and Pain. London: Edward Arnold, 1964. 24. Han Z-S, Zhang E-T, Craig AD. Nociceptive and thermoreceptive lamina I neurons are anatomically distinct. Nat Neurosci 1998; 1:218225. 25. Andrew D, Craig AD. Spinothalamic lamina I neurons selectively sensitive to histamine: a central neural pathway for itch. Nat Neurosci 2001a; 4:7277. 26. Craig AD, Krout K, Andrew D. Quantitative response characteristics of thermoreceptive and nociceptive lamina I spinothalamic neurons in the cat. J Neurophysiol 2001; 86:14591480. 27. Andrew D, Craig AD. Spinothalamic lamina I neurones selectively responsive to cutaneous warming in cats. J Physiol (Lond) 2001b; 537:489495. 28. Craig AD Jr, Kniki K-D. Spinothalamic lumbosacral lamina I cells responsive to skin and muscle stimulation in the cat. J Physiol (Lond) 1985; 365:197221. 29. Reeh PW, Kocher L, Jung S. Does neurogenic inammation alter the sensitivity of unmyelinated nociceptors in the rat? Brain Res 1986; 384:4250. 30. Schmidt R, Schmelz M, Forster C, Ringkamp M, Torebjo rk HE, Handwerker HO. Novel classes of responsive and unresponsive C nociceptors in human skin. J Neurosci 1995; 15:333341. 31. Carstens E. Responses of rat spinal dorsal horn neurons to intracutaneous

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Andrew and Craig microinjection of histamine, capsaicin, and other irritants. J Neurophysiol 1997; 77:24992514. Jinks SL, Carstens E. Supercial dorsal horn neurons identied by intracutaneous histamine: chemonociceptive responses and modulation by morphine. J Neurophysiol 2000; 84:616627. , Sta hle-Ba Hsieh J-C, Ha germark O ckdahl M, Ericson K, Eriksson L, StoneElander S, Ingvar M. Urge to scratch in the human cerebral cortex during itch. J Neurophysiol 1994; 72:30043008. Drzezga A, Darsow U, Treede R-D, Siebner H, Frisch M, Max, Munz F, Weilke F, Ring J, Schwaiger M, Bartenstein P. Central activation by histamineinduced itch: analogies to pain processing: a correlational analysis of O-15 H2O positron emission tomography studies. Pain 2001; 92:295305. Craig AD. In: Besson J-M, ed. Forebrain Processing of Pain. Paris: John Libby, 1995:1325. Craig AD, Bushnell MC, Zhang E-T, Blomqvist A. A thalamic nucleus specic for pain and temperature sensation. Nature 1994; 372:770773. Davis KD, Lozano RM, Manduch M, Tasker RR, Kiss ZH, Dostrovsky JO. Thalamic relay site for cold perception in humans. J Neurophysiol 1999; 81: 19701973. Blomqvist A, Zhang ET, Craig AD. Cytoarchitectonic and immunohistochemical characterization of a specic pain and temperature relay, the posterior portion of the ventral medial nucleus, in the human thalamus. Brain 2000; 123: 601619. Musil SY, Olson CR. Organization of cortical and subcortical projections to anterior cingulate cortex in the cat. J Comp Neurol 1988; 272:203218. Yasui Y, Itoh K, Kamiya H, Ino T, Mizuno N. Cingulate gyrus of the cat receives projection bers from the thalamic region ventral to the ventral border of the ventrobasal complex. J Comp Neurol 1988; 274:91100. LaMotte RH. Secondary cutaneous dysesthesiae. In: Belmonte C, Cervero F, eds. Neurobiology of Nociceptors. New York: Oxford University Press, 1996: 300417. Simone DA, Ngeow JY, Whitehouse J, Becerra-Cabal L, Putterman GJ, LaMotte RH. The magnitude and duration of itch produced by intracutaneous injections of histamine. Somatosens Res 1987; 5:8192. Craig AD, Dostrovsky JO. Dierential projections of thermoreceptive and nociceptive lamina I trigeminothalamic and spinothalamic neurons in the cat. J Neurophysiol 2001; 86:856870. Zhang E-T, Han Z-S, Craig AD. Morphological classes of spinothalamic lamina I neurons in the cat. J Comp Neurol 1996; 367:537549.

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5
Animal Models of Itch: Scratching Away at the Problem
Earl Carstens
University of California, Davis, Davis, California, U.S.A.

Yasushi Kuraishi
Toyama Medical and Pharmaceutical University, Toyama, Japan

I.

INTRODUCTION

Itch is widely considered to be an unpleasant sensation associated with the desire to scratch. Although humans distinguish between itch and acute pain sensations, it is more dicult to evaluate if an animal experiences itch as opposed to pain. It is often assumed that scratching behavior may reect itch sensation in animals, particularly in cases where the region of skin receiving a pruritogenic stimulus is scratched. On the other hand, responses of animals to an acute noxious stimulus usually involve withdrawal and protection of the stimulated body part. In humans, acute pruritic stimuli, such as focal application of histamine, elicit a sensation of itch than can be well localized with errors of less than 10 mm (1). It has been assumed that animals also experience a sensation of itch following a cutaneous pruritic stimulus, and that this is reected by scratching directed toward the stimulus site. This has led to the assessment of hindlimb scratching directed toward the site of intradermal (i.d.) injection of pruritogens in rodents as an animal model of itch (2,3). This model is of
35

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potential benet in studies of normal itch sensation and its physiological mechanisms, as discussed extensively below. There is also a pressing need for the development of animal models of chronic itch that mimic the pathophysiology of atopic dermatitis and other dermatological and systemic conditions associated with severe chronic itching in humans. Currently, there are few such animal models, and these are also discussed. A variety of systemic disorders have itching as a symptom (4), in particular liver dysfunctions such as cholestasis or biliary cirrhosis (5), and renal failure (6). The pathophysiological mechanisms for these types of itch are unknown. The possibility of pathophysiological alterations in central itch signaling mechanisms, with emphasis on opioid involvement, is also considered below.

II.

HINDLIMB SCRATCHING AND RELATED BEHAVIORAL MODELS OF PERIPHERALLY EVOKED ITCH

The association between itch sensation and scratching has led to the use of scratching behavior in animals as an assay for itch. Most studies involve i.d. injection of a pruritogen into the nape of mice or rats, and count the number of bouts of hindlimb scratching directed toward the stimulus (2,3). To what extent is this a viable itch model? To be a selective model of itch, the behavioral scratching response should be consistent with the following properties of itch:
 selectively induced by pruritic but not algesic stimuli  alloknesis (itchy skin) (i.e., manifestations of itch sensation elicited by innocuous mechanical stimulation of skin surrounding the pruritic area)  induction or exacerbation of itch by opioids  suppression of itch by

opioid antagonist, naloxone noxious stimuli (scratching, heat) innocuous stimuli (cooling, rubbing) distraction mast cell degranulation (e.g., compound 48/80) pretreatment of skin with capsaicin. Regarding the rst point, there is evidence both for and against a specic association between itch and scratching. Spontaneous scratching behavior occurs in arthritic rats (7); the scratching was reduced by morphine in a

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naloxone-reversible manner but was not reduced by an antihistamine (astemizone), suggesting that the scratching may reect pain rather than itch. Hindlimb scratching is also elicited by intrathecal microinjection of a variety of chemicals, including neurokinins, capsaicin, morphine, and many others (810). In some instances, the intrathecally induced scratching was reduced by morphine (10), again suggesting that it was pain-related. However, scratching is evoked by intrathecal drugs in spinalized rats (8), raising the possibility that it reects the activation of motor scratch reex circuits rather than sensory systems. Facial scratching is also elicited by intracerebroventricular injection of morphine (11,12) and other substances (see below). Scratching is also a component of normal grooming behavior. These data therefore indicate that scratching behavior per se does not necessarily reect itch sensation. However, recent behavioral data suggest that directed hindlimb scratching may distinguish between itch and pain (Table 1). Intradermal injection of substances that induce itch in humans, including substance P (13), the mast cell degranulator compound 48/80 (14), serotonin (5-HT; 15), and plateletactivating factor (PAF; 16), elicit dose-related scratching in rodents (2,3,17 19) (Figs. 1a, b and 3b). In contrast, i.d. injection of algesic agents, such as capsaicin and formalin, elicits either no or very little scratching, which is not dose-related (3,18,19). Curiously, i.d. histamine does not elicit scratching in ddY mice (3,18) (Fig. 1a and b) or SpragueDawley rats (19) even though it is the denitive pruritogen in humans (20,21). This discrepancy may be explained by the fact that cutaneous mast cells in rodents contain little histamine but high concentrations of 5-HT (2224), which may be pruritic in certain rodent strains. Other rodent strains, including the ICR mouse (25) and hairless guinea pig (17), exhibit scratching dose-related to i.d. histamine (Table 1). In the latter study, PAF also elicited signicant scratching. The

Table 1 Chemicals That Do (+) and Do Not () Induce Directed Scratching When Given i.d. in Three Rodent Species Chemical Histamine Substance P Compound 48/80 5-HT PAF Leukotriene B4 Capsaicin Formalin Mouse (ddY); + (ICR) + + + + Hairless guinea pig + Rat

+ +

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Figure 1 Hindlimb scratching elicited by various chemicals injected i.d. in mice. (a) Graph plots mean number of scratching bouts per hour (error bars: S.E.M.) in mice receiving i.d. 5-HT (lled circles), with little scratching following i.d. histamine (lled diamonds). Open circle: vehicle (saline). (From Ref. 18.) (b) Graph plotting mean scratching bouts per hour elicited by i.d. injection of compound 48/80 (lled circles) and substance P (lled triangles), with little scratching following i.d. histamine (diamonds). (From Ref. 3.)

available behavioral data thus indicate that directed hindlimb scratching behavior may distinguish between pruritic and algesic stimuli, supporting it as a viable animal model of itch. In a recent study of scratching induced by i.d. 5-HT in rats, head or whole body shaking was correlated with scratching (19), suggesting that this type of grooming behavior may also be a useful parameter to assess itch. The possibility of alloknesis, to our knowledge, has not yet been addressed using animal scratching models. The third point, that opioids should evoke the itch-related behavior, is supported by several studies showing that facial scratching is elicited by opioids delivered by intracerebroventricular, intramedullary, or intrathecal routes (9,11,12,2630). The opioid-evoked scratching was shown in some of these studies to be reversed by naloxone. Naloxone signicantly attenuated directed hindlimb scratching elicited by i.d. injection of 5-HT (18) or substance P (31). Substance Pinduced hindlimb scratching was also signicantly reduced by pretreating the injected skin area with capsaicin or compound 48/80 (31). The capacity for noxious or innocuous counterstimulation to reduce hindlimb scratching in animals has not yet been investigated. Interestingly, the degree of scratching elicited by i.d. 5-HT was markedly less when the investigator was present, rather than absent during data collection (18), suggesting that scratching is susceptible to distraction. In summary, many of the expected properties of itch are fullled in studies of directed hindlimb scratching by rodents, supporting its utility as

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an animal behavioral model of itch. Furthermore, the data suggest that 5HT, substance P, mast cell degranulators, and PAF are pruritogenic in rodents, whereas histamine appears not to be pruritic in some common rodent strains. Hindlimb scratching directed toward the eye after topical application of chemicals to the ocular surface has been used to assess conjunctival itch in hairless guinea pigs (17). In this model, histamine, 5-HT, PAF, and prostaglandin E2 elicited signicant dose-related ocular scratching, whereas even high concentrations of the algesic agents bradykinin, acetic acid, or saline did not. Biting has also been suggested to reect itch, based on a recent study assessing licking and biting directed toward the site of i.d. 5-HT injected into the hindpaw of mice (32). 5-HT elicited approximately equal numbers of licks and bites over a 60100 nmol dose range. Biting, but not licking, was signicantly attenuated by both naloxone and the 5-HT antagonist, methysergide. In contrast, formalin elicited a characteristic biphasic temporal pattern of hindpaw licking but no biting. These results suggest that hindpaw biting is analogous to scratching and may represent a means of noxious counterstimulation of the paw to relieve itch sensation.

III.

MULTIPLE ITCH MECHANISMS

The pharmacology of peripherally evoked scratching has recently come under study (Table 2). In humans, itch elicited by histamine, substance P, and PAF is reduced by H1 receptor antagonists as well as mast cell degranulation, implicating histamine liberated from mast cells as the nal eector (21). Consistent with this, the H1 antagonist, pyrilamine, substantially reduced histamine-evoked ocular scratching in guinea pigs (17). However, recent data from mice indicate that substance P-evoked scratching may partly involve a separate NK-1 receptor-mediated mechanism (31) (Table 2). Moreover, PAFinduced scratching in guinea pigs was reduced by PAF antagonists (WEB 2086 and CV-6209) but not by H1 antagonists (17). Leukotriene B4 (LTB4) elicits scratching in mice that is attenuated by an LTB4 antagonist (33). LTB4 may play a role in substance P-induced scratching (34). Emedastine, which blocks histamine H1 receptors as well as histamine release from mast cells, signicantly attenuated scratching induced by i.d. LTB4, substance P, and histamine, but not 5-HT, in ICR mice (35). Interestingly, the blocking eect of emedastine was much greater for scratching elicited by LTB4 and substance P compared to histamine, suggesting that part of emedastines antipruritic eect may be via a blockade of LTB4 activity. The other H1 antagonist, azelastine, which reduces pruritus in chronic hemodialysis patients (36), may involve the action and production of LTB4 in its

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Table 2 Multiple Itch Mechanisms (See Text for Explanation) Chemical Histamine Substance P/ NK-A PAF 5-HT Animals scratching # by H1 receptor antagonists NK-1 antagonists; naloxone; pretreatment of skin with capsaicin; compound 48/80 PAF antagonists 5-HT1/2 antagonists, not 5-HT3; naloxone; pretreatment of skin with capsaicin; compound 48/80 LTB4 antagonist (ONO-4057); emedastine; azelastine Humans itch # by H1 antagonists H1 antagonists; compound 48/80 H1 antagonists; compound 48/80 5-HT3 antagonists (ondansetron) Azelastine (hemodialysis patients)

Leukotriene B4

antipruritic eect (37). Collectively, the data presented above suggest that there may be multiple mechanisms involved in itch, in addition to the liberation of 5-HT or histamine from cutaneous mast cells. Scratching was elicited in mice by 5-HT2, but not 5-HT1A or 5-HT3, agonists (Fig. 1a), and was reduced by 5-HT1/2 antagonists (methysergide and cyproheptadine) but not by 5-HT3 antagonists including ondansetron (18), indicating that 5-HT-induced scratching in mice is at least partly mediated via a peripheral 5-HT2 receptor. These dierences might be explained by species dierences in 5-HT receptor mechanisms involved in itch, and/or pathophysiological changes in 5-HT signaling due to the dermatitis. The currently available data therefore suggest the existence of multiple pharmacologically distinct peripheral itch mechanisms. It will be interesting to determine if a common population of peripheral itch receptors expresses a multiplicity of molecular receptors for each of the suspected pruritic agents, or if there is some degree of chemical selectivity in responses of peripheral chemonociceptors that project to central itch signaling pathways.

IV.

MODELS OF ALLERGIC ITCH

When the ICR mouse was given an i.d. injection of antigen-specic immunoglobulin E and then an intravenous injection of antigen, it showed scratching directed toward the immunoglobulin-injected site (38). The passive cutaneous anaphylaxis-induced scratching was suppressed by H1 receptor antagonists (cetirizine and terfenadine), but the inhibition of scratching was

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incomplete at a dose that almost completely abolished plasma extravasation. H2 receptor antagonists (famotidine and ranitidine) inhibited the scratching without aecting plasma extravasation. These ndings suggest that histamine is a key mediator in itch associated with immunoglobulin E-dependent allergic reactions. Mosquito bites frequently cause allergic skin reactions and itching in humans. When ICR mice were exposed to mosquitos (Aedes albopictus), the initial mosquito bites did not elicit scratching but repeated bites (twiceweekly exposure) led to a gradual increase in scratching (39). In mice receiving repeated injections of an extract from the mosquito salivary gland, the rst mosquito bites elicited marked scratching and plasma extravasation, suggesting that mosquito biteinduced scratching resulted from an immediate allergic reaction. Terfenadine did not aect mosquito biteinduced scratching at a dose that almost completely abolished plasma extravasation and markedly suppressed histamine-induced scratching (39). The reason why histamine has a larger role in itch-associated responses following passive cutaneous anaphylaxis compared to mosquito bites is unclear. The amount of histamine released by mosquito bites might be too small to cause itching. Taken together, these ndings suggest the presence of histamine-mediated and histamine-independent mechanisms of immediate allergic itching.

V.

MODEL OF DRY SKINASSOCIATED ITCH

Skin dryness is apparent in several pruritic skin diseases, such as senile xerosis, seasonal xerosis in winter, and atopic dermatitis. It may be also associated with itch in patients with renal failure or cholestasis (5,6). Daily treatment of mouse skin with a mixture of acetone and ether followed by tape stripping led to an increase in spontaneous scratching (40). This treatment disrupts the cutaneous barrier and decreases the hydration of the stratum corneum during the initial 2 days, and resulted in a gradual increase in spontaneous scratching from days 3 to 5. The treatment did not aect the number of total and degranulated mast cells in the skin and increased spontaneous scratching in mast cell-decient mice, suggesting that scratching was independent of cutaneous mast cells.

VI.

MODELS OF CHRONIC ITCH

Potentially promising models include the itchy (NC/jic) mouse (41,42), the hairless guinea pig (17), and neonatal capsaicin treatment in rats (43).

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A potential animal model of chronic itch is neonatal treatment of rats with capsaicin, which destroys a substantial fraction of unmyelinated primary aerent bers and leads to a signicant elevation in spontaneous scratching and associated skin damage (43). Administration of morphine resulted in a signicant delayed increase in scratching in these animals, whereas naloxone signicantly decreased scratching. Control animals receiving vehicle as neonates showed little spontaneous scratching that was not inuenced by morphine. Another potential chronic itch model is the NC/jic mouse (41,42). Within 26 months after birth, the majority of these animals spontaneously develop skin lesions (eczema, bleeding, and alopecia) associated with excessive scratching. They scratched the face and the rostral part of the body all day long. Under 12-hr light/dark conditions, there was a greater number of scratching bouts during darkness than during light, but a circadian rhythm was not apparent (Fig. 2). Using dierential gene display analysis, the animals that developed skin lesions expressed an increased level of mRNA for myocyte-specic enhancer-binding factor compared to animals that did not develop skin lesions and did not show increased scratching (41). A subsequent study of these animals revealed that the spontaneous scratching was reduced by distraction and naloxone, suggesting that it was itch-related (42). 5-HT, but not histamine or substance P, elicited scratching when given i.d. (42). 5-HT antagonists reduced the 5-HT-evoked, but not spontaneous, scratching, indicating that 5-HT may not play a signicant role in mediating spontaneous scratching. It was also shown that the animals did not develop skin lesions, scratching, or increased plasma immonoglobulin G levels when reared in a specic pathogen-free environment. However, when transferred to a conventional environment, the animals developed all of these symptoms within about 4 weeks. These results suggest that the NC/jic mouse may represent an animal model of itch associated with chronic dermatitis, aording the possibility to develop novel antipruritic treatment strategies for clinical cases of itch that are poorly treated by antihistamines or other drugs.

VII.

MODELS OF CENTRALLY MEDIATED ITCH

As mentioned above, the microinjection of opioids and other substances via the intracerebroventricular (11,12,28), intramedullary (26,27), or intrathecal route (8,10,29) elicits facial scratching behavior. It has been suggested that scratching induced by central opioid administration may represent central itch, presumably via activation of central itch signaling pathways as dis-

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Figure 2 Spontaneous scratching of NC mice. Small magnets were worn just above the ankle of both hindlimbs of NC mice (2023 weeks old) and the limb movement was automatically monitored using a scratching counting system (NS-SC01; Neuroscience, Inc., Osaka, Japan). The height of the columns represents the number of scratch bouts per hour. Results are expressed as the mean F S.E.M. of four animals.

cussed further below. In mice, facial scratching was elicited by intracerebroventricular administration of morphine and the A-receptor agonist, DAMGO (but not y-receptor or n-receptor agonists), in a dose-dependent manner, and morphine-evoked scratching was reduced or abolished by distraction (experimenter present during data collection) and naloxone (12). These data suggest that scratching may be itch-related and that it is mediated by a A-opiate receptor. It should be noted, however, that a variety of other substances given via the intracerebroventricular route elicit scratching and other grooming behaviors, including substance P (44,45), ACTH (46), and neuropeptides such as TRH, bombesin, neurotensin, and neuromedin (28,4749). However, the neuropeptide-induced scratching was antagonized by naloxone (47) in support of a role for central opioid receptors. The idea that opioids activate a central itch signaling pathway is relevant to the pruritus of cholestasis, which is associated with an increase in circulating opioids and can be relieved, to some degree, by naloxone (5). Rats with experimental biliary stenosis exhibited naloxone-sensitive analgesia (50) and increased hepatic concentrations of opioids and mRNA for preproenkephalin (51,52), although they did not show increased scratching

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(5). Moreover, intramedullary microinjection of plasma extracts from cholestasis patients with pruritus elicited a naloxone-reversible facial scratching in monkeys (53). These data suggest that chronic itch suered under certain systemic diseases may involve the activation of central itch pathways by circulating pruritic agents such as opioids.

VIII.

NEURAL MECHANISMS OF ITCH

A major benet of an animal model of itch is that it aords the opportunity to investigate the underlying neural mechanisms. Two main theories have been proposed to explain itch. Specicity theory proposes the existence of specic itch receptors linked to an itch signaling sensory pathway. Intensity theory postulates that itch and pain are signaled by a common population of neurons responsive to both pruritic and algesic stimuli. Itch would be signaled by a low ring rate and pain by a higher ring rate in such a nonspecic sensory pathway. Recent studies have provided evidence favoring itch specicity. Human microneurographic studies have uncovered a class of mechanically insensitive cutaneous receptors with slowly conducting unmyelinated aerent bers that respond to cutaneous histamine over a time course that closely matches that of concomitant itch sensation (54). Subsequently, a subpopulation of spinothalamic tract neurons in the supercial dorsal horn (lamina I) with similar response characteristics was identied in the cat (55). A small number of the latter neurons responded selectively to histamine but not the algesic agent, mustard oil, whereas others responded nonselectively to both histamine and mustard oil. The existence of an itch-specic sensory pathway is further supported by intraneural microstimulation experiments. Stimulation near the axon of one or a few polymodal nociceptors elicits a sensation of pain that increases with stimulus frequency, but does not become itch at low frequencies (56). Conversely, microstimulation at some intraneural sites elicits itch that increases in intensity with stimulus frequency, but never becomes painful at high stimulus frequencies (57). Although there may exist a small population of itch-selective spinal cord neurons, supercial dorsal horn neurons more commonly respond to both algesic and pruritic stimuli. Using i.d. histamine as a search stimulus, Jinks and Carstens (19,58) identied nociceptive-specic and wide dynamic range (WDR)-type neurons in the rat supercial dorsal horn that responded to subsequent i.d. histamine, as well as a variety of other suspected pruritic (5-HT) and algesic chemicals (capsaicin, mustard oil, and nicotine). Some of

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these neurons were insensitive to mechanical stimuli, but still responded to pruritic as well as algesic chemical stimulation. Of note, the responses of such neurons to i.d. 5-HT were prolonged, often lasting 2040 min (Fig. 3a). This matches the time course of scratching elicited by i.d. 5-HT in behavioral studies (Fig. 3b) (19). Furthermore, both behavioral scratching and neuronal responses showed signicant tachyphylaxis to repeated i.d. 5-HT injections. These correlations suggest that the chemically nonselective supercial dorsal horn neurons might carry information relevant to itch. How the nervous system discriminates between itch and pain based on input from such nonselective neurons is not clear, but might conceivably depend on ring rate. In this regard, supercial dorsal horn neuronal responses to noxious stimuli (e.g., capsaicin) exhibited a higher-frequency ring rate compared to responses to 5-HT (19). Although the role that WDR and nociceptive-specic dorsal horn neurons play in itch is far from clear, they exhibit some properties consistent with itch sensation. The histamine-evoked responses of dorsal horn neurons are suppressed by mechanical (rub and scratch) and noxious heat stimuli as

Figure 3 Prolonged responses of supercial dorsal horn neurons to i.d. 5-HT compared with scratching. (a) Averaged peristimulustime histogram (PSTH; bin width: 1 sec) of neuronal ring in response to i.d. microinjection of 5-HT (60 mM; 1 Al) at arrow. Error bars on PSTH are omitted for clarity. Single units were recorded in pentobarbital-anesthesized SpragueDawley rats. 5-HT was microinjected i.d. into neuronal receptive eld on ipsilateral hindpaw. Inset shows recordings sites (dots) compiled on section through the L5 dorsal horn. (b) Graph plots mean number of hindlimb scratching bouts (error bars: S.E.M.) directed toward the site of injection of 5-HT in the nape of SpragueDawley rats. Scratching bouts were counted in 2-min intervals. (From Ref. 19.)

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well as cooling (5860), consistent with the antipruritic eects of these counterstimuli (6165). The histamine-evoked responses of supercial dorsal horn neurons were often facilitated by low doses of morphine given intrathecally, although higher morphine doses uniformly depressed neuronal responses to histamine as well as noxious heat (58). It should be borne in mind, however, that histamine may not be pruritic in SpragueDawley rats and future studies of itch mechanisms should focus instead on 5-HT, which may be pruritic in this species.

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46. Van Wimersma Greidanus TB. Eects of naloxone and neurotensin on excessive grooming behavior of rats induced by bombesin, beta-endorphin and ACTH. NIDA Res Monogr 1986; 75:477480. 47. Van Wimersma Greidanus TB, Maigret C. Neuromedin-induced excessive grooming/scratching behavior is suppressed by naloxone, neurotensin and a dopamine D1 receptor antagonist. Eur J Pharmacol 1991; 209(12):5761. 48. Van Wimersma T, Greidanus B, Maigret C, Krechting B. Excessive grooming induced by somatostatin or its analog SMS 201995. Eur J Pharmacol 1987; 144(3):277285. 49. Van Wimersma Greidanus TB, Maigret C, Rinkel GJ, Metzger P, Panis M, Van Zinnicq Bergmann FE, Poelman PJ, Colbern DL. Some characteristics of TRH-induced grooming behavior in rats. Peptides 1988; 9(2):283288. 50. Bergasa NV, Alling DW, Vergalla J, Jones EA. Cholestasis in the male rat is associated with naloxone-reversible antinociception. J Hepatol 1994; 20(1):85 90. 51. Bergasa NV, Sabol SL, Young WS, Kleiner DE, Jones EA. Cholestasis is associated with preproenkephalin mRNA expression in the adult rat liver. Am J Physiol 1995; 268(2 part 1):G346354. 52. Bergasa NV, Vergalla J, Swain MG, Jones EA. Hepatic concentrations of proenkephalin-derived opioids are increased in a rat model of cholestasis. Liver 1996; 16(5):298302. 53. Bergasa NV, Thomas DA, Vergalla J, Turner ML, Jones EA. Plasma from patients with the pruritus of cholestasis induces opioid receptor-mediated scratching in monkeys. Life Sci 1993; 53:12531257. 54. Schmelz M, Schmidt R, Bickel A, Forster C, Handwerker HO, Torebjork HE. Specic C-receptors for itch in human skin. J Neurosci 1997; 17:80038008. 55. Andrew D, Craig AD. Spinothalamic lamina I neurons selectively sensitive to histamine: a central neural pathway for itch. Nat Neurosci 2001; 4:7276. 56. Ochoa J, Torebjork E. Sensations evoked by intraneural microstimulation of C nociceptor bres in human skin nerves. J Physiol (Lond) 1989; 415:583599. 57. Schmidt R, Torebjork E, Jorum E. Pain and itch from intraneural microstimulation. Abstracts of the 7th World Congress on Pain, 1993; 143. 58. Jinks SL, Carstens E. Supercial dorsal horn neurons identied by intracutaneous histamine: chemonociceptive responses and modulation by morphine. J Neurophysiol 2000; 84:616627. 59. Carstens E. Responses of rat spinal dorsal horn neurons to intracutaneous microinjection of histamine, capsaicin, and other irritants. J Neurophysiol 1997; 77:24992514. 60. Jinks SL, Carstens E. Spinal NMDA receptor involvement in expansion of dorsal horn neuronal receptive eld area produced by intracutaneous histamine. J Neurophysiol 1998; 79:16131618. 61. Bickford RG. Experiments relating to the itch sensation, its peripheral mechanism and central pathway. Clin Sci 1937; 3:377386. 62. Frustorfer H, Hermanns M, Latzke L. The eects of thermal stimulation on clinical and experimental itch. Pain 1986; 24:259269.

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63. Gammon GD, Starr I. Studies on the relief of pain by counterirritation. J Clin Invest 1941; 20:1320. 64. Murray FS, Weaver MM. Eects of ipsilateral and contralateral counterirritation on experimentally induced itch in human beings. J Comp Physiol Psychol 1975; 89:819826. 65. Ward L, Wright E, McMahon SB. A comparison of the eects of noxious and non-noxious counterstimuli on experimentally induced itch and pain. Pain 1996; 64:129138.

6
Histamine-Induced Discriminative and Affective Responses Revealed by Functional MRI
Francis McGlone
Unilever Research and Development, Wirral, England, and Center for Cognitive Neuroscience, University of Wales, Bangor, Wales

Roman Rukwied and David Hitchcock


Unilever Research and Development, Wirral, England

Matt Howard
University of Liverpool, Liverpool, England

I.

INTRODUCTION

For the greater part of the last century, it had been believed that the sensation of itch (pruritus) was a subliminal form of pain. This assumption was derived from experiments showing, on the one hand, that both somatosensations (itch and pain) are abolished after cordotomy (1), and, on the other hand, that pruritic stimuli caused the activation of nociceptors that are usually involved in the transmission of pain (2). However, the hypothesis that itch is conveyed by the same population of nerve bers transmitting pain has to be reconsidered, because recent ndings employing microneurographical recordings from human C-bers have demonstrated that a particular subgroup of mechanically insensitive C-bers in human skin discharges in a pattern that
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matched perfectly the perception of itch (3). Additionally, spinothalamic tract neurons in lamina I, which respond selectively to histamine (4) and in a way that was equivalent to the discharge patterns of the itch nerve bers recorded by Schmelz et al. (3), have been identied in the cat. These data provide, for the rst time, evidence that itch is conveyed by a unique subset of peripheral nerve bers and transmitted by spinal cord neurons, which can be dierentiated from the termination of pain-mediating nociceptors that project to lamina I and II (5,6), further endorsing the specicity theory of somatosensation postulated by McMahon and Koltzenburg (7). However, very little is known about the cortical representations of itch, or whether these, if identied, can be discriminated from those involved in the processing of pain. In contrast, the cortical response to pain, particularly its aectivemotivational and sensorydiscriminative components, has been studied excessively over the past few years. The rst investigations, employing positron emission tomography (PET) during thermally induced pain, revealed the activation of the cingulate cortex and thalamus (8,9). Further research broadened this knowledge and demonstrated activation contralateral to the stimulation site in the secondary somatosensory cortex (SII) (10), the frontal lobe, and the prefrontal cortex (10,11). These results have been conrmed by studies using functional magnetic resonance imaging (fMRI) during heat-induced pain. The data from these studies demonstrated a contralateral activation of the primary and secondary cortices (SI and SII) (12,13), insula, thalamus, cerebellum, and prefrontal cortex (14,15). Some of the identied brain structuresfor instance, the limbic structures (cingulate cortex) and thalamic nuclei (16), but also the prefrontal cortex (17)are relevant to the emotional valence of the stimulus and demonstrate the negative aective quality of painful sensations (18). Additionally, the activation of the primary somatosensory cortex SI has been associated with the sensorydiscriminative aspect of pain [for instance, the stimulus localization, its intensity, and the qualitative discrimination (19)]. Itch, like pain, is accompanied by an aective component but importantly leads to dierent motivational and behavioral consequences (i.e., the scratch reex) compared to pain, which induces withdrawal or guarding behavior. Moreover, chronic itch can reach such an aective intensity that suerers of this condition induce pain in the aected body site (i.e., by intense scratching), which is perceived to be preferable to the itch. Only two neuroimaging studies have investigated the activation of brain areas responsive to itch so far (20,21) and in both studies PET has been used to detect cerebral blood ow changes following the intracutaneous injection (21) or pinprick (20) of histamine solutions. Administration of histamine is a commonly used and reliable model for the experimental induction of itch. Hsieh et al. (21) found a signicant activation of the pre-

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frontal cortex, the premotor areas, and the cingulate gyrus, whereas Drzezga et al. (20) reported an activation of the somatosensory cortex (SI), the motor areas, and the prefrontal cortex. Although these studies imaged for the rst time distinct brain areas involved in the processing of itch, PET imaging has poor temporal resolution and the method of histamine delivery employed in these reports would have induced nociceptive inputs that may have distorted the PET activations. To overcome these shortcomings, we sought to provide measures of brain activities employing fMRI and in which histamine was administered iontophoretically (i.e., without any concomitant mechano-nociceptive input). The aims of this investigation (Study I) were: (a) to validate the methodology, (b) to compare the results with previously generated PET data, (c) to reveal cortical structures involved in the aective and discriminative perception of itch, (d) to compare these data with cortical areas that have been associated with pain processing, and, nally, in a separate scanning session (Study II), (e) to evaluate the eect of mechanical counterstimulation on the aective representation of itch.

II.

MATERIALS AND METHODS

The local Ethics Committee approved the experimental protocol and all participants provided, after completion of a condential medical questionnaire, a written informed consent. Subjects receiving medical treatment inuencing psycho-physical behavior were excluded from the study. Nine right-handed subjects participated in the study (ve females and four males, aged 2337 years) and two sets of experiments were performed to run the investigation.

A.

Study I

One week prior to the fMRI data acquisition, all subjects were pretested with histamine iontophoresis, applied to the dorsum of the left foot. This screening phase of the study was performed to accustom the participants to the experimental procedure and to evaluate the current delivery level required to induce a value of suprathreshold itch intensity of approximately 23 min duration. A 1% solution of histamine (Sigma, Dorset, England), dissolved in methylcellulose and in double-distilled degassed water, was delivered via a purpose-designed chamber, incorporating a ne platinum wire (anode) connected to a constant current stimulator (Moor Instruments, Devon,

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England). The reference (cathode), an Ag/AgCl ECG electrode, was attached to a nearby skin site. All subjects responded with a suprathreshold itch intensity to the iontophoretic delivery (100 AA for 20 sec) of histamine. Itch ratings were recorded using a 100-mm linear visual analog scale (VAS) with 0 corresponding to no itch and 100 corresponding to worst itch imaginable. A level of 30 was designated as that corresponding to the urge to scratch. After positioning the participant in the scanner, the iontophoresis chamber and reference electrode were positioned on the dorsum of the left foot and the participant was given a small handheld VAS, displaying the same scale as the pretest VAS. The operation of the scale required minimal movement of the index nger of the participants right hand and readout was displayed on a screen, relayed via a data projector placed at the end of the magnet, which was viewed by the use of prism glasses. Following a baseline period of 30 sec, and synchronized to image acquisition, histamine was administered as described above. Delivery current (100 AA) was monitored and controlled with an ammeter during fMRI. Participants were instructed to report the real-time intensity of itch sensation by means of the VAS. Administration of histamine was repeated three times during a scanning session at intervals determined by the participants reported itch intensity. A repeat stimulus was delivered only after a return to VAS baseline (no itch) lasting 30 sec. Imaging was performed on a 1.5-T LX/Nvi system (General Electric, Milwaukee, WI) and 24 contiguous axial T2*-weighted gradient echo EPI slices (TE 40 msec, TR 3 sec, ip angle 90j, matrix 6464, eld of view 19 cm, slice thickness 5 mm) were prescribed through the brain. Three hundred volume images were captured during the observation period of 15 min. Throughout the experiments, the subjects head was immobilized using inatable cushions to minimize movement artifacts. B. Study II

The counterstimulation study was carried out 10 days after completion of Study I. The counterstimulus comprised a purpose-built piezoelectrical bender element (T220-H4-503 Standard Brass Shim Bending Element; Piezo Systems Inc., Cambridge, MA), which was attached to the dorsum of the left foot and right foot, respectively, and next to the skin site where the histamine was going to be delivered. Following a preceding scanning period of 30 sec (baseline), histamine iontophoresis (1% solution, 100 AA, 20 sec) was administered to the dorsum of the left foot and right foot, respectively, as previously described. Once the maximum itch intensity had been reached, vibrotactile stimulation was ap-

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plied in the form of sinusoidal waveforms delivered to the bender element and produced by an ICL-8038CCPD (Harris Semiconductor Corp., MA) precision waveform generator. These were externally triggered to deliver frequencies of 30 and 250 Hz, respectively, at an approximate peak-to-peak deection of 100 Am. The stimulator was controlled by a PC, which was interfaced to the scanner so as to allow a precise synchronization of stimulus presentation and image acquisition. Electrical connections of the driving voltage to the iontophoresis chamber and the bender element were made using 8 m of shielded, twisted-pair, tinned copper wires, and no MRI degradation was found to result from performing iontophoresis or using the piezoelectrical stimulator in the scanner. C. Data Analysis

Data were analyzed with SPM99 software (Wellcome Functional Imaging Laboratory), which included motion correction, spatial normalization, and smoothing with a 6-mm FWHM Gaussian kernel. A group correlation analysis was performed between the BOLD signal and the perceived intensity of itch (VAS). A cluster analysis then identied brain regions where the correlation was signicant at a corrected level of p<0.05 (parametric Pearson correlation). Single subject responses were analyzed as epoch design to identify brain regions that responded directly to the iontophoresis of histamine (Study I). Epochs used were the 30-sec window before iontophoresis onset and the 30sec window following iontophoresis. For Study II, group analysis was performed to detect brain regions in which activity was consistently suppressed or increased by the counterstimulation. Signicant clusters ( p<0.05, corrected) are indicated by Brodmann area (BA) and Talairach coordinates (22). Note that the nature of the experiment implied that counterstimulation could have been performed only once per session.

III.

RESULTS

All participants experienced varying degrees of itch, which typically lasted 3 4 min following iontophoresis and took 12 min to reach its maximum level. Group analysis revealed that the BOLD signal was correlated with the perceived intensity of itch (VAS) in the prefrontal cortex BA 10 (10, 11,61), the cerebellum, the associative cortex of the parietal lobe BA 40 (47, 38, 43), and the temporal lobe BA 21/22 (48, 5, 11) (Fig. 1). Single subject analysis of the response to histamine iontophoresis showed activation of the frontal

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Figure 1 Activation of the prefrontal cortex (BOLD; left scale) and simultaneously recorded perception of itch (VAS; right scale) during repetitive iontophoresis of histamine (100 AA for 20 sec; black bar) of a specimen.

lobe, particularly the supplementary motor area of the left and right hemispheres (BA 6) in seven subjects, the oculomotor eld (BA 8) and the prefrontal cortex (BA 10) in ve subjects, as well as in the cerebellum in eight subjects. Group analysis of vibrotactile stimuli showed that counterstimulation delivered at a frequency of 30 Hz caused a signicant activation of the limbic system [i.e., the anterior cingulate cortex (ACC) and the insula (BA 23, 24, and 31)]. Histamine-evoked activation of the prefrontal cortex (BA 10) was reduced signicantly ( P<0.05). In contrast, delivery of vibrotactile stimuli at a frequency of 250 Hz had no eect on the BOLD signals induced by the administration of histamine. No activation of the somatosensory cortices SI and SII was detected at either frequency. A summary of the activated brain regions obtained in this study is shown in Table 1, and this can be compared to the activation maps generated by previous PET studies as well as previous studies investigating pain.

IV.

DISCUSSION

Iontophoretic delivery of histamine provides a noninvasive means of delivery of a controlled amount of charged molecules (23) and has been widely used in

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Table 1 Comparison of Neuroimaging Studies Performed with fMRI or PET in Response to Pruritogenic (Itch) or Nociceptive (Pain) Stimuli Itch PET Activated cortex region (Brodmann area) Supplementary and premotor area G. frontalis, BA6 Prefrontal cortex G. frontalis, BA8 G. superior, BA10 Somatosensory cortex Primary, SI, BA3 Secondary, SII, BA 1 and 3 Primary motor area G. praecentralis, BA4 Associative cortex G. temporalis, BA 39 and 40 G. parietalis, BA 20 and 21 Cerebellum fMRI Hsieh et al. (21) Drzezga (20) fMRI Pain PET

Yes Yes Yes No No

Yes Yes Yes No No

Yes No Yes Yes No

Yes (15) Yes (15) Yes (15) Yes Yes (14,12)

Yes (28)

Yes (1,24) Yes (24) Yes (10,11)

No Yes Yes Yes

No Yes No Yes

Yes Yes No No

Yes (15)

Yes (10) Yes (10) Yes (10)

Yes

the study of itch. However, the technique has not been employed in an fMRI environment before and, to that end, we have validated this method and described a network of brain areas involved in the processing of itch in the absence of any mechano-sensory input. Given the experimental setup of the present study, particularly a current controlled stimulus delivery system and the monitoring of visually controlled estimation of itch, we successfully delivered histamine molecules across the skin and reliably induced a suprathreshold itch perception in all participants. In response to this stimulus, we have identied an extensive activation of ipsilateral prefrontal cortical areas. It is well documented that areas of the prefrontal cortex are activated by a variety of aective somatosensory stimuli, not only in response to painful stimulation (15,24), but also due to touch (25), vision (17), smell, and taste (26), although in these studies the activated prefrontal areas were ipsilateral as well as contralateral to the stimulation site.

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The prefrontal cortex subserves a diverse range of functions, and it has been suggested that the participation of this area in emotional processing reects estimation of the aective valence of a stimulus or context (27). Activation of this area during the perception of itch lends further support to a largely aective role for this region. A similar conclusion had been drawn by Hsieh et al. (21) and Drzezga et al. (20), who revealed the activation of the prefrontal cortices after injection (21) or pinprick (20) of histamine and subsequent PET imaging. However, in their studies, subjective measures of itch intensity were not recorded during image acquisition. In the present investigation, we demonstrated for the rst time that brain activation of the prefrontal cortex was directly and signicantly correlated with the subjective perception of itch, providing evidence that these brain regions contribute to the aective intensity of itch. Principal connections of the prefrontal cortex with other brain regions are the associative cortex of the anterior cingulate and cortical structures associated with motor planning and execution (supplementary motor areas). These cortical association areas are critical participants in emotional and behavioral information processing. For instance, the activation of premotor and motor cortices has been identied during pain (28) or noxious thermal stimuli (15), indicating that cortical motor mechanisms are activated in anticipation of movement preparation to escape those noxious stimuli. In the present study, we identied the activation of premotor and supplementary motor areas in response to a pruritic stimulus and consider these ndings in the context of an itch-motivated defensive action (i.e., the scratch reex), which reects a dierent behavioral response to pain-evoked withdrawal or guarding behavior. Activation of neurons in the anterior cingulate cortex is seen as a prerequisite for the judgment of the aversiveness of nociceptive stimuli (18,29,30), and output connections of the ACC to brainstem areas such as the medial thalamus, periaqueductal gray, or ventral striatum indicate that the ACC may be part of an executive response selection system (31), perhaps for the emotional states related to aversive somatosensory stimuli. Interestingly, we found a signicant activation of the ACC in response to vibrotactile stimulation, delivered at 30 Hz and simultaneously to the perception of itch, accompanied by a diminished activation of the prefrontal cortex. In contrast, high-frequent (250 Hz) vibrotactile stimulation had no eect on the activation of either ACC or the prefrontal cortex. It has been demonstrated that Meissner corpuscles respond to utter (vibration delivered at low frequencies; i.e., 3050 Hz) and are supercially located in the skin, whereas Pacinian corpuscles respond to high frequencies in the range of 150600 Hz (32) and are located in deeper layers of the skin. The fact that, in response to itch, the activation of supercial mechanoreceptive units at 30

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Hz evoked an activation of the ACC and simultaneously decreased prefrontal cortex activity indicates a possible role of both the ACC and the Meissner corpuscles on the cognitive and aective evaluation of itch.

V.

CONCLUSION

In the present study, we have shown that activation of the prefrontal cortex correlates directly with the subjective perception of itch intensity employing an iontophoretic delivery procedure with fMRI. The concomitant delivery of a vibrotactile counterstimulus at 30 Hz evoked the activation of the anterior cingulate cortex and diminished the itch-induced activation of the prefrontal cortex. These data suggest that the recruitment of supercially located Meissner corpuscles and/or the activation of the anterior cingulate cortex is involved in the alleviation of itch. Activation and deactivation of the prefrontal cortices by means of appropriate stimuli revealed further insights into emotional, motivational, and behavioral consequences of itch.

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Nathan PW. Touch and surgical division of the anterior quadrant of the spinal cord. J Neurol Neurosurg Psychiatry 1990; 53:935939. 2. Handwerker HO, Forster C, Kirchho C. Discharge patterns of human Cbers induced by itching and burning stimuli. J Neurophysiol 1991; 66:307315. 3. Schmelz M, Schmidt R, Bickel A, Handwerker HO, Torebjo rk HE. Specic Creceptors for itch in human skin. J Neurosci 1997; 17:80038008. 4. Andrew D, Craig AD. Spinothalamic lamina I neurons selectively sensitive to histamine: a central neural pathway for itch. Nat Neurosci 2001; 4:7277. 5. Carstens E. Responses of rat spinal dorsal horn neurons to intracutaneous microinjection of histamine, capsaicin, and other irritants. J Neurophysiol 1997; 77:24992514. 6. Nahas GG, Harvey DJ, Sutin KM. Psychoactive cannabinoids and membrane signaling. Hum Clin Exp Psychopharmacol 2000; 15:535. 7. McMahon SB, Koltzenburg M. Itching for an explanation. Trends Neurosci 1992; 15:497501. 8. Jones AK, Brown WD, Friston KJ, Qi LY, Frackowiak RS. Cortical and subcortical localization of response to pain in man using positron emission tomography. Proc R Soc Lond B Biol Sci 1991; 244:3944. 9. Talbot JD, Marret S, Evans AC, Meyer E, Bushnell MC, Duncan GH. Multiple representations of pain in human cerebral cortex. Science 1991; 251: 1355 1358. 10. Svensson P, Minoshima S, Beydoun A, Morrow TJ, Casey KL. Cerebral pro1.

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25. Francis S, Rolls ET, Bowtell R, McGlone F, ODoherty J, Browning A, Clare S, Smith E. The representation of pleasant touch in the brain and its relationship with taste and olfactory areas. NeuroReport 1999; 10:453459. 26. ODoherty J, Rolls ET, Francis S, Bowtell R, McGlone F. Representation of pleasant and aversive taste in the human brain. J Neurophysiol 2001; 85:1315 1321. 27. Phan KL, Wager T, Taylor SF, Liberzon I. Functional neuroanatomy of emotion: a meta-analysis of emotion activation studies in PET and fMRI. Neuroimage 2002; 16:331348. 28. Casey KL. Forebrain mechanisms of nociception and pain: analysis through imaging. Proc Natl Acad Sci USA 1999; 96:76687674. 29. Hurt RW, Ballantine HTJ. Stereotactic anterior cingulate lesions for persistent pain: a report on 68 cases. Clin Neurosurg 1974; 21:334351. 30. Johansen JP, Fields HL, Manning BH. The aective component of pain in rodents: direct evidence for a contribution of the anterior cingulate cortex. Proc Natl Acad Sci USA 2001; 98:80778082. 31. Vogt BA, Derbyshire S, Jones AK. Pain processing in four regions of human cingulate cortex localized with co-registered PET and MR imaging. Eur J Neurosci 1996; 8:14611473. 32. Douglas PR, Ferrington DG, Rowe M. Coding of information about tactile stimuli by neurones of the cuneate nucleus. J Physiol 1978; 285:493513.

7
Central Nervous System Imaging of Itch with PET
Ulf Darsow, Alexander Drzezga, and Johannes Ring
Technical University of Munich, Munich, Germany

I.

INTRODUCTION

In 1660, Hafenreer dened itch as unpleasant sensation eliciting the urge to scratcha denition that still holds true today from a clinical point of view (1). Whereas the peripheral pathways of the neural signaling of itch were the subject of many recent and older studies, not much is known about the central nervous, supraspinal processing of itch, and the corresponding scratch response (24). The itch receptor, a subpopulation of chemosensitive unmyelinated C-bers, has been identied (57). There is evidence for spinal gating of the sensation (8,9). Emotional modulation of the perception of itch is also well known (1014) and results in marked inter- and intraindividual variations. Thus, there is a need for an objective measurement of itch as it has been established in pain research (8,1519). Results of our previous studies on objective covariates of itch using axon reex correlations (20) and a new multidimensional itch questionnaire (10,11) suggest the existence of several components of itch perception. Itch is a multidimensional experience. Moreover, a prominent inuence of psychological and cerebral factors on skin inammation has been suggested, but the mechanisms are unclear (4,13, 14,21).

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II.

POSITRON EMISSION TOMOGRAPHY

The development of noninvasive techniques such as functional magnetic resonance imaging (fMRI) and positron emission tomography now enables new approaches to the questions of an itch center in the brain and the relation of the sensation to the scratch response. The rst functional imaging study on itch using positron emission tomography (PET) by Hsieh et al. (22) used intracutaneous histamine injections of a xed concentration as stimulus. With these methods, the coactivation of anterior cingulate cortex, supplementary motor area (SMA), premotor area, and inferior parietal lobe was seen. Primary and secondary somatosensory areas were not signicantly activated. However, intracutaneous injections of histamine elicit pain (20,23 24)a contaminating sensation in itch studies. Therefore, we performed a PET correlation study (25) with a validated epidermal stimulus model (8,20) with increasing intensity to elicit a pure, painless pruritic sensation. The applied methodology delivers histamine by a pain-free skin prick puncture to the area of the skin with the highest itch receptor densitythe dermal epidermal junction (3,21). The axon reex are responses at the stimulus site in this model have been shown to correlate with itch intensity (8,20). Thus, a coactivation of skin reactions and cerebral activation patterns could be expected. Data processing used a statistical parametric mapping procedure (SPM96b), which allowed the correlation of the regional cerebral blood ow (rCBF) as a covariate of neuronal activation of the human cerebral cortex (2627) with subjective and objective variables. Six healthy, male, righthanded volunteers without a history of neurological or pruritic skin disease (mean age 32 F 2 years) were enrolled. After informed consent, each subject received in a single-blinded fashion nine logarithmically increasing histamine dihydrochloride stimuli of 0.038% on the volar side of the right forearm on randomized sites. The concentrations had been determined in a pilot study. Three control stimuli with saline (0.9%) were given. The peak intensity of elicited itch occurred 120 sec after administration, at which time the PET scans were made. Each subject underwent 12 scans at 15-min intervals. PET scans were performed with a Siemens 951 R/31 PET scanner (CTI, Knoxville, TN) in 3D mode with 10.5-cm total axial eld of view after H215O bolus injection. Images were 3D-reconstructed by ltered backprojection with a Hanning lter after corrections for randoms, dead time, and scatter. Thirtyone slices with a 128 128 pixel matrix (pixel size: 2.0 mm) and an interplane separation of 3.375 mm were obtained. Adjusted rCBF voxel values were used for statistical analysis. rCBF changes were summarized as sets of voxel values in SPM[t] maps, which were transformed into normally distributed Z statistics (SPM[Z] maps). All statistical results are based on a single-voxel Z threshold of 4.26 (corresponding to p < 0.00001, uncorrected

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65

Figure 1 Repeated measurements design of the PET study on central nervous activation patterns of itch were done in 6 healthy volunteers. During 3 skin prick tests pure vehicle solution was administered (control) and during 9 skin prick tests a histamine solution was applied. 120s after the skin prick injection, the isotope (350 MBq H2O-15) was administered over 35s and scanning was performed for 50s. After each stimulation, the subjects were asked to rate their intensity and unpleasantness using VAS, and diameters of wheal and are and skin temperature were measured. n = 6.

for multiple comparisons). As the image data were spatially normalized, activation foci were reported with the respective stereotactic coordinates. Correlation analysis was performed on a voxel-by-voxel basis in the SPM routine. For correlation with histamine concentration as objective stimulus intensity, a lower threshold of p < 0.01 corrected for multiple comparisons (corresponding to a single-voxel Z threshold of 3.72) was applied. After each PET scan, the subjective itch intensity was recorded with a 100-mm visual analog scale. Skin reactions, including wheal and are (perpendicular diameters) and skin temperature (nontactile infrared thermometry), and heart rate were recorded at 4 min after stimulus application. Figure 1 describes the time schedule of the study.

III.

RESULTS OF IMAGING, CORRELATION ANALYSIS, AND CONCLUSIONS

From 0.03% to 8% histamine, all six volunteers reported a localized pure itch sensation. Pain was not reported during the study. Mean itch visual analog scale ratings ranged from 24 F 15% to 51 F 31%. Skin reactions ranged from 2 to 8 mm (wheal) and from 4 to 55 mm (are). Skin temperature was in the range of minimum 27.9jC to maximum 34.5jC. A mean skin temperature increase of 0.87jC occurred after histamine stimulation. Subtraction analysis

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of histamine stimulus vs. control averaged for all six volunteers revealed a signicant activation of the left and right primary sensory cortices and bothsided motor-associated areas [mainly left primary motor cortex, SMA, and premotor cortex]. Predominantly left-sided activations of prefrontal, orbitofrontal, and superior temporal cortices, and anterior cingulate were also observed (Fig. 2; see color insert). The skin reactions wheal and are and skin temperature could be correlated with signicant activation patterns involving most of the structures described before. With higher signicance, the wheal correlated with areas 5 (bilateral) and 19 (right); the are correlated with areas 25 (left); and skin temperature correlated with area 10 (left) and the left insula. Activations found by subtraction analysis (Fig. 2) were mostly conrmed by correlation analysis with histamine concentration: Activations of the superior and parts of the middle temporal gyrus were detected. Not identied by subtraction analysis, the left posterior insula and right inferior parietal cortex were also related to the stimulus intensity. Subjective itch intensity rating was associated with left SMA, motor, and sensory areas (Table 1) (26). Right-sided

Figure 2 Cortex areas with signicant increase in regional blood ow 2 min after histamine stimulus at the right lower arm projected onto a 3D anatomical reference derived from magnetic resonance imaging. Brodmann areas and corresponding structures (area 29) are given. n = 6, nine repeated scans subtraction analysis vs. three saline puncture controls. *Areas also described by Hsieh et al. (From Refs. 22,25,26.) (See color insert.)

CNS Imaging of Itch with PET Table 1 Correlation Analysis: Itch Intensity and Activated Areas

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BA = Brodmann area; SMA = supplementary motor area; xyz = Talairach coordinates. (From Ref. 26.)

lower Z scores for this parameter were seen for Brodmann areas 6, 8, 9, and 19. The PET study on itch showed a complex pattern of cerebral activation; no single itch center in the brain was identied. Primary sensory cortex involvement was shown for the rst time, whereas a pronounced increase of regional blood ow in motor-associated areas was previously also demonstrated by Hsieh et al. (22). Figure 2 identies the Brodmann areas with an asterisk at the areas that were also signicantly activated in the study by Hsieh et al. (22). Extensive motor area activation can be seen as a conrmation of the old denition of itch as a sensation inherently connected with the urge to scratch. We found specic sensory and motor areas in a bilateral distribution with left-sided predominance. This can be interpreted as the planning of a scratch response; both arms may be involved because the stimulus is given on the right lower arm: Bilateral SMA activations were previously described in complex motor planning (22). Brodmann areas 4, 6, and 8 are involved in limb control, whereas area 46 may play a role in the timing of motor activity (22,28). The involvement of the anterior cingulum may point to emotional components (17,19). Extensive bilateral prefrontal cortex activation (Brodmann areas 8, 9, 10, 32, 44, 45, and 46) was observed in the study by Hsieh et al. (22). Some of these sites are already known to be involved in sustained attention and association or planning (26). We also found these areas, among others, to be signicantly activated and could correlate area 10 with skin temperature. The processing of pruritogenic stimuli showed a rather left-hemispherically dominated characteristic increase in regional blood ow, which is in contrast to a concept of right-

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lateralized processing of nociception (19). To date, it is not clear whether this is a unique feature of the itch sensation. This underscores again that the stimulus paradigm must be as pain-free as possible. The results of the PET studies show that the search for a single itch center in the brain will not lead to a conclusive result because this concept does not take the multidimensionality of the sensation into account. With the background of the often encountered psychological inuence on the course of inammatory dermatoses such as atopic eczema (14), one may speculate on the practical signicance of the shown correlations of histamine-elicited skin reactions and specic activation patterns in the brain. Because the autonomic balance was not altered during our study, humoral and autonomic nerve eects are unlikely to play a signicant role in the association of skin and cerebral activation, but both factors may be covariates of histamine concentrations. In analogy to pain, a more dierentiated understanding of the central nervous processing of itch in the future may lead to the development of new specic antipruritic drugs. The developed methods also allow further investigations on the functional correlates of chronication of the itch sensation in patients with pruritic diseases.

REFERENCES
1. Hafenreer S. Nosodochium, in quo cutis, eique adaerentium partium, aectus omnes, singulari methodo, et cognoscendi et curandi delisime traduntur. Ulm: Ku hnen, 1660:98102. Bernhard JD. Pruritus in skin disease. In: Bernhard JD, ed. Itch. Mechanisms and Management of Pruritus. New York: McGraw-Hill, 1994:15. Shelley WB, Arthur RP. The neurohistology and neurophysiology of the itch sensation in man. Arch Dermatol 1957; 76:296323. Tausk F, Christian E, Johansson O, Milgram S. Neurobiology of the skin. In: Fitzpatrick TB, Eisen AZ, Wol K, Freedberg IM, Austen KF, eds. Dermatology in General Medicine. Vol. 1. New York: McGraw-Hill, 1993:396403. Handwerker HO, Forster C, Kirchho C. Discharge patterns of human Cbers induced by itching and burning stimuli. J Neurophysiol 1991; 66:307315. Schmelz M, Schmidt R, Bickel A, Handwerker HO, Torebjo rk HE. Specic Creceptors for itch in human skin. J Neurosci 1997; 17:80038008. Schmidt R, Schmelz M, Forster C, Ringkamp M, Torebjo rk HE, Handwerker HO. Novel classes of responsive and unresponsive C nociceptors in human skin. J Neurosci 1995; 15:333341. Bromm B, Scharein E, Darsow U, Ring J. Eects of menthol and cold on histamine-induced itch and skin reactions in man. Neurosci Lett 1995; 187:157160.

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Melzack R, Wall PD. Pain mechanisms: a new theory. Science 1985; 190:971 979. Darsow U, Mautner V, Scharein E, Bromm B, Ring J. Der Eppendorfer Juckreizfragebogen. Hautarzt 1997; 48:730733. Darsow U, Scharein E, Simon D, Walter G, Bromm B, Ring J. New aspects of itch pathophysiology: component analysis of atopic itch using the Eppendorf Itch Questionnaire. Int Arch Allergy Immunol 2001; 124:326331. Droge U, Mautner V, Hoting E. Dierenzierung von Pruritusqualita ten. Dtsch Dermatol 1986; 34:919932. Gupta MA, Gupta AK, Schork NJ. Depression modulates pruritus perception: a study of pruritus in psoriasis, atopic dermatitis, and chronic idiopathic urticaria. Psychosom Med 1994; 56:3640. Panconesi E. Stress and skin diseasespsychosomatic dermatology. In: Parish LC, ed. Clinics in Dermatology. Philadelphia: Lippincott, 1984. Bromm B. Laboratory animals and human volunteers in the assessment of analgesic ecacy. In: Chapman RC, Loeser H, eds. Issues in Pain Measurement. New York: Raven, 1989:117144. Bromm B, Frieling A, Lankers J. Laser-evoked brain potentials in patients with dissociated loss of pain and temperature sensibility. Electroencephalogr Clin Neurophysiol 1991; 80:284291. Jones AKP, Brown WD, Friston KJQLY, Frackowiak RSJ. Cortical and subcortical localization of response to pain in man using PET. Proc R Soc Lond B 1991; 244:3944. Piero VD, Ferracuti S, Sabatini U, Pantano P, Cruccu G, Lenzi GL. A cerebral blood ow study on tonic pain activation in man. Pain 1994; 56:167173. To lle TR, Kaufmann T, Siessmeier T, Lautenbacher S, Berthele A, Munz F, Zieglga nsberger W, Willoch F, Schwaiger M, Conrad B, Bartenstein P. Regionspecic encoding of sensory and aective components of pain in the human brain: a PET-correlation analysis. Ann Neurol 1999; 54:4047. Darsow U, Ring J, Scharein E, Bromm B. Correlations between histamineinduced wheal, are and itch. Arch Dermatol Res 1996; 288:436441. Darsow U, Ring J. Neuroimmune interactions in the skin. Curr Opin Allergy Clin Immunol 2001; 7:435439. , Stahle-Ba Hsieh JC, Ha germark O ckdahl M, Ericson K, Eriksson L, StoneElander S, Ingvar M. Urge to scratch represented in the human cerebral cortex during itch. J Neurophysiol 1994; 72:30043008. Lindahl O. Experimental skin pain. Acta Physiol Scand 1961; 51:179. Woodward DF, Conway JL, Wheeler LA. Cutaneous itching models. Maibach HI, Lowe NJ, eds. Models in Dermatology. Vol. 1. Basel: Karger, 1985:187 195. Darsow U, Drzezga A, Frisch M, Munz M, Weilke F, Bartenstein P, Schwaiger M, Ring J. Processing of histamine-induced itch in the human cerebral cortex: a correlation analysis with dermal reactions. J Invest Dermatol 2000; 115:1029 1033. Drzezga A, Darsow U, Treede RD, Siebner H, Frisch M, Munz M, Weilke F,

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Ring J, Schwaiger M, Bartenstein P. Central activation by histamine-induced itch: analogies to pain processing. Pain 2001; 92:295305. 27. Raichle M. Circulatory and metabolic correlates of brain function in normal humans. In: Mountcastle VB, Plum F, Geiger SR, eds. Handbook of Physiology. The Nervous System. Vol 5. Bethesda: Am Physiol Soc 1987:643679. 28. Fuster JM. The Prefrontal Cortex: Anatomy, Physiology and Neuropsychology of the Frontal Lobe. New York: Raven Press, 1989:609625.

8
Skin Nerve Anatomy: Neuropeptide Distribution and Its Relationship to Itch
Dieter Metze
nster, Mu nster, Germany University of Mu

I.

INTRODUCTION

The skin is equipped with an eective communication and control system designed to protect the organism in a constantly changing environment. For this purpose, a dense network of highly specialized aerent sensory and eerent autonomic nerve branches exists in all cutaneous layers. The sensory system contains receptors for touch, temperature, pain, itch, and various other physical and chemical stimuli. The information is either processed in the central nervous system, or may directly elicit an inammatory reaction by antidromic propagation of the impulses. An understanding of the sensory functions, in general, and itch, in particular, is not possible without knowledge of skin nerve anatomy and the distribution of neuropeptides and receptors in normal and diseased skin (1). However, the relevance of histological, ultrastructural, and immunohistochemical ndings of the skin has to be interpreted very carefully; the integration of new physiological investigation techniques and functional studies is mandatory.

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A.

Skin Nerve Anatomy

The integument of the body is innervated by large, cutaneous branches of musculocutaneous nerves that arise segmentally from the spinal nerves. In the face, branches of the trigeminal nerve are responsible for cutaneous innervation. The main nerve trunks enter the subcutaneous fat tissues, divide, and form a branching network at the dermalsubcutaneous junction. This deep nervous plexus supplies the deep vasculature, adnexal structures, and sensory receptors. Subsequently, the nerve bers reorganize into small nerve bundles, which ascend along with the blood vessels and lymphatic vessels to form a network of interlacing nerves beneath the epidermis (i.e., the supercial nerve plexus of the papillary dermis) (2). The cutaneous nerves contain only sensory or autonomic nerve bers. The sensory nerves conduct aerent impulses from the periphery to their cell body in the dorsal root ganglia, or, for the face, to the trigeminal ganglion. Cutaneous sensory neurons are unipolar; one branch of a single axon extends from the cell body toward the periphery, and the second one extends toward the central nervous system. As many as 1000 aerent nerve bers may innervate 1 cm2 of the skin. The sensory innervation follows well-dened segments (i.e., dermatomes); however, an overlapping innervation may occur. Autonomic postganglionic bers are codistributed with the sensory nerves until they arborize into the terminal autonomic plexus, which supplies skin glands, blood vessels, and arrector pili muscles. As the peripheral nerves approach the skin and branch, the number of myelinated bers decreases and the epineural connective tissue sheaths that surround the larger nerve trunks disintegrate (Fig. 1). In the dermis, perineural layers and the endoneurium envelop the primary neural functional unit (i.e., the Schwann cellaxon complex). The multilayered perineurium comprises attened cells and collagen bers, and serves mechanical as well as barrier functions. The perineural cells are surrounded by a basement membrane, possess intercellular tight junctions of the zonula occludens type, and show high pinocytotic activity. The endoneurium is composed of ne connective tissue bers, broblasts, capillaries, and, occasionally, a few histiocytes and mast cells. The endoneural tissue is separated from the Schwann cells by a basement membrane and subserves nutritive functions for the Schwann cells (3). The Schwann cellaxon complex consists of the cytoplasmic processes of the neurons that propulse the action potentials and the enveloping Schwann cells. The peripheral axon may be myelinated or unmyelinated. In myelinated nerve bers, the Schwann cell membranes wrap themselves around the axon repeatedly, thus forming the regular concentric layers of the myelin sheath. In nonmyelinated nerves, several axons are found in the

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Figure 1 Larger subcutaneous nerve trunk with disintegration of epineural connective tissue sheaths (E). Perineural layers (P) and the endoneurium envelop the primary neural functional unit (i.e., the Schwann cellaxon complex). Routine histology, H and E staining.

cytoplasm of Schwann cells, forming characteristic polyaxonal units (Fig. 2). However, these axons are not enclosed beyond the initial stage of enfolding and therefore are invested with only a single or a few layers of Schwannian plasma membranes without formation of thick lipoprotein sheaths (4). This intimate relationship implies a crucial role of Schwann cells for the development, mechanical protection, and function of the nerves. In addition, the Schwann cells serve as a tube to guide regenerating nerve bers. The axons are long and thin cytoplasmic extensions of the neurons that may reach a length of more than 100 cm. Ultrastructurally, the cytoplasm of the axons contains neurolaments belonging to the intermediate lament family, mitochondria, longitudinally orientated endoplasmic reticulum, neurotubuli, and small vesicles and granules that represent packets of neurotransmitters and neuropeptides (3). In general, unmyelinated-type C-bers constitute autonomic and sensory bers whereas myelinated-type A-bers correspond to a subgroup of sensory neurons. The myelinization of the axons allows for a high conduction velocity of 470 m/sec compared to a lower speed of 0.52 m/sec in the unmyelinated bers. The sensory myelinated bers are further divided based on their diameter and conduction speed into rapidly conducting A-subcate-

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Figure 2 In nonmyelinated nerves, several axons are found in the cytoplasm of a Schwann cell forming the polyaxonal unit. The axons contain secretory granules. A basement membrane (arrow) separates the Schwann cellaxon complex and endoneural tissue (E). Electron microscopy.

gories and slowly conducting A-subcategories. Because the conduction velocity of the action potentials of individual axons remains constant and myelinated and unmyelinated bers show no overlap, this feature is a useful tool in the classication of sensory nerve bers. Several neurophysiological experiments have shown that the A-bers conduct tactile sensitivity, whereas A-bers and C-bers transmit temperature, noxious sensations, and itch (5). The detection of the ne nerve bers can be achieved by impregnation with silver salts, vital and in vitro methylene blue staining, and histochemical reaction for acetylcholinesterase (6). Immunohistochemistry allows for visualization of constitutional and structural proteins in the peripheral nervous system. Protein gene product 9.5 (PGP 9.5) is a pan neuronal cytoplasmic protein that is invariably expressed over the entire length of the axons (7). Other less sensitive neuronal markers are neurolament proteins (NFs) (Fig. 3; see color insert), neuron-specic enolase (NSE), nerve growth receptor (NGF), synaptophysin (membrane protein of neural vesicles), nerve cellspecic clathrin (LCb subunit, neuronal-coated vesicles involved in receptormediated endocytosis), and calcium-binding S-100 proteinthe latter being also expressed in Schwann cells. Myelinated nerve bers stain for myelin basic protein (a component of the myelin sheath), N-CAM (CD56), leu 7 (CD57, a marker for a subset of natural killer lymphocytes that crossreacts with a myelin-related glycoprotein) (8).

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Figure 3 Dermal nerve bers as stained for neurolaments (arrows) in close proximity to blood vessels and inammatory cells (star). Immunoperoxidase staining. (See color insert.)

In the upper dermis, small myelinated nerve bers are only surrounded by a monolayer of perineural cells and a small endoneurium whereas in thin peripheral branches of unmyelinated nerve bers, perineural sheaths are absent (9). After losing their myelin sheaths, cutaneous nerves terminate either as free nerve endings or in association with receptors, such as Merkel cells or special nerve end organs. Beneath the epidermis, nerve bers obtain a coiled conguration and multiple varicosities. According to the concept of Cauna (10), the terminal part of cutaneous nerve bers ramies and forms brushlike penicillate free nerve endings. Skin nerves terminate not only in the subepidermal connective tissues or close to skin appendages, but also intraepidermally (Fig. 4; see color insert). Visualization of intraepidermal nerves is not possible on light microscopy. However, silver impregnation techniques and immunohistochemistry have clearly identied nerve bers in all layers of the epidermis. PGP 9.5 proved to be the most sensitive immunomarker for intraepidermal nerve bers. Other proteins such as NF, NSE, N-CAM, clathrin, nerve growth factor, pituitary adenylate cyclase-activating polypeptide (PACAP), and gMSH show a more variable expression (1114). Some of the nerve bers have been shown to go straight up to the supercial layers; others follow a more tortuous pattern or show some branching (Fig. 5; see color insert).

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Figure 4 Small sensory nerve ber (arrow) as visualized by the expression of CGRP in the papillary dermis. Positive immunouorescence staining for CGRP depicted in red pseudocolors. Confocal laser scanning microscopy. (See color insert.)

Figure 5 Intraepidermal nerve ber as immunostained for PGP 9.5 (arrows). The tortuous course can be best demonstrated by optical sectioning using confocal laser scanning microscopy (optical sections ac). Keratinocytes (K), junctional zone of epidermis, and dermis (stars). The positive immunouorescence staining is depicted in red pseudocolors. (See color insert.)

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Intraepidermal nerves may occur at every site of the hairy and glabrous skin. The density of intraepidermal nerves, as evaluated by immunoreactivity for PGP 9.5, is within the range of 2.99.6 per 1000 basal keratinocytes (14). The highest number of intraepidermal nerves has been found in facial skin (15). According to some authors, the number of nerves seems to decrease from the trunk to the distal parts of the limbs (13), whereas others found the opposite. Apart from using detection systems with dierent sensitivities, sun exposure, age, and other factors may account for the conicting results. For example, intraepidermal nerve bers may not be distributed evenly in normal human skin but may be present focally so that the epidermis may lack bers in small biopsy specimens. In general, immunostaining of the distal parts of nerves for neuropeptides is dicult because retrograde axonal transport results in low peripheral concentrations (16). In vivo pretreatment of the skin with the neuropharmacological agent, capsaicin, induces loss of most, but not all, of the epidermal bers staining, suggesting that these are sensory bers of the unmyelinated C-type (7). However, in addition to sensory functions, intraepidermal nerve bers fulll neurotrophic functions on keratinocytes and enable the neuroimmunological modulation of Langerhans cell functions (17,18). B. Sensory Receptors

The sensory receptors of the skin can be divided into free and corpuscular nerve endings. Corpuscular endings contain both neural and nonneural components and are of two main types: nonencapsulated Merkels touch spot and encapsulated receptors (19,20). In the past, many of the free and corpuscular nerve endings in humans and animals have been associated with specic sensory functions according to their distribution and complex architecture. Because it is dicult to identify specic sensory modalities within individual terminal axons by means of neurophysiological techniques, many of the assumptions remain speculative (21,22). The free nerve endings of nonmyelinated C-bers and, to some extent, of small myelinated A-bers are widely distributed throughout the body and form the majority of the sensory receptors. In humans, the free nerve endings do not represent naked axons but remain covered by small cytoplasmic extensions of Schwann cells and a basement membrane that may show continuity with that of the epidermis (23). The terminal of the axon may be beaded and, besides mitochondria, harbors vesicles and granules lled with sensory neuropeptides. The free nerve endings of polymodal C-bers are chemosensitive, mechanosensitive, and thermosensitive, and mediate multiple sensory modalities such as touch, temperature, pain, and itch. Alterations of sensory nerves,

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such as axonal deposition of polyvinylpyrrolidone (PVP) (24) and hydroxyethyl starch (25,26), will induce a highly characteristic burning pruritus of noninamed skin. Micrographic recordings have clearly shown that the sensation of itch is transmitted by a subpopulation of unmyelinated Cpolymodal nociceptive neurons (27). The terminals of nociceptive neurons are free nerve endings in the dermis and epidermis (Figs. 4 and 5; see color insert). Interestingly, after removing the epidermis, itch is not inducible, whereas pain still can be provoked. It can be speculated that rubbing, scratching, and pressing will temporarily relieve the sensation of itch by impairment of supercial intraepidermal nociceptors responsible for the generation of itch. In the epidermis, innervation patches show up, which can be identied in confocal microscopy as one morphological terminal eld coming from the same dermal nerve bundle (13). Physiologically, two-point discrimination of itch may be attributed to this distribution mode of intraepidermal nerve bers (14). The sensory neurons express specic receptors for histamine, serotonin, prostaglandin, and bradykinin. It can be hypothesized that pruritogenic agents specically bind to itch receptors on the surface of chemosensitive nerve endings and thereby cause ring of the axons. The existence of specic binding sites on chemosensitive neurons may account for the observation that experimental pruritus induced by intradermal histamine injection, but not of pruritus induced by mucunain, is blocked by systemically administered H1 antagonists (28). Others, such as vanilloid receptors, bind exogenous capsaicin, are heat-sensitive, and can be sensitized by protons (see also Chapter 28). Only recently, a proteinase-activated receptor 2 (PAR2) which is activated by trypsin and related proteases, including mast cell tryptasehas been localized to sensory nerve bers (29). The activation of these receptors leads to depolarization of nerve bers and release of neuropeptides. C. Sensory Neuropeptides

Skin nerves express a battery of biologically active peptides that are synthesized in the neural cell body of the dorsal root ganglions, subjected to posttranslational modication to the active form, packed in storage granules, and transferred to the nerve terminals in the skin. Finally, depolarization of peripheral nociceptive nerve endings will release neuropeptides from the neurosecretory granules (30). In dermal nerve bers, staining has been demonstrated for the tachykinins substance P (SP) and neurokinin A (NKA), calcitonin generelated peptide (CGRP), vasoactive intestinal peptide (VIP), galanin (Gal), g-mela-

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nocyte-stimulating hormone (g-MSH), atrial natriuretic peptide (ANP), peptide histidine methionine (PHM), neurotensin (NT), and dynorphin (Dyn) (18,30,31). Epidermal nerves have shown immunoreactivity for SP, NKA, CGRP, and, more variably, for neuropeptide Y (NPY), VIP, somatostatin (Som), and h-endorphin (11,14). Some of the immunohistochemical ndings are still contradictory, but the list of neuropeptides is ever-increasing. A dierential expression pattern has been described for sensory and autonomic nerve bers (Fig. 6; see color insert). Although SP, NKA, CGRP, VIP, Som, and Gal have been demonstrated in sensory nerves, VIP, PHM, and NPY seem to occur in autonomic nerves. More than one sensory neuropeptide may be colocalized in a single nerve ber whereas neuropeptides in the autonomic system occur together with classical neurotransmitters. However, many of these neuropeptides are not only expressed in skin nerves but may be derived from keratinocytes, Merkel cells, endothelial cells, broblasts, and immune cells (18). Neuropeptides diuse to specic receptors on blood vessels, skin glands, epidermis, connective tissue cells, and immune cells where they mediate biological responses. In contrast to neurotransmitters, reuptake is not the major mechanism of inactivation. The action of neuropeptides is limited by

Figure 6 Expression of sensory neuropeptides within axons of dierent nerve bers (ac) suggesting a variable codistribution of autonomic and sensory bers. Positive immunouorescence staining for CGRP depicted in red pseudocolors. Confocal laser scanning microscopy. (See color insert.)

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hydrolytic enzymes including tryptase, neutral endopeptidase, and angiotensin-converting enzyme (30). D. Neurogenic Inflammation and Neuroimmunology

The function of sensory nerves is not only to conduct nociceptive information to the central nervous system for further processing; sensory bers also have the capacity to respond directly to noxious stimuli by initiating a local inammatory reaction. Noxious stimulation of polymodal C-bers produces action potentials that travel centrally to the spinal cord and, in a retrograde fashion, along the ramifying network of axonal processes. The antidromic impulses that start from the branching points cause secretion of neuropeptides stored along the peripheral nerves. A consequence of their eects on vessels and resident inammatory cells in close proximity is arteriolar vasodilation (are reaction) and increased permeability of the postcapillary venules (whealing). Neurogenic inammation can be elicited by antidromic electrical stimulation of sensory nerves and administration of histamine or various neuropeptides, and can be abolished by denervation, capsaicin, and local anesthetics (32). Overall, the nature of the are and wheal reaction is far more complex than previously thought. Apart from direct initiation of vasodilation, and leakage of plasma and inammatory cells, neuropeptides may exert their eects via the activation of mast cells (33). Ultrastructural and more recent immunohistochemical ndings suggest a close proximity of mast cells to neuropeptide-containing nerves (34,35). Hence, neuropeptide release from nerves has been suggested to induce mast cell degranulation. However, even potent mast cell-activating neuropeptides induce histamine release in concentrations that seem not to be present in vivo (see also Chapter 15). Other experiments and stimulation of nerves in mast cell-decient mice support the notion that mast cells are not essential for neurogenic inammation (32). The observation of histamine-immunoreactive nerves in the skin of Sprague Dawley rats even suggests a more direct route of cutaneous histamine eects, mediated exclusively by the peripheral nervous system (36). Recent studies strongly suggest an interaction between the nervous system and the immune system far beyond that described for the classical model of axon are reaction (37). The close anatomical association of cutaneous nerves with inammatory and immunocompetent cells and the well-recognized immunomodulatory eect of many neuropeptides indicate the existence of a neuroimmunological network. Nerves have been described in the Peyers patches and the spleen. In the skin, lymphocytes are regularly found in close proximity to small nerve bers (Metze, personal observation). This anatomical association is consistent with the capacity of SP to inuence

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T-cell proliferation and homing (38,39). By the release of CGRP and substance P, some cutaneous nerve bers may activate polymorphonuclear cells (40) and stimulate macrophages (41). Secretory neuropeptides further stimulate endothelial cells to transport preformed adhesion molecules, such as P-selectin and E-selectin, from intracellular WeibelPalade bodies to the endothelial surface and thereby enhance chemotactic functions (42). Moreover, substance P stimulates the production of proinammatory as well as immunomodulating cytokines and, conversely, cytokines such as interleukin (IL)-1 enhance the production of SP in neurons (43,44). Nerve bers are also intimately associated with monocytoid cells, including Langerhans cells. Immunohistochemical results strongly suggest that intraepidermal nerve bers are capable of depositing SP, CGRP, and MSH at or near Langerhans cells. Via receptor binding, neuropeptides inhibit the function of immunocompetent cells and induce tolerance to potent contact allergens (17,45). In addition, subepidermal and epidermal nerve bers may recruit Langerhans cells and, vice versa, Langerhans cells induce nerve dierentiation via interleukin-6, nerve growth factor, and broblast growth factor (FGF). These ndings strongly support the concept of an interaction between the immune system and the neuroendocrine system in the skin. The complex innervation of the skin with sensory nerve bers and the potential release of a variety of neuropeptides imply a participation of neuroimmunological mechanisms in many skin diseases and related symptoms including itch.

E. 1.

Itchy Skin Diseases Atopic Dermatitis

Pruritus is a cardinal symptom of atopic dermatitis; still, its mechanism and association with the cutaneous nervous system have not been fully understood. Increased numbers of neurolament-positive, CGRP-positive, and SPpositive nerve bers were observed in the papillary dermis, at the dermal epidermal junction, in the epidermis, and around sweat glands (4649). Dierent densities of PGP 9.5-positive peripheral nerves were found in acute, lichenied, and prurigo lesions in comparison to noninvolved skin of patients with atopic dermatitis (50). Electron microscopical investigation of lesional skin of atopic patients revealed hyperplastic nerve bers with enlarged axons (49,50) possibly due to an increased release of nerve growth factor and NT-4 by basal keratinocytes (51). In addition, axons focally lost their surrounding cytoplasm of Schwann cells and thus communicated directly with dermal cells. These axons con-

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tained many mitochondria and neurolaments, with abundant neurovesicles conrming a high content of neuropeptides. In general, an increase of sensorybut a decrease of adrenergic autonomic nerve bers was observed, indicating a dierential role of primary aerent and autonomic nerve bers for the pathophysiology of pruritus in atopic dermatitis (47). Apart from alterations in the neuropeptide prole of nerve bers, their receptors as well as neuropeptide-degrading enzymes may play a crucial role in the pathophysiology of pruritus in atopic dermatitis. Because PAR-2 immunoreactivity is enhanced in atopic dermatitis patients (M. Steinho, unpublished observation), it can be hypothesized that tryptase may activate PAR-2 in inammatory conditions when there is mast cell inltration and degranulation. Thus, PAR-2 may be involved in the pruritus of patients with atopic dermatitis, explaining why atopic patients show a rather weak response following treatment with antihistamines. Moreover, IL-2 and other cytokines, as released from various cutaneous and immune cells during inammation, have been demonstrated to induce pruritus and activate neuropeptide release from sensory nerves in the skin of patients with atopic dermatitis (52,53). 2. Dry Skin (Xerosis)

Itch in the dry skin of older patients, or in atopic patients, is a common symptom that may be attributed to a high density of nerve C-bers within the epidermis. Only recently, animal studies showed that dry skin induces the expression of nerve growth factor in keratinocytes, leading to the elongation and penetration of sensory nerve bers into the epidermis (Takamori et al., International Workshop for Study of Itch, Singapore, 2001). In addition, dry skin reects an increased transepidermal water loss due to an incomplete arrangement of intercellular lipid lamellae in the stratum corneum (54,55). This impaired barrier function in the skin supports the entrance of irritants and itchy agents (56). Additionally, pH changes within the skin can be assumed to activate itch receptors (57).

F.

Prurigo Nodularis

Prurigo nodularis is a distressing condition characterized by intensely pruritic, lichenied, or excoriated papules and nodules rst described by Hyde in 1909. It represents a cutaneous reaction pattern to repeated rubbing or scratching caused by pruritus of a dierent origin, rather than a disease per se (28). In fact, prurigo nodularis is common in patients with atopic dermatitis and other itchy dermatoses such as scabies, dry skin, and bullous pemphigoid. In addition, prurigo nodularis often signals systemic diseases.

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Histologically, prurigo nodularis lesions are characterized by compact hyperkeratosis and a remarkable irregular epidermal hyperplasia. The papillary dermis shows brosis and a perivascular lymphocytic inltration with eosinophils and scattered melanophages. Morphological and immunohistochemical investigations reveal variably prominent S-100-positive dermal nerve bundles as well as neural hyperplasia (58,59). An increased content of SP, CGRP, and VIP in prurigo nodularis may stimulate the proliferation of keratinocytes and broblasts (6062). Furthermore, SP is capable of upregulating the production of proinammatory cytokines such as IL-1a, IL-1h, and IL-8. SP also participates in leukocyte recruitment by the induction of adhesion molecule upregulation (18). Overexpression of neuropeptides may explain the pathological ndings and contribute to the sensation of itch; yet, the basic understanding of the itchscratch circle in prurigo nodularis remains an enigma. (For further details, see Chapter 28.)

REFERENCES
Metze D, Luger T. Nervous system in the Skin. In: Freinkel RK, Woodley D, eds. Biology of the Skin. London: Parthenon Publishing, 2000:153. 2. Sinclair DC. Normal anatomy of sensory nerves and receptors. In: Jarrett A, ed. The Physiology and Pathophysiology of the Skin: The Nerves and Blood Vessels. Vol. 2. London: Academic Press, 1973:347. 3. Winkelmann RK. Cutaneous nerves. In: Zelickson AV, ed. Ultrastructure of Normal and Abnormal Skin. Philadelphia: Lea and Febiger, 1967:202. 4. Breathnach AS. Electron microscopy of cutaneous nerves and receptors. J Invest Dermatol 1977; 69:8. 5. Lynn B. Cutaneous sensation. In: Goldsmith LA, ed. Physiology, Biochemistry, and Molecular Biology of the Skin. New York: Oxford University Press, 1991:779. 6. Montagna W, Kligman AM, Carlisle KS. Atlas of Normal Human Skin. New York: Springer Verlag, 1992. 7. Karanth SS, Springall DR, Kuhn DM, et al. An immunocytochemical study of cutaneous innervation and the distribution of neuropeptides and protein gene product 9.5 in man and commonly employed laboratory animals. Am J Anat 1991; 191:369. 8. Wallace ML, Smoller BR. Immunohistochemistry in diagnostic dermatopathology. J Am Acad Dermatol 1996; 34:163. 9. Bourlond A, Winkelmann RK. Nervous pathways in papillary layer of human skin: an electron microscopic study. J Invest Dermatol 1966; 47:193. 10. Cauna N. Fine morphological characteristics and microtopography of the free nerve endings of the human digital skin. Anat Rec 1980; 198:643. 11. Reilly DM, Ferdinando D, Johnston C, et al. The epidermal nerve bre network: characterization of nerve bres in human skin by confocal microscopy and assessment of racial variations. Br J Dermatol 1997; 137:163. 1.

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12. Steinho M, McGregor GP, Radle-Schlimme A, et al. Identication of pituitary adenylate cyclase activating polypeptide (PACAP) and PACAP type 1 receptor in human skin: expression of PACAP-38 is increased in patients with psoriasis. Regul Pept 1999; 80:49. 13. Johansson O, Wang L, Hilliges M, et al. Intraepidermal nerves in human skin: PGP 9.5 immunohistochemistry with special reference to the nerve density in skin from dierent body regions. J Peripher Nerv Syst 1999; 4:43. 14. Kawakami T, Ishihara M, Mihara M. Distribution density of intraepidermal nerve bers in normal human skin. J Dermatol 2001; 28:63. I, Descombes C, Breton L. Human sensory epidermal innervation: den15. Besne sity variation according to the age and anatomical sites. Ann Dermatol Venereol 2002; 129:1S329. 16. Ljungberg A, Johansson O. Methodological aspects on immunohistochemistry in dermatology with special reference to neuronal markers. Histochem J 1993; 25:735. 17. Hosoi J, Murphy GF, Egan CL, et al. Regulation of Langerhans cell function by nerves containing calcitonin gene-related peptide. Nature 1993; 363:159. 18. Scholzen T, Armstrong CA, Bunnett NW, et al. Neuropeptides in the skin: interactions between the neuroendocrine and the skin immune systems. Exp Dermatol 1998; 7:81. 19. Munger BL, Ide C. The structure and function of cutaneous sensory receptors. Arch Histol Cytol 1988; 51:1. 20. Halata Z. The mechanoreceptors of the mammalian skin: ultrastructure and morphological classication. Vol. 5. In: Brodal A, ed. Advances in Anatomy, Embryology and Cell Biology. New York: Springer Verlag, 1975:1. 21. Hensel H, Bomann KKA. Aerent impulses in cutaneous sensory nerves in human subjects. J Neurophysiol 1960; 23:564. 22. Iggo A, Young DW. Cutaneous thermoreceptors and thermal nociceptors. In: Kornhuber H, ed. The Somatosensory System. Stuttgart: Georg Thieme, 1975: 5. 23. Orfanos CE, Mahrle G. Ultrastructure and cytochemistry of human cutaneous nerves. J Invest Dermatol 1973; 61:108. 24. Thivolet J, Leung TK, Duverne J, et al. Ultrastructural morphology and histochemistry (acid phosphatase) of the cutaneous inltration by polyvinylpyrrolidone. Br J Dermatol 1970; 83:661. 25. Metze D, Reimann S, Szepfalusi Z, et al. Persistent pruritus after hydroxyethyl starch (HES) infusiona result of long-term storage in cutaneous nerves. Br J Dermatol 1997; 136:553. 26. Sta nder S, Szepfalusi Z, Bohle B, et al. Dierential storage of hydroxyethyl starch (HES) in the skinan immunoelectron microscopical long-term study. Cell Tissue Res 2001; 304:261. 27. Schmelz M, Schmidt R, Bickel A, et al. Specic C-receptors for itch in human skin. J Neurosci 1997; 17:8003. 28. Bernhard JD. Itch: Mechanisms and Management of Pruritus. New York: McGraw-Hill, Inc., 1994. 29. Steinho M, Vergnolle N, Young SH, et al. Agonists of proteinase-activated

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30. 31. 32. 33. 34.

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receptor 2 induce inammation by a neurogenic mechanism. Nat Med 2000; 6:151. Eedy DJ. Neuropeptides in skin. Br J Dermatol 1993; 128:597. Lotti T, Hautmann G, Panconesi E. Neuropeptides in skin. Am Acad Dermatol 1995; 33:482. Baraniuk JN. Neuropeptides in the skin. In: Bos J, ed. The Skin Immune System. 2nd ed. Boca Raton: CRC Press, 1997:311. Foreman J, Jordan C. Histamine release and vascular changes induced by neuropeptides. Agents Actions 1983; 13:105. Weisner-Menzel L, Schultz B, Vakilzadeh F, et al. Electron microscopic evidence for a direct contact between nerve bres and mast cells. Acta DermVenereol 1981; 61:465. Skotsch G, Savitt JM, Jacobovitz DM. Suggestive evidence for a functional unit between mast cells and substance P bers in the rat diaphragm and mesentery. Histochemistry 1985; 82:5. Johansson O, Virtanen M, Hilliges M. Histaminergic nerves demonstrated in the skin. A new direct mode of neurogenic inammation? Exp Dermatol 1995; 4:93. Ansel JC, Kaynard AH, Armstrong CA, et al. Skinnervous system interactions. J Invest Dermatol 1996; 106:198. Stanisz AM, Scicchitano R, Dazin P, et al. Distribution of substance P receptors on murine spleen and Peyers patch T and B cells. J Immunol 1987; 139:749. Zhu LP, Chen D, Zhang SZ, et al. Observation of the eect of substance P on human T and B lymphocyte proliferation. Immunol Commun 1984; 13:457. Payan DG, Levine JD, Goetzl EJ. Modulation of immunity and hypersensitivity by sensory neuropeptides. J Immunol 1984; 132:1601. Lotz M, Vaughan JH, Carson DA. Eect of neuropeptides on production of inammatory cytokines by human monocytes. Science 1988; 241:1218. Smith CH, Barker JN, Morris RW, et al. Neuropeptides induce rapid expression of endothelial cell adhesion molecules and elicit granulocytic inltration in human skin. J Immunol 1993; 151:3274. Freidin M, Kessler JA. Cytokine regulation of substance P expression in sympathetic neurons. Proc Natl Acad Sci USA 1991; 88:3200. Ansel JC, Brown JR, Payan DG, et al. Substance P selectively activates TNFalpha gene expression in murine mast cells. J Immunol 1993; 150:4478. Grabbe S, Bhardwaj RS, Steinert M, et al. Alpha-melanocyte stimulating hormone induces hapten-specic tolerance in mice. J Immunol 1996; 156:473. Pincelli C, Fantini F, Massimi P, et al. Neuropeptides in skin from patients with atopic dermatitis: an immunohistochemical study. Br J Dermatol 1990; 122:745. Tobin D, Nabarro G, de la Faille HB, et al. Increased number of immunoreactive nerve bers in atopic dermatitis. J Allergy Clin Immunol 1992; 90:613. Ostlere LS, Cowen T, Rustin MH. Neuropeptides in the skin of patients with atopic dermatitis. Clin Exp Dermatol 1995; 20:462. Urashima R, Mihara M. Cutaneous nerves in atopic dermatitis. A histological, immunohistochemical and electron microscopic study. Virchows Arch 1998; 432:363.

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50. Sugiura H, Omoto M, Hirota Y, et al. Density and ne structure of peripheral nerves in various skin lesions at atopic dermatitis. Arch Dermatol Res 1997; 289:125. 51. Albers KM, Wright DE, Davis BM. Overexpression of nerve growth factor in epidermis of transgenic mice causes hypertrophy of peripheral nerve system. J Neurosci 1994; 14:1422. , et al. Itch and inammation 52. Wahlgren CF, Tengvall Linder M, Ha germark O induced by intradermally injected interleukin-2 in atopic dermatitis patients and healthy subjects. Arch Dermatol Res 1995; 287:572. 53. Darsow U, Scharein R, Bromm B, et al. Skin testing of the pruritogenic activity of histamine and cytokines (interleukin-2 and tumor necrosis factor-alpha) at the dermalepidermal junction. Br J Dermatol 1997; 137:415. 54. Werner Y, Lindberg M, Forslind B. Membrane-coating granules in dry noneczematous skin of patients with atopic dermatitis. A quantitative electron microscopic study. Acta Derm-Venereol 1987; 67:385. 55. Fartasch M, Diepgen TL. The barrier function in atopic dry skin. Disturbance of membrane-coating granule exocytosis and formation of epidermal lipids? Acta Derm-Venereol Suppl (Stockholm) 1992; 176:26. 56. Wahlgren CF. Itch and atopic dermatitis. J Dermatol 1999; 26:770. 57. Caterina MJ, Schumacher MA, Tominaga M, et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997; 389:816. 58. Harris B, Harris K, Penneys NS. Demonstration by S-100 protein staining of increased numbers of nerves in the papillary dermis of patients with prurigo nodularis. J Am Acad Dermatol 1992; 26:56. 59. Sandbank M. Cutaneous nerve lesions in prurigo nodularis. J Cutan Pathol 1976; 3:125. 60. Nilsson J, von Euler AM, Dasgaard C-J. Stimulation of connective tissue cell growth by substance P and substance K. Nature 1985; 315:61. 61. Tanaka T, Danno K, Ikai K, et al. Eect of substance P and substance K on the growth of cultured keratinocytes. J Invest Dermatol 1988; 90:399. 62. Abadia Molina F, Burrows NP, Russel Jones R, Terenghi G, Polak JM, et al. Increased sensory neuropeptides in nodular prurigo: a quantitative immunohistochemical analysis. Br J Dermatol 1992; 127:344.

9
Substance P and Itch
Tsugunobu Andoh and Yasushi Kuraishi
Toyama Medical and Pharmaceutical University, Toyama, Japan

I.

INTRODUCTION

Substance P (SP), an undecapeptide belonging to the tachykinin family, has a widespread distribution in the central and peripheral nervous system. Although SP is present in primary aerents and involved in nociceptive transmission in the dorsal horn, intradermal injection of SP elicits itch, rather than pain, in human subjects (1,2). SP may be primarily released not only from peripheral terminals of primary sensory neurons, but also from keratinocytes in stressed conditions. From indirect evidence, it has been speculated that SP is involved in hemodialysis-associated pruritus (3) and the pruritus of atopic dermatitis (4) and psoriasis (5). The role of SP as an itch mediator is described in this chapter.

II.

SP-INDUCED ITCH IN HUMANS

Intradermal injection of SP as well as histamine elicits an itch sensation in humans (2). SP releases histamine from cutaneous mast cells through calciumdependent processes (6). SP-induced itch is suppressed by pretreatment with the histamine liberator compound 48/80 and with the H1 histamine receptor antagonist chlorcyclidine (18). These ndings suggest the involvement of histamine released from mast cells (Fig. 1). However, since itch elicited by a
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Figure 1 Possible mechanisms of substance P-induced itch and scratch. Substance P (SP) may act directly on primary aerents. SP acts on mast cells to release histamine, in which NK1 tachykinin receptors (NK1R) are not involved. SP acts on NK1R of keratinocytes to release leukotriene B4 (LTB4), which elicits scratching. Keratinocytes may produce various mediators, such as SP itself, nitric oxide (NO), nerve growth factor (NGF), platelet-activating factor (PAF), vasoactive intestinal polypeptide (VIP), enkephalin (ENK), and cytokines, some of which may also be involved in SP-induced scratching. NK1R is also present in Langerhans cells, macrophages, and endothelial cells, but the role of these cells in SP-induced itch and/or scratch remains unclear.

higher dose of SP is not aected by the H1 antagonist, other mechanisms may also be involved (2). Additional evidence for the importance of substance P in itch is that repeated treatment with capsaicin, a substance P depletor, inhibits experimental itch induced by histamine (7) and by capsaicin itself (8). It alleviates pruritus of patients with psoriasis (5), notalgia paresthetica (9), and uremic pruritus in hemodialysis patients (10) (see Chapter 28).

III.

SP-INDUCED SCRATCHING IN MICE

An injection of SP into the rostral back elicits scratching of the injection site by the hind paws in mice, while algogenic agents such as capsaicin and

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formalin do not elicit scratching, suggesting that the scratching is not a pain-related behavior in mice (11). SP-induced scratching is suppressed by repeated treatment with capsaicin and by pretreatment with the opioid antagonist naloxone (12). Similarities in responses to capsaicin and opioid antagonist between human itching and murine scratching suggest that SPinduced scratching is an itch-associated response.

IV.

SP-INDUCED ITCH, MAST CELL, AND HISTAMINE

In human subjects, SP elicits itching by histamine-dependent and -independent mechanisms (2). In mice, especially the ICR strain that responds to histamine, the H1 histamine receptor antagonist chlorpheniramine does not aect SP-induced itch-associated response at a dose that inhibits histamineinduced scratching (13). In addition, SP elicits scratching in mast cell-decient (WBB6F1 W/Wv) mice as well as control (WBB6F1 +/+) mice (12). In mice, SP may elicit itch-associated responses mainly by mast cell/ histamine-independent mechanisms.

V.

SP-INDUCED ITCH AND TACHYKININ RECEPTORS

SP belongs to the tachykinin family, which includes neurokinin A and neurokinin B (14). These tachykinins bind to tachykinin receptors that have three subtypes, NK1 (descending order of anity, SP > neurokinin A>neurokinin B), NK2 (neurokinin A>neurokinin BSP), and NK3 (neurokinin B>neurokinin A>SP) (15). An intradermal injection of the NK1 receptor agonist GR73632, but not the NK2 receptor agonist GR64349 and the NK3 receptor agonist senktide, elicits itch-associated responses in mice. In addition, SP-induced response is inhibited by the NK1 receptor antagonists L-668,169 and spantide, but not the NK2 receptor antagonist L-659,877. These results suggest that SP elicits scratching through the activation of NK1 tachykinin receptors. The immunosuppressant cyclosporine A inhibits pruritus of patients with atopic dermatitis (16). Immunosuppressive action may be responsible for antipruritic eect. However, cyclosporine A was reported to have NK1 receptor antagonistic activity (17). It is also possible that this action plays a role in the antipruritic eect. Since NK1 tachykinin receptors are present in primary sensory neurons (18), it is possible that intradermal injection of SP acts directly on primary aerents (Fig. 1). However, the expression level of NK1 tachykinin receptors in the dorsal root ganglia is as low as in the cerebellum (18). In the

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skin, there are several NK1 receptor-expressing cells, including keratinocytes (1921), Langerhans cells (22), endothelial cells (23), and macrophages (24) (Fig. 1). Endogenous mediators released from the cutaneous cells after SP injection may play a bigger role in the induction of itch-associated responses (see below). Mast cells also express NK1 and NK2 receptors. Neurokinin A stimulates NK2 receptors to release histamine, whereas the amount of histamine released by stimulation of NK1 receptors is substantially less than that of NK2 receptors (25). On the other hand, SP was reported to activate directly G protein in mast cells, which may result in the release of histamine through a receptor-independent process (26). Thus, NK1 tachykinin receptors may not play a key role in histamine-dependent mechanisms of SPinduced itching.

VI.

SP-INDUCED ITCH AND ARACHIDONIC ACID METABOLITES

In human subjects, prostaglandin E2 (PGE2) is a weak pruritogen and prolongs experimentally induced itch (27,28). Aspirin inhibits itching of patients with polycythemia vera (27). In mice, although an intradermal injection of PGE2 alone does not elicit scratching (29), it enhances itch-associated response induced by serotonin (30). In contrast to PGE2, leukotriene B4 (LTB4) elicits apparent scratching in mice (29). Eective doses are much less than those of SP and histamine, but doseresponse curve is reverse V shape, and higher doses show negligible eects in mice (30) and humans (31). Scratching elicited by intradermal LTB4 is suppressed by the LTB4 antagonist 5-[2-(2-carboxyethyl)-3-(6-(para-methoxyphenyl)-5E-hexenyl) oxyphenoxy] valeric acid (ONO-4057) (30). LTB4 may elicit scratching through the activation of LTB4 receptors, although LTB4 can directly activate VR1 capsaicin receptors (32). SP-induced scratching is inhibited by the phospholipase A2 inhibitor arachidoryltriuoromethyl ketone at a dose that inhibits the SP-induced production of PGE2 and LTB4 (33). There are two major enzymes, cyclooxygenase (COX) and 5-lipoxygenase (5-LOX), for metabolizing arachidonic acid. The 5-LOX inhibitor zileuton, but not COX inhibitors (indomethacin and diclofenac), suppresses SP-induced scratching, suggesting that 5-LOX metabolites are involved in the SP action. Furthermore, the LTB4 antagonist ONO-4057, but not the LTC4/D4/E4 antagonist pranlukast, suppressed SP-induced scratching (19). Intradermal injections of arachidonic acid (unpublished observation) and LTB4, but not LTD4, elicit scratching.

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LTB4 is increased in the skin of patients with pruritic diseases such as atopic dermatitis and psoriasis. The antihistamine azelastine alleviates pruritus of chronic hemodialysis patients (34,35). This agent inhibits SP-induced scratching and LTB4 production and more markedly inhibits LTB4induced scratching (33). Another potent antihistamine, emedastine, is eective against pruritus of conditions such as atopic dermatitis and prurigo (36,37). It inhibits more potently SP- and LTB4-induced scratching than histamine-induced scratching (13). These results suggest that LTB4 receptor system in the skin is involved in SP-induced scratching (Fig. 1). Some antihistamine may alleviate pruritus at least partly through the inhibition of production and/or action of LTB4. An intradermal injection of SP induces LTB4 production through NK1 tachykinin receptor in mouse skin (19). SP can act on several kinds of cutaneous cells such as keratinocytes (20) and mast cells (6). Cutaneous mast cells may release LTB4 (38). However, LTB4 receptor antagonist inhibits SPinduced scratching in mast cell-decient mice (19). Therefore, the mast cells may not be the primary source of pruritogenic LTB4 in the skin. SP acts on mouse keratinocytes to produce LTB4 through NK1 tachykinin receptor (19). Considering that keratinocytes are the largest cell group in the epidermis, epidermal keratinocytes may be the primary site of the LTB4 production after intradermal SP. Itch signals are conveyed mainly by C-bers (39). LTB4 sensitizes cutaneous C-ber nociceptors (40). In primary cultures of mouse dorsal root ganglion neurons, LTB4 increases intracellular Ca2+, especially capsaicinsensitive neurons (our unpublished observation). In addition, the mRNA level of LTB4 receptor is higher in dorsal root ganglion than in skin, suggesting that LTB4 acts directly on primary aerent terminals to produce itch signals.

VII.

SP-INDUCED ITCH AND OTHER KERATINOCYTE MEDIATORS

Itch is a sensation of the supercial layer of the skin. When stimulation is applied to the boundary area (basal layer) between epidermis and dermis, itch sensation is strongly felt (41). Removal of the epidermis and the subepidermal nerve network abolishes itch (42). Primary aerents innervating the boundary area between epidermis and dermis may receive localized stimulation in the epidermis and transmit itch signals to the dorsal horn. Thus, keratinocytes may be important cells to produce endogenous itch mediators and regulators.

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As discussed above, keratinocytes produce and release LTB4, PGE2 (13,19,33), and substance P (43). Keratinocytes may also produce many mediators, including nitric oxide (44), nerve growth factor (45), plateletactivating factor (46), vasoactive intestinal polypeptide (47), enkephalin (48), and various cytokines. All may be induced by substance P induction. Further studies of mediator production and secretion by substance P may contribute to the discovery of new itch mediators and regulators.

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associated response mediated by cutaneous NK1 tachykinin receptors in mice. J Pharmacol Exp Ther 1998; 286:11401145. Andoh T, Kuraishi Y. Involvement of blockade of leukotriene B4 action in antipruritic eects of emedastine in mice. Eur J Pharmacol 2000; 406:149152. Nakanishi S. Substance P precursor and kininogen: their structures, gene organizations, and regulation. Physiol Rev 1987; 67:11171142. Nakanishi S. Mammalian tachykinin receptors. Annu Rev Neurosci 1991; 14:123136. Wahlgren CF. Itch and atopic dermatitis: clinical and experimental studies. Acta Derm-Venereol Suppl (Stockh) 1991; 165:153. Gitter BD, Waters DC, Threlkeld PG, Lovelace AM, Matsumoto K, Bruns RF. Cyclosporin A is a substance P (tachykinin NK1) receptor antagonist. Eur J Pharmacol 1995; 289:439446. Andoh T, Nagasawa T, Kuraishi Y. Expression of tachykinin NK1 receptor mRNA in dorsal root ganglia of the mouse. Brain Res Mol Brain Res 1996; 35:329332. Andoh T, Katsube N, Maruyama M, Kuraishi Y. Involvement of leukotriene B4 in substance P-induced itch-associated response in mice. J Invest Dermatol 2001; 117:16211626. Koizumi H, Yasui C, Fukaya T, Ueda T, Ohkawara A. Substance P induces inositol 1,4,5-trisphosphate and intracellular free calcium increase in cultured normal human epidermal keratinocytes. Exp Dermatol 1994; 3:4044. Staniek V, Doutremepuich J, Schmitt D, Claudy A, Misery L. Expression of substance P receptors in normal and psoriatic skin. Pathobiology 1999; 67:5154. Staniek V, Misery L, Peguet-Navarro J, Abello J, Doutremepuich JD, Claudy A, Schmitt D. Binding and in vitro modulation of human epidermal Langerhans cell functions by substance P. Arch Dermatol Res 1997; 289:285291. Tominaga K, Honda K, Akahoshi A, Makino Y, Kawarabayashi T, Takano Y, Kamiya H. Substance P causes adhesion of neutrophils to endothelial cells via protein kinase C. Biol Pharm Bull 1999; 22:12421245. Marriott I, Bost KL. IL-4 and IFN-gamma up-regulate substance P receptor expression in murine peritoneal macrophages. J Immunol 2000; 165:182191. Krumins SA, Broomeld CA. Evidence of NK1 and NK2 tachykinin receptors and their involvement in histamine release in a murine mast cell line. Neuropeptides 1992; 21:6572. Mousli M, Bronner C, Landry Y, Bockaert J, Rouot B. Direct activation of GTP-binding regulatory proteins (G-proteins) by substance P and compound 48/80. FEBS Lett 1990; 259:260262. . Pruritus in polycythemia vera: treatment with aspirin Fjellner B, Ha germark O and possibility of platelet involvement. Acta Derm-Venereol 1979; 59:505512. , Strandberg K. Pruritogenic activity of prostaglandin E2. Acta Ha germark O Derm-Venereol 1977; 57:3743. Andoh T, Kuraishi Y. Intradermal leukotriene B4, but not prostaglandin E2, induces itch-associated responses in mice. Eur J Pharmacol 1998; 353:9396. Yamaguchi T, Nishikawa Y, Tohda C, Sugimoto Y, Ichikawa A, Ushikubi F,

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Andoh and Kuraishi Narumiya S, Kuraishi Y. Involvement of EP3 receptors in the prostaglandin E2induced potentiation of 5-HT-induced itch-associated response in mice. Soc Neurosci Abs 1999; 29:P1140. Camp RD, Coutts AA, Greaves MW, Kay AB, Walport MJ. Responses of human skin to intradermal injection of leukotrienes C4, D4 and B4. Br J Pharmacol 1983; 80:497502. Hwang SW, Cho H, Kwak J, Lee SY, Kang CJ, Jung J, Cho S, Min KH, Suh YG, Kim D, Oh U. Direct activation of capsaicin receptors by products of lipoxygenases: endogenous capsaicin-like substances. Proc Natl Acad Sci USA 2000; 97:61556160. Andoh T, Kuraishi Y. Inhibitory eects of azelastine on substance P-induced itch-associated response in mice. Eur J Pharmacol 2002; 436:235239. Kanai H, Nagashima A, Hirakata E, Hirakata H, Okuda S, Fujimi S, Fujishima M. The eect of azelastin hydrochloride on pruritus and leukotriene B4 in hemodialysis patients. Life Sci 1995; 57:207213. Matsui C, Ida M, Hamada M, Morohashi M, Hasegawa M. Eects of azelastin on pruritus and plasma histamine levels in hemodialysis patients. Int J Dermatol 1994; 33:868871. Furue M, Yamashita N. Eectiveness of emedastine difumarate in atopic dermatitis. Shinryo to Shinyaku 1997; 34:817823. Abstract in English. Ishibashi Y, Harada S, Niimura M, Imamura S, Yamamoto S, Hori Y, Yoshida H. Clinical study of KG-2413 (emedastine difumarate) on eczema/dermatitis, prurigo and pruritus cutaneous. Clin Phys 1994; 10:19191935. Abstract in English. Harris RR, Wilcox D, Bell RL, Carter GW. The role of tissue mast cells in polyacrylamide gel-induced inammation in mice. Inamm Res 1998; 47:104 108. Schmelz M, Schmidt R, Bickel A, Handwerker HO, Torebjork HE. Specic Creceptors for itch in human skin. J Neurosci 1997; 17:80038008. Martin HA, Basbaum AI, Goetzl EJ, Levine JD. Leukotriene B4 decreases the mechanical and thermal thresholds of C-ber nociceptors in the hairy skin of the rat. J Neurophysiol 1988; 60:438445. Shelley WB, Arthur RP. The neurohistology and neurophysiology of the itch sensation in man. Arch Dermatol 1957; 76:296323. Keele CA, Armstrong D. Substances Producing Pain and Itch. Baltimore: Williams & Wilkins, 1964:288304. Katayama I, Bae SJ, Hamasaki Y, Igawa K, Miyazaki Y, Yokozeki H, Nishioka K. Stress response, tachykinin, and cutaneous inammation. J Invest Dermatol Symp Proc 2001; 6:8186. Baudouin JE, Tachon P. Constitutive nitric oxide synthase is present in normal human keratinocytes. J Invest Dermatol 1996; 106:428431. Burbach GJ, Kim KH, Zivony AS, Kim A, Aranda J, Wright S, Naik SM, Caughman SW, Ansel JC, Armstrong CA. The neurosensory tachykinins substance P and neurokinin A directly induce keratinocyte nerve growth factor. J Invest Dermatol 2001; 117:10751082.

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46. Liu BJ, Zheng MR, Zhang SZ, Dai FP. Eects of antipsoriatic drugs on biosynthesis of platelet activating factor by human keratinocytes. Chin Med J (Engl) 1994; 107:326331. 47. Sung KJ, Chang SE, Paik EM, Lee MW, Choi JH. Vasoactive intestinal polypeptide stimulates the proliferation of HaCaT cell via TGF-alpha. Neuropeptides 1999; 33:435446. 48. Shah PK, Borchardt RT. A comparison of peptidase activities and peptide metabolism in cultured mouse keratinocytes and neonatal mouse epidermis. Pharm Res 1991; 8:7075.

10
Peripheral Opiate Receptor System in Human Epidermis and Itch
Paul Lorenz Bigliardi and Mei Bigliardi-Qi
Basel University Hospital, Basel, Switzerland

I.

BACKGROUND

Opioid-induced pruritus is a well-known side eect in pain treatment with morphine and other A-opiate receptor agonists. This eect is probably caused by A-opiate receptors, as it has been reported that the A-opiate receptor antagonist naltrexone suppresses these itch sensations. Opioid-induced pruritus and constipation seem to be initiated peripherally. Methylnaltrexone, a novel quaternary derivative of naltrexone that does not cross the bloodbrain barrier, acts as a selective peripheral opioid receptor antagonist and decreases pruritus and constipation, as well as shows an adequate maintenance of pain control (1). Moreover, naltrexone was found to signicantly reduce both itching and alloknesis in patients with atopic dermatitis. Cetirizine (H1blocking agent) reduced focal itch but failed to inuence alloknesis (2). Alloknesis is the phenomenon mainly found in atopic dermatitis, dened as itch elicited by a slight mechanicalotherwise nonitchingstimulus. Various treatments of pruritus with opiate receptor antagonists have been reported (see also Chapter 26). Monroe (3) observed a signicant improvement of severe pruritus in patients with atopic dermatitis and chronic
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urticaria after a single oral dose of nalmefene, a potent A-opiate receptor antagonist, and Metze et al. (4) observed a signicant relief of pruritus in dierent skin diseases such as cutaneous lymphoma, atopic dermatitis, xerosis cutis, macular amyloidosis, psoriasis, and especially in prurigo nodularis. Additionally, opiate receptor antagonists have already been used successfully to relieve itching in patients with chronic liver disease with cholestasis (5) and in patients with uraemia (6). The treatment of cholestatic pruritus with naloxone may precipitate a transient opioid withdrawal-like reaction (7), suggesting the importance of opioid-like substances in the elicitation of itch in cholestasis. In addition, it has been recently reported that the activation of n-opiate receptor antagonizes various A-opiate receptor-mediated actions, but not the analgesic action. Togashi et al. (8) have reported that a novel n-receptor agonist (TRK-820), when administered subcutaneously or orally, reduces scratching in a mouse model for pruritus (see Chapter 11). The pruritus in these mice was created by the injection of substance P intradermally. Therefore, this group speculates that n-opioid receptor is itch-suppressive, whereas A-opioid receptor is itch-stimulating. We have demonstrated that human epidermal keratinocytes express the A-opiate receptor at both the mRNA and protein levels (9). The A-opiate receptor is expressed in all layers of the epidermis. In the dermis, the receptor is expressed in the adnexal structures, especially in ducts of sweat glands, in sebaceous glands, and in the pilosebaceous unit of hair follicles. Additionally, we have shown that h-endorphin at concentrations of about 50 nM signicantly downregulates A-opiate receptor expression and upregulates cytokeratin (CK) 16 expression in the epidermis of human skin organ cultures. The same pattern was observed in psoriatic lesional skin (i.e., A-opiate receptor expression was signicantly downregulated and cytokeratin 16 expression was upregulated). These results suggest that the A-opiate receptor system and its ligand, h-endorphin, are involved in the pathogenesis of psoriasis, especially in terms of dierentiation. The clinical observations with opiate receptor antagonist mentioned above suggest that the opiate receptor system is also involved peripherally in the genesis of itch. Therefore, we looked into the expression of epidermal nerve endings and their colocalization with dierent opiate receptors and ligands in normal skin and in dierent pruritic skin diseases. Prurigo nodularis was chosen as a model for the pruritic state. It is an intensively chronic pruritic disorder in which persistent scratching leads to the formation of distinctive epidermodermal nodules. The histopathological features of prurigo nodularis include a dome-shaped epidermal hyperplasia, hypergranulosis, and compact hyperkeratosis. Inltrates of inammatory cells can vary from sparse to dense.

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II. A.

METHODS Immunohistochemistry

Human skin was obtained with informed consent from patients with prurigo nodularis by punch biopsy (3 mm), and, for normal skin, from the edges of excisional skin from dierent locations. The antibody used to stain the Aopiate receptor is a commercially available, anity-puried, polyclonal rabbit anti-A-opioid receptor antibody (rabbit OR600; Gramsch Laboratories, Schwabhausen, Germany). The antibody used to stain the nerve bers was a polyclonal rabbit anti-protein gene product (PGP) 9.5 (UltraClone Limited, Wellow, England, UK). PGP 9.5 is a neuron-specic cytoplasmic protein commonly used to stain epidermal nerve endings. For localization of PGP 9.5 together with A-opioid receptor in human skin, we used the staining method of Hordinsky and Ericson (10). The skin biopsies were xed in Zambonis paraformaldehyde/picric acid overnight at 4j C, then cryoprotected with 20% sucrose in 0.1 M phosphate-buered saline (PBS). Floating sections of 2550 Am were rst blocked with 5% normal goat serum containing 0.3% Triton for 1 hr. A mixture of 0.1 M PBS with 0.3% Triton X-100 and 1% normal goat serum was used as diluent and wash solution. Nonimmune serum controls were run simultaneously. The sections were incubated for 8 hr at room temperature with the primary antibodies, whereas the controls were left in normal goat serum. After washing for 8 hr, the sections were all incubated with Cy2-, Cy3-, or Cy5-conjugated goat antirabbit IgG (H+L) (Jackson ImmunoResearch Laboratories, Inc., West Grove, PA) at room temperature for 6 hr. The secondary antibodies had been tested for minimal cross-reaction to human, mouse, and rat serum proteins. Sections were mounted with FluorSave (Calbiochem, Darmstadt, Germany). B. Confocal Microscopy

Confocal microscopy was performed with a Zeiss Confocal Laser Scanning Microscope LSM 510, inverted Axiovert 100 M (Carl Zeiss AG, Jena, Germany). It operates in the sequential acquisition mode to exclude crosstalk between channels. The 488 (for Cy2), 568 (for Cy3), and 647 (for Cy5) excitation lines were used with a Zeiss Plan-Neouar 40 oil immersion objective with a numerical aperture of 1.3. Optical sections of 0.9 Am thickness were scanned through the z-plane of the sample. The 3D reconstruction was carried out with the Full 3D function of the Imaris 3.0 software (Bitplane AG, Zurich, Switzerland). The confocal 3D images were constructed with multiple 0.9-Am layers.

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III. A.

RESULTS Expression of M-Opiate Receptor in Epidermis of Normal Skin and Prurigo Nodularis

The epidermis of prurigo nodularis is hypertrophic, with the presence of hyperkeratosis. Even though there are more keratinocytes in the epidermis of prurigo (Fig. 1b; see color insert), the expression of A-opiate receptor is signicantly reduced compared to normal skin (Fig. 1a; see color insert). There is no change of A-opiate receptor expression along the nerve endings in prurigo and normal skin. The epidermal nerve endings in Figure 1b are dierent in quantity and quality in prurigo compared to normal skin. Figure 2 shows biopsies from nine patients with prurigo nodularis. There is a signicant downregulation of the A-opiate receptor expression in the epidermis compared to normal skin. The Cy-5 staining was semiquantied by digital imaging analysis. The signicant downregulation of the Aopiate receptor expression in the epidermis could be conrmed by staining 20 skin biopsies from patients with prurigo nodularis with peroxidase, and using normal light microscopy instead of uorescent confocal microscopy (data not shown).

Figure 1 (a) Expression of A-opiate receptor (blue) and PGP 9.5 (red) in the epidermis of normal human skin; 3D confocal micrograph. (b) Expression of Aopiate receptor (blue) and PGP 9.5 (red) in the epidermis of prurigo nodularis; 3D confocal micrograph. (See color insert.)

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Figure 2 Downregulation of A-opiate receptor expression in nine patients with prurigo nodularis (semiquantitative analysis).

B.

Expression of Nerve Endings in Epidermis of Normal Skin and Prurigo Nodularis

In normal skin, the nerve endings branch at the dermo-epidermal junction and run with many curves through the epidermis to just below the corneal layer. The nerve endings are plainly visible and rather thick (Fig. 3a; see color insert). In prurigo nodularis, the dermal nerve endings are similar in structure and amount compared to normal skin. However, the structure of the nerve endings changes markedly at the dermo-epidermal junction in prurigo (Fig. 3b; see color insert). The epidermal nerve endings are thin, almost not visible, and run without curving through the epidermis (see also Fig. 1b). The epidermis is digitally marked by green or white color to allow orientation.

IV.

DISCUSSION

Up to now, morphological structures have been identied as specic itch receptors. It is assumed that itch receptors are linked to the free nerve endings of C-bers close to the dermo-epidermal junction (11). Previous data show that the peripheral A-opiate receptor system is localized in

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Figure 3 (a) Expression of PGP 9.5 (red) in the dermis and epidermis of normal human skin; 3D confocal micrograph. (b) Expression of PGP 9.5 (red) in the dermis and epidermis of prurigo nodularis; 3D confocal micrograph. (See color insert.)

Figure 7.2 Cortex areas with signicant increase in regional blood ow 2 min after histamine stimulus at the right lower arm projected onto a 3D anatomical reference derived from magnetic resonance imaging. Brodmann areas and corresponding structures (area 29) are given. n = 6, nine repeated scans subtraction analysis vs. three saline puncture controls. *Areas also described by Hsieh et al. (From Refs. 22,25,26.)

Figure 8.3 Dermal nerve bers as stained for neurolaments (arrows) in close proximity to blood vessels and inammatory cells (stars). Immunoperoxidase staining. Figure 8.4 Small sensory nerve ber (arrow) as visualized by the expression of CGRP in the papillary dermis. Positive immunouorescence staining for CGRP depicted in red pseudocolors. Confocal laser scanning microscopy. Figure 8.5 Intraepidermal nerve ber as immunostained for PGP 9.5 (arrows). The tortuous course can be best demonstrated by optical sectioning using confocal laser scanning microscopy (optical sections ac). Keratinocytes (K), junctional zone of epidermis, and dermis (stars). The positive immunouorescence staining is depicted in red pseudocolors. Figure 8.6 Expression of sensory neuropeptides within axons of dierent nerve bers (ac) suggesting a variable codistribution of autonomic and sensory bers. Positive immunouorescence staining for CGRP depicted in red pseudocolors. Confocal laser scanning microscopy.

Figure 10.1 (a) Expression of A-opiate receptor (blue) and PGP 9.5 (red) in the epidermis of normal human skin; 3D confocal micrograph. (b) Expression of A-opiate receptor (blue) and PGP 9.5 (red) in the epidermis of prurigo nodularis; 3D confocal micrograph.

Figure 10.3 (a) Expression of PGP 9.5 (red) in the dermis and epidermis of normal human skin; 3D confocal micrograph. (b) Expression of PGP 9.5 (red) in the dermis and epidermis of prurigo nodularis; 3D confocal micrograph.

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peripheral nerve endings in the upper dermis and epidermis, and indicate that human keratinocytes and nerve endings communicate through the Aopiate receptor and its ligand, h-endorphin. The colocalization experiments reveal that the peripheral nerve bers in the upper dermis and epidermis express the A-opiate receptor, and that these nerve bers are unmyelinated (12). Opioid receptors (A, y) have already been identied on peripheral sensory nerve bers and their terminal endings (13,14). Coggeshall et al. (13) have shown that 29% and 38% of unmyelinated cutaneous sensory axons in rats can be immunostained for A-opioid or y-opioid receptors, respectively. Local cutaneous injection of DAMGO, a A-opioid ligand, ameliorates the nociceptive behaviors caused by local cutaneous injection of glutamate, a purely nociceptive chemical stimulus, showing that the A-receptors are functional. By contrast, the y-opioid ligand, DPDPE ([2-D-penicillamine, 5-D-penicillamine]enkephalin), had no eect on these behaviors. Inammation seems to be crucial for the manifestation of peripheral antinociceptive eects (15,16). The reason for this could be an enhancement of the permeability of the perineurium for ligands and an activation of opioid receptors in the terminal nerve endings. Several days after induction of inammation, opioid receptors are newly formed and expressed in peripheral nerve terminals via axonal transport, which leads to an upregulation in the nerve endings (17). It has been shown that in nodular prurigo, pain thresholds were lower both in itching and in unaected skin areas than in healthy control subjects, suggesting an impairment of the nociceptive Cbers in the periphery. Our observations support this statement because in prurigo nodularis, the nerve endings in the epidermis of lesional skin are thinner compared to normal skin and run straight through the epidermis to the corneal layer. These observations and the colocalization of the A-opiate receptor on peripheral epidermal nerve endings suggest that prurigo is regulated and perceived not only in the central nervous system (18) but also in the periphery at unmyelinated C-bers in the epidermis. This theory is supported by the observation in clinical trials that the quaternary alkaloid, methylnaltrexone, which does not cross the bloodbrain barrier, can decrease opioid-induced pruritus and constipation while showing adequate maintenance of pain control (1). These data suggest additionally that the ways of pain perception and itch perception are related but not exactly the same, as reported before (19). In our investigations, the number of epidermal nerve endings was not increased in prurigo. There are reports describing an increase in PGP-immunoreactive nerve bers in lesions of nodular prurigo, but this increase was observed in the dermis and not in the epidermis (20). Because the removal of epidermis reduces itch but not pain, we hypothesize that the opiate receptor system on the epidermal nerve endings is involved in the induction of itch at the periphery.

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Our results show a downregulation of the A-opiate receptor expression in the epidermis of patients with prurigo nodularis compared to normal skin. The downregulation could be a sign of tachyphylaxis after exposure to large amounts of endogenous opioids such as endorphins. We have previously seen a similar downregulation of the A-opiate receptor in lesional skin of patients with psoriasis vulgaris (21) and lichen simplex chronicus (unpublished data). All three skin diseases itch and histologically have a hyperproliferative epidermis. These results suggest that the opiate receptor system on human keratinocytes has an important impact on epidermal homeostasis. Furthermore, the downregulation of the opiate receptor on keratinocytes in pruritic skin diseases such as prurigo or lichen simplex could indicate the presence of more free opioid receptor ligands in the epidermis because these ligands are not bound to the opiate receptors on keratinocytes. This makes the opioid peptides more available to bind to the opioid receptors on the epidermal nerve endings, possibly inducing an itch signal. h-Endorphin serum concentrations in children with pruritic atopic dermatitis (14.95 F 2.75 pmol/L) are signicantly ( p V 0.001) elevated compared to children with atopic dermatitis without itch (9.4 F 2.46 pmol/L) and normal controls (8.85 F 2.39 pmol/L) (22). Similar observations have been made by Glinski et al. (23,24) in the serum of adult patients with severe atopic dermatitis and psoriasis. It is suggested that the elevated h-endorphin concentrations in atopic patients with pruritus conrm the hypothesis that there is an increased activity of their opioid system, and that an opioid antagonist might block itching, which is their major clinical symptom. Although opioid agonists such as h-endorphin or morphine can induce histamine release from mast cells, doses of morphine and h-endorphin that are insucient to cause histamine release resulted in enhancement of histamine-induced itch (25). The potentiation occurred in skin depleted of histamine and after pretreatment with indomethacin. Therefore, itch associated with morphine is neither completely due to histamine release from mast cells or basophils, nor to prostaglandin production in the skin. Additionally, antihistamines seldom completely block pruritus after administration of morphine, and they sometimes provide only little relief, suggesting a direct action of opioid peptides modulating the perception of itching. Additional studies carried out with A-opiate receptors on human epidermis suggest the important role of opiate receptors not only in itch perception, but also in wound healing (12,26). In skin organ cultures, we could demonstrate that the A-opiate receptor system is functionally active and that opioid agonists such as h-endorphin at concentrations around 50 nM can signicantly change the dierentiation pattern of keratinocytes by increasing the expression of cytokeratin 16. This in vitro eect of h-endorphin was inhibited after incubation with the A-opiate receptor antagonist, naltrexone

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(21). CK 16 is not expressed in normal skin, but appears in the suprabasal dierentiating compartment of the epidermis during wound healing and hyperproliferative skin diseases such as psoriasis and skin cancer (27). In conclusion, we have shown that the A-opiate receptor system plays a role in pruritic skin diseases, and skin organ culture experiments reveal that this receptor system is functionally active in epidermis. More work must be done to prove the direct connection between the dierent epidermal opiate receptor systems and the peripheral nerves and their role in itch. However, the above-described observations show a new way of understanding the pathophysiology of itch and could lead to new therapeutic approaches for the treatment of disabling pruritus.

REFERENCES
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11
Antipruritic Activity of a Novel n-Opioid Receptor Agonist, TRK-820
Jun Utsumi
Toray Industries, Inc., Tokyo, Japan

Yuko Togashi, Hideo Umeuchi, Kiyoshi Okano, Toshiaki Tanaka, and Hiroshi Nagase
Pharmaceutical Research Laboratories, Toray Industries, Inc., Kamakura, Kanagawa, Japan

I.

INTRODUCTION

One of the most common side eects of epidurally or intrathecally administered morphine (a A-opioid receptor agonist) in humans is pruritus (1,2). This eect is caused by the A-opioid receptor; furthermore, the A-opioid antagonists naloxone and naltrexone are known to suppress pruritus in patients with chronic cholestasis, chronic renal failure, or atopic dermatitis (35). These observations suggest that the A-opioid system has a role in itch. There are only a few data on the involvement of other opioid receptors in itch. We recently discovered a novel n-opioid agonist, TRK-820 [()-17-(cyclopropylmethyl)-3,14h-dihydroxy-4,5a-epoxy-6 h-[N-methyltrans-3-(3-furyl) acrylamido]morphinan hydrochloride], which has a 4,5epoxymorphinan structure with a tyrosineglycine moiety that attracts the
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endogenous n-opioid peptide, dynorphin (6). The compound may have characteristics dierent from other n-opioid agonists, and has a potent antinociceptive activity in animals (7,8). The important characteristic of TRK-820 is that it has far weaker adverse eects than other n-opioid agonists (9). Most recently, we demonstrated the antipruritic activity of TRK-820 in morphine-induced (10), histamine-induced, and substance P-induced mouse scratching models (11). In these models, TRK-820 was more eective than antihistamines such as ketotifen or chlorpheniramine, suggesting that TRK-820 has ecacy against antihistamine-resistant pruritus via the nopioid receptor. In the present chapter, we describe several studies we have conducted to assess the antipruritic eect of this compound in animals.

II. A.

MATERIALS AND METHODS Drugs

Substance P and morphine were used to induce scratching behavior. Ketotifen, chlorpheniramine, oxatomide, and astemizole were used as antihistamines. A novel n-opioid agonist, TRK-820 [()-17-(cyclopropylmethyl)-3, 14h-dihydroxy-4,5a-epoxy-6h-[N-methyl-trans-3-(3-furyl) acrylamido] morphinan hydrochloride] (Fig. 1) was originally synthesized by Toray Industries, Inc. (Tokyo, Japan). Naloxone was used as a A-opioid antagonist. B. Measurement of Scratching Behavior in Mice

Male ICR mice, 45 weeks of age, were used to receive substance P as a peripheral pruritogenic substance. The scratching behavior was observed

Figure 1

Chemical structure of TRK-820.

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according to the method described by Kuraishi et al. (12). Briey, 30 min before testing, mice were placed in a cage for acclimatization. Immediately after an intradermal (i.d.) injection of substance P, mice were put back into the same cage and their behaviors were recorded with a videocamera for 30 min under unmanned conditions. A volume of 50 AL of substance P was injected i.d. into the superior part of the back. Test compounds were administered orally (p.o.) 30 or 60 min before injection with the pruritogen. Male ddy mice, 45 weeks of age, were used to receive morphine as a central pruritogenic substance. Morphine was injected intracisternally (i.c.) and TRK-820 and naloxone were injected subcutaneously (s.c.) into the back, 30 or 15 min before morphine injection. In both experiments, we performed scratching measurements and measured spontaneous locomotor activity by using the mouse wheel running test as an index of the sedative eect of test drugs. Statistical signicance was analyzed using comparisons made by repeated measurements of one-way or two-way analysis of variance, and the post hoc Dunnetts or unpaired t-test; p<0.05 was considered signicant.

III. A.

RESULTS Classification of Opioid System

The opioid system was classied into four subtypes, depending on specic receptors as shown in Table 1. B. Substance P-Induced Scratching Behavior in Mice

Scratching behavior was induced by substance P but not by formaldehyde of a pain inducer (Fig. 2). Eects of antihistamines or TRK-820 on the substance P-induced scratching behavior are shown in Fig. 3. TRK-820 dose-dependently inhibited scratching behavior and a statistically signicant inhibition was seen in the 100-Ag/kg group. The ED50 value of TRK-820 was calculated as 19.6 Ag/kg (95% condence limits; 9.640.0 Ag/kg). At the same time, the ED50 value for the suppression of spontaneous locomotor activity was calculated as 102.8 Ag/kg (95% condence limits; 64.9163.0 Ag/ kg). Antihistamines did not signicantly suppress mouse-scratching behavior except for the highest dose of astemizole (100 mg/kg, p.o.). These results suggested that TRK-820 has a potent therapeutic ecacy for peripherally induced itching. In this model, TRK-820 was expressed through the n-opioid receptor as conrmed by a specic n-opioid antagonist, nor-binaltorphimine, as previously described (11).

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Table 1 Classication of Opioid Systems A h-Endorphin Dynorphin A Pentazocine, U50448H, TRK-820 Nor-binaltorphimine NTI Analgesia, respiratory suppression Analgesia, sedation (itch suppression), aquaresis DPDPE, deltorphin Leu-enkephalin n y Nociceptin (ORL-1) Nociceptin (Not found)

Receptor types

Opioid peptides (endogenous agonist) Agonistic compounds

Antagonistic compounds Pharmacological actions

Morphine, fentanyl, buprenorphine Naloxone, naltrexone Analgesia, sedation, itch induction, respiratory suppression, peristalsis suppression

Nociceptin derivatives Hyperalgesia, learning disability, hyponmesia

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Figure 2 Mouse pruritus model to evaluate substance Pinduced scratching behavior.

Figure 3 Antipruritic evaluation in substance Pinduced scratching behavior in mice.

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Figure 4

Antipruritic evaluation in morphine-induced scratching behavior in mice.

C.

Morphine-Induced Scratching Behavior in Mice

Figure 4 shows the eects of TRK-820, naloxone, and ketotifen in morphineinduced scratching behavior. The scratching behavior was signicantly suppressed by TRK-820 (ED50=2.32 Ag/kg) and naloxone (ED50=9.4 mg/kg). In this model, morphine (0.10.3 nmol/mouse, i.c.) induced a dose-dependent increase in scratching behavior accompanied by an apparent increase in locomotor activity. These results suggested that TRK-820 has a potential therapeutic value in antihistamine-resistant centrally induced itching.

IV.

DISCUSSION

We have demonstrated that a novel n-opioid agonist, TRK-820, was able to signicantly suppress substance P-induced and morphine-induced scratching behavior in mice. These results suggest that TRK-820 may have therapeutic potential for peripherally and centrally induced itching. It should be noted that in animal models, any compound that aects motor activities or has a muscle-relaxing eect may inhibit scratching activity, but we have demonstrated that TRK-820 exerts antipruritic activity with no apparent inhibition of spontaneous locomotor activity in mice. These results imply that TRK-820 can express antipruritic ecacy with no sedative side eects in clinical treatment.

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Figure 5 A hypothetical mechanism of pruritus/itching.

Figure 5 summarizes the possible antipruritic mechanisms of TRK-820. It has both a central and a peripheral eect. This suggested mechanism is supported by a recent report stating that the activation of n-opioid antagonizes various A-receptor-mediated actions, excluding analgesic action (15). The suggested peripheral eect of TRK-820 is supported by the recent work of Bigliardi et al., who demonstrated the expression of functional A-opioid receptors on keratinocytes (see Chapter 10) (16). In conclusion, TRK-820 shows potential as an eective antipruritic, which seems more eective in inhibiting itch in mice than the A-opioid antagonist, naloxone (Fig. 4). Recent studies performed in humans (see Chapter 27) show promising results with TRK-820 in uremic pruritus. REFERENCES
1. 2. 3. Cousins MJ, Mather LE. Intrathecal and epidural administration of opioids. Anesthesiology 1984; 61:276310. Ballantyne JC, Loach AB, Carr DB. Itching after epidural and spinal opiates. Pain 1988; 33:149160. Bergasa NV, Talbot TL, Alling DW, Schmitt JM, Walker EC, Baker BL, Korenman JC, Park Y, Hoofnagle JH, Jones EA. A controlled trial of naloxone infusions for the pruritus of chronic cholestasis. Gastroenterology 1992; 102: 544549. Peer G, Kivity S, Agami O, Fireman E, Silverberg D, Blum M, Iaina A. Ran-

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Utsumi et al. domised crossover trial of naltrexone in uraemic pruritus. Lancet 1996; 348: 15521554. Metze D, Reimann S, Beissert S, Luger T. Ecacy and safety of naltrexone, an oral opiate receptor antagonist, in the treatment of pruritus in internal and dermatological diseases. J Am Acad Dermatol 1999; 41:533539. Nagase H, Hayakawa J, Kawamura K, Kawai K, Takezawa Y, Matsuura H, Tajima C, Endo T. Discovery of a structurally novel opioid kappa-agonist derived from 4,5-epoxymorphinan. Chem Pharm Bull 1998; 46:366369. Endoh T, Matsuura H, Tajima A, Izumimoto N, Tajima C, Suzuki T, Saitoh A, Suzuki T, Narita M, Tseng L, Nagase H. Potent antinociceptive eects of TRK-820, a novel kappa-opioid receptor agonist. Life Sci 1999; 65:16851694. Endoh T, Tajima A, Suzuki T, Kamei J, Suzuki T, Narita M, Tseng L, Nagase H. Characterization of the antinociceptive eects of TRK-820 in the rat. Eur J Pharmacol 2000; 387:133140. Tsuji M, Takeda H, Matsumiya T, Nagase H, Narita M, Suzuki T. The Novel kappa-opioid receptor agonist TRK-820 suppresses the rewarding and locomotor-enhancing eects of morphine in mice. Life Sci 2001; 68:17171725. Umeuchi H, Tanaka T, Kawamura K, Okano K, Endoh T, Kamei J, Nagase H. Anti-pruritic eect of n opioid receptor agonist TRK-820. 31st Meeting of the International Narcotics Research Conference, Mon40, P64, 2000. Togashi Y, Umeuchi H, Okano K, Ando N, Yoshizawa Y, Honda T, Kawamura K, Endoh T, Utsumi J, Kamei J, Tanaka T, Nagase H. Antipruritic activity of the kappa-opioid receptor agonist, TRK-820. Eur J Pharmacol 2002; 435:259264. Kuraishi Y, Nagasawa T, Hayashi K, Satoh M. Scratching behavior induced by pruritogenic but not algesiogenic agents in mice. Eur J Pharmacol 1995; 275: 229233. Andoh T, Nagasawa T, Satoh M, Kuraishi Y. Substance P induction of itchassociated response mediated by cutaneous NK1 tachykinin receptors in mice. J Pharmacol Exp Ther 1998; 286:11401145. Ebertz JM, Hirshman CA, Kettelkamp NS, Uno H, Hanin JM. Substance Pinduced histamine release in human cutaneous mast cells. J Invest Dermatol 1987; 88:682685. Pan ZZ. Opposing actions of the kappa-opioid receptor. TIPS 1998; 19:9499. Bigliardi PL, Bigliardi-Qi M, Buechner S, Rui T. Expression of mu-opiate receptor in human epidermis and keratinocytes. J Invest Dermatol 1998; 111:297301.

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Putative Role of Cannabinoids in Experimentally Induced Itch and Inflammation in Human Skin
Roman Rukwied, Melita Dvorak, and Allan Watkinson
Unilever Research and Development, Wirral, England

Francis McGlone
Unilever Research and Development, Wirral, England, and Center for Cognitive Neuroscience, University of Wales, Bangor, Wales

I.

INTRODUCTION

The history of the therapeutic use of Cannabis sativa L. in humans goes back approximately 3000 years, rst mentioned by the Emperor Shen Nung in the Chinese Compendium of Medicine, in which the medical properties of Cannabis were described (1). The psychoactive component of Cannabis is D9tetrahydrocannabinol (THC), and because it has been widely used and abused over the past decades and because of legal issues, little research has been conducted into its potential clinical therapeutic use. However, recent studies have shown that its properties include antiemetic, anticonvulsive, analgesic, and anti-inammatory eects. Therapeutic investigations have included the
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treatment of glaucoma, asthma, tetanus, neuralgia, migraine, depression, and gonorrhea (for an overview, see Ref. 2). In 1986, the development of a synthetic cannabinoid led to the detection of cannabinoid-binding sites in the brain (3), and shortly after its discovery, a specic cannabinoid receptor (CB1 receptor) was cloned from rat brain (4). Interestingly, researches on human tissues have shown that CB1 receptors are not only expressed in the central nervous system, but also in peripheral tissues, such as the adrenal glands, heart, lung, and peripheral neurons (5,6). Homology cloning techniques and polymerase chain reaction enabled the detection of an alternative cannabinoid-binding site, named CX5 or CB2 receptor (7). This receptor has been identied in human peripheral tissues, particularly of the immune system (i.e., spleen, tonsils, natural killer cells, and macrophages) (5,7,8), which implicate a widespread immunomodulatory function of cannabinoid receptors and their agonists (9). Once specic cannabinoid receptors had been characterized, inevitably the question of synthetic cannabinoid ligands was raised. A variety of endogenous cannabinoid agonists have been identied [e.g., anandamides (10); 2-arachidonyl-glycerol (11); palmitoylethanolamide and oleamide (12)]. Anandamide has been demonstrated in animal studies to reduce mechanical nociception (13) and pain behavior (14) in response to formalin injections. Nevertheless, the duration of action of anandamide is relatively short, presumably because of the rapid hydrolysis by an intracellularly located membrane-bound fatty acid amidohydrolase (FAAH) (15), which cleaves anandamide into arachidonic acid and ethanolamine. Hence, the antinociceptive pathway of this cannabinoid is still not fully understood (16), but recently the cannabinoid receptor agonist HU210 [6aR-trans-3-(1,1-dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo(b,d) pyran-9-methanol] has been synthesized. Despite the lack of any central (psychoactive) eects, HU210 has been shown to be 100800 times more potent than D9-THC, with a high anity for CB1 receptors (16,17), and its high potency and stereoselective activity make this cannabinoid agonist an excellent candidate for investigation. Studies investigating cannabimimetic activities were mainly focused on the CNS-depressing or analgesic eect. Although the pharmacological eects of cannabinoids are becoming more and more discerned (18), there is little information regarding the cannabinoid-mediated response in humans in vivo, particularly regarding their putative antipruritic, anti-inammatory, and antinociceptive potentials. Therefore, in the present study, we investigated the eect of cannabinoid receptor agonist, HU210, applied to human skin, on histamine-induced itch and inammation, as well as on capsaicin-evoked pain and hyperalgesia.

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II.

MATERIALS AND METHODS

All experiments were carried out at room temperature between 21jC and 23jC and at a relative humidity of 62 F 12%. The Safety and Environmental Assurance Center (SEAC) as well as the local Ethics Committee approved the experimental protocols. A. Subjects

All participants were required to complete a condential medical questionnaire to exclude volunteers with atopic symptoms, as well as any subjects taking antihistamines or receiving corticosteroid therapy or other medical treatments inuencing vascular reactions and psychophysical behavior. All participants provided signed informed consent. B. 1. Histamine Iontophoresis Training of Participants

Twelve healthy male volunteers (mean age 28 F 7 years) were recruited. All participants were accustomed to the experimental procedure by conductance of a training session on a randomly allocated volar forearm site distant to the experimental areas. Histamine iontophoresis, as described below and elsewhere in detail (19), was performed and the volunteers were trained in the use of the visual analogue scale (VAS) for the estimation of the perceived itch. 2. Administration of HU210 by Skin Patch

Left and right volar forearm sites were prepared by tape stripping (Tape 1601; Hadleigh Enterprise Ltd., UK) and the skin patches (8-mm Finn Chambers; Bio-Diagnostics Ltd., UK) containing the test solution were randomly attached. Filter disks were soaked in 50 AL of 50 mM HU210 (cannabinoid agonist; Tocris Cookson Ltd., Bristol, UK), dissolved in HPLC-grade 80% ethanol or 50 AL of 80% HPLC-grade ethanol, placed in the Finn Chambers, and subsequently applied to the right and left forearms, respectively, or vice versa. The patches were secured in place for 24 hr and removed from the skin immediately prior to histamine iontophoresis. 3. Experimental Protocol

The forearms were immobilized prior to the experiments. An iontophoresis chamber (Moor Instruments Ltd., UK) was attached at the HU210-pretreated or ethanol-pretreated skin site. Histamine dihydrochloride (1%)

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(Sigma Chemical Ltd., UK), dissolved in 2% methylcellulose (Sigma Chemical Ltd.) in double-distilled and degassed water, was placed in the reservoir of the iontophoresis chamber. A platinum electrode in the chamber was connected to the positive terminal of a constant current source and a reference electrode xed several centimeters away served as a cathode. Blood ow was continuously monitored by means of a solid-state singlefrequency laser probe inserted into the center of the iontophoresis chamber (DRT4; Moor Instruments Ltd.). After the rst minute of baseline measurements, 0.57 Ag of histamine was transcutaneously delivered by applying 50 AA of constant current for 10 sec. The approximate dose of 0.57 Ag of histamine was calculated using the following equation: Maximum mass of drug delivered (Ag) = [time (sec) current (AA) molecular weight]/[electron charge (1.6 1019 C) Avogadro constant (6.02 1023)]. Measurements continued for 5 min after histamine application. Participants were instructed to assess the magnitude of the perceived pruritus (itch) only, by sliding a lever on a linear visual analogue scale with the endpoints of 010 representing no itch and unbearable itch, respectively. All ratings were analyzed and depicted over time. Values were additionally normalized by subtraction to the grand mean (i.e., the average value of all given ratings of all sessions over time). After normalization to the grand mean, positive values represent increased itch and negative values represent less itch. Blood ow and magnitude estimation of itch perception were monitored throughout the experiment.

C.

Microdialysis

Six subjects (three males, three females; mean age 28 F 5 years) participated in these experiments. 1. Experimental Procedure

Four sterile microdialysis bers (Asahi Medical Co., Japan) with a pore size of 0.3 Am were inserted intradermally (total inserted length=1.5 cm) at equidistant (5 cm) volar forearm sites using 25-gauge injection cannulas, as described previously (2023). TygonR tubing (Dow Corning Ltd., UK) was used to connect the bers with the perfusion pump (pump 22; Harvard Apparatus Ltd., UK). After insertion, bers were led into precision-bore capillary tubes (Fisher Scientic, UK) to improve the collection of the dialysate out of the skin. Microdialysis membranes were continuously perfused at a constant ow rate of 4 AL/min with sterile saline (Braun Medical Ltd., UK) for 60 min. During the 30-min stimulation period, bers were randomly perfused

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with saline only, 5 mM HU210, 5 AM histamine, or both 5 mM HU210 and 5 AM histamine. After the stimulation, saline was perfused through all bers for a further 60 min to allow the return to baseline conditions. The samples were collected at 15-min intervals throughout the experiment. 2. Sample Analysis

The protein content of the samples was determined using Coomassie blue dye as described previously (21,22,24) using a multiplate absorbance reader (Ceres UV900C; BioTek Ltd., UK). Bovine serum albumin (Sigma Chemical Ltd.) was used as a standard. Sensitivity of the test was 0.02 mg of protein per milliliter of sample. 3. Assessment of Skin Blood Flow and Flare Size

A single-frequency heliumneon laser Doppler scanner attached to dedicated software (Moor Instruments Ltd.) was used to measure blood ow in dened areas (10 20 cm) above the microdialysis bers. The velocity of the scan was set at 4 msec per pixel, requiring approximately 2.5 min for image capture. Recorded images were analyzed above the microdialysis bers at a constant area of 1.5 cm2 or 250 pixels using the manufacturers image processing system (Moor LDI, version 3.01). The maximum sizes of the are were outlined during the experiment and transferred to an acetate sheet after the completion of the procedure. The are areas were planimetrically evaluated using dedicated software (25).

D.

Capsaicin Administration

In this study, 20 healthy volunteers (10 males, 10 females; mean age 29 F 8 years) participated. The volunteers were seated in a dentists chair, and both volar forearms were placed in supine position in front of the abdomen and immobilized by well-padded cushions. To accustom subjects to the experimental equipment and procedures, one site of the volunteers forearm was selected to assess pressure sensibility, followed by the estimation of heat pain thresholds. 1. Pressure Sensibility

Pressure sensibility was assessed with SemmesWeinstein monolaments (North Coast Medical, Inc., Cambell, CA) using the von Freys method (26). Each nylon lament was applied at a right angle to the skin until it bent, representing a calibrated force. The subject was asked to report the presence or absence of sensation. The lament was applied three times and the subject

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was questioned four times to test for any false positives. Ascending and descending sizes of laments were applied until a detection threshold was obtained (i.e., when 50% of delivered stimuli from a particular lament were detected). 2. Heat Pain Thresholds

The thresholds for heat pain were assessed 5 and 30 min after capsaicin administration and ethanol administration by means of a computer-controlled thermode (surface area 1.2 cm2), based on Peltier elements and provided by a custom-modied version of a Thermal Sensory Analyzer (TSA; Medoc Ltd., UK). Detection thresholds were measured by increasing the thermode temperature until a sensation of heat pain was perceived by the volunteer, indicated by depressing a button on a response unit, after which the thermode temperature immediately returned to the adaptation temperature preset to 30jC. The rate of temperature increase was constantly held at 0.2jC/sec and three stimuli of increasing temperature were presented consecutively, with an interval of 10 sec built in the paradigm. A mean was automatically taken to derive the heat pain threshold. 3. Administration of HU210 by Skin Patch

Volar forearm sites of the participants were prepared by tape stripping (Tape 1601; Hadleigh Enterprise Ltd.). Four lter disks (12 mm in diameter) were placed into Finn Chambers (Bio-Diagnostics Ltd.) and soaked with 50 AL of a 50-mM solution of the cannabinoid receptor agonist, HU210 (Tocris Cookson Ltd.), as described above. The chambers were attached to the skin sites in close proximity to each other, covering an area of 4 cm2, and ethanol was applied to the contralateral forearm site serving as the vehicle control. Patches were secured in place for 24 hr and removed from the skin immediately prior to the capsaicin test. In control experiments, heat pain thresholds and mechanical thresholds to punctate pressure were investigated after administration of HU210, using a computer-controlled thermode (surface 1.2 cm2) and Semmes Weinstein monolaments, respectively, as described above. 4. Administration of Capsaicin

Capsaicin (8-methyl-N-vanillyl-trans-6-nonenamide; Sigma Chemical Ltd.) was dissolved in 80% ethanol to a 1% solution. A lter disk (8 mm in diameter) was soaked with 40 AL of capsaicin, placed in the center of the pretreated skin sites, and secured for 15 min.

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5.

Experimental Procedure During Capsaicin Application

During the administration of capsaicin, participants were instructed to estimate the magnitude of sensation by means of a numeric scale ranging from 0 (no sensation) to 10 (maximal sensation imaginable) at 2-min intervals. A point of reference was set at 3, representing an intensity of sensation eliciting the desire to intervene (e.g., by cooling the skin). 6. Experimental Procedure After Capsaicin Application

Five, 15, and 30 min after capsaicin administration, the areas of pinprick and touch hyperalgesia were estimated. Pinprick hyperalgesia was assessed with a pointed probe (0.6 mm in diameter) delivering a calibrated force of 50 mN, whereas hyperalgesia to touch (allodynia) was investigated by stroking the skin with a cotton pad. The area of the hypersensitive zone was determined by means of stimulating along a series of at least ve linear paths arranged radially around the capsaicin patch site and in steps of 10 mm. When the subject reported a denite change of sensation between two consecutive points of stimuli, the rst one was marked on the skin. At the end of the experiment, the marks were connected together to form a continuous border and the enclosed area was traced onto clear acetate for planimetrical evaluation by means of appropriate software (25). Heat pain thresholds were assessed, as described above, at the application site 5 and 30 min after removal of the capsaicin patch. 7. Data Analysis

Data were statistically evaluated by a two-way repeated-measures analysis of variance (ANOVA). To determine intraindividual signicant dierences of subjective perception, thermal thresholds, pinprick hyperalgesia, and allodynia, parametric paired t tests were used. Data are expressed as mean F standard error of the mean (SEM) and values at p<0.05 were considered statistically signicant.

III. A. 1.

RESULTS Effect of Cannabinoids on Histamine Responses Blood Flow

Iontophoresis of histamine induced a signicant increase of skin blood ow at the application site ( p<0.05), which was not altered by the ethanol pretreatment alone. In contrast, the 24-hr skin patch application of HU210

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attenuated the increase in blood ow markedly in comparison to both the training session and the ethanol control ( p<0.003). 2. Magnitude Estimation of Itch Perception

Histamine-induced development of itch was not altered by the skin patch or the ethanol vehicle ( p > 0.6), whereas HU210 treatment signicantly reduced the magnitude estimation of pruritus during the rst 2 min after the administration of histamine ( p<0.05). Analysis of the grand mean corroborates the signicant attenuation of histamine-induced itch perception subsequent to the administration of HU210 ( p<0.04). 3. Axon Reflex Flare

Following the microdialysis application of 5 AM histamine, the largest are area developed was 4.8 F 0.9 cm2. In contrast, coadministration of 5 mM HU210 with 5 AM histamine markedly reduced this axon reex are response to 2.4 F 0.6 cm2 ( p<0.03). 4. Protein Extravasation

In the dialysate collected at 15-min intervals from the microdialysis bers, which were perfused with saline or 5 mM HU210, the amount of protein was, on average, 0.4 F 0.03 mg/mL. These values did not signicantly dier from the baseline ( p>0.05), indicating no signicant increase in plasma protein extravasation due to HU210. In contrast, perfusion with 5 AM histamine induced an approximately twofold increase ( p<0.04) in the extravasation of plasma protein; as soon as the histamine was replaced with saline, the values returned to baseline. Compared to the ethanol and HU210 controls, administration of 5 AM histamine with 5 mM HU210 provoked a signicant elevation in protein extravasation ( p<0.02) (approximately 0.8 F 0.08 mg/mL), throughout both the stimulation period and the 60-min washout period that followed. Furthermore, the increase in the protein extravasation resulting from the coadministration of the two agonists is signicantly higher (on average 0.6 F 0.05 mg/mL) even from the histamineinduced values (0.3 F 0.03 mg/mL) during the washout period ( p<0.02).

B. 1.

Effect of Cannabinoids on Capsaicin Responses Estimation of Pain Sensation

Administration of capsaicin induced a stinging perception, which nally culminated in burning pain. In comparison to the vehicle (3.2 F 0.4), mag-

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nitude estimation of sensation was signicantly reduced ( p<0.05) at the HU210-pretreated skin site (2.6 F 0.3) after the 10th minute of capsaicin application. 2. Thermal Hyperalgesia

In the control experiments, heat pain thresholds at the untreated skin site (46.3 F 0.7jC) were not signicantly dierent from thresholds at the ethanol-pretreated and HU210-pretreated sites (45.6 F 0.4jC and 46.8 F 0.2jC, respectively; p>0.9). Five minutes after the application of capsaicin, the mean heat pain threshold was signicantly reduced at the ethanol-pretreated site (38.6 F 1.9jC) in comparison to the HU210-pretreated site (43.4 F 2.2jC; p<0.05). However, 30 min after the capsaicin administration, mean heat pain threshold was not signicantly dierent at the ethanol-pretreated skin site (37.1 F 0.8jC) in comparison to the HU210-pretreated site (38.2 F 0.8jC; p>0.05). 3. Pinprick Hyperalgesia

Throughout the experiment, the average area of pinprick hyperalgesia increased at the ethanol-pretreated skin site [13.3 F 3.5 cm2 (5 min), 18.5 F 4.7 cm2 (15 min), 20.6 F 5.2 cm2 (30 min)]. Likewise, at the HU210-pretreated skin site, the mean area of pinprick hyperalgesia gradually increased [16.3 F 5.3 cm2 (5 min), 18.5 F 5.6 cm2 (15 min), 20.2 F 4.2 cm2 (30 min)] after capsaicin administration. However, no signicant dierences were observed between the pretreatments. 4. Allodynia

Prior to the experiments, control studies were conducted where capsaicin was omitted from the protocol. We delivered a calibrated force to the skin surface and determined the thresholds of pressure detection. At the ethanolpretreated site, an average force of 29.8 F 1.3 mNand at the HU210pretreated site, a force of 28.9 F 1.7 mNwas required to induce a perception of pressure. These thresholds did not dier signicantly ( p>0.5). Secondary hyperalgesia to touch (allodynia) was estimated within the 5th, 15th, and 30th minutes after the administration of capsaicin. In the vehicle control experiment, the area of allodynia extended from 7.5 F 2.2 cm2 (5 min) to 10 F 2.7 cm2 (15 min), and it did not increase further at the nal time point (9.9 F 3.2 cm2). In comparison to the control, the pretreatment with HU210 signicantly reduced the area of allodynia measured during the 5th and 15th minutes after the application of capsaicin (3.1 F 0.7 and 4.8 F 1.4 cm2, respectively; p<0.05). Thirty minutes after capsaicin admin-

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istration, HU210 pretreatment did not signicantly reduce the area of allodynia with respect to the ethanol control (8.5 F 2.8 cm2; p =0.8).

IV.

DISCUSSION

Administration of histamine specically activates thin unmyelinated nerve bers (27), of which a subpopulation conveys the perception of itch (21,22). Retrograde conduction of action potentials at branch points of these nerve bers spreads excitation to nonstimulated terminals, which then release additional inammatory mediators, for instance the neuropeptide calcitonin generelated peptide (CGRP) (21,22), which induces a long-lasting increase of blood ow (23,28). Besides its eects on nerve bers, histamine causes activation of, particularly, H1 receptorspotent stimulators of endothelial cells. It increases vascular permeability and induces the generation of nitric oxide (NO) (29), which results in the extravasation of plasma proteins (edema) (30) and the development of a localized increase in blood ow (erythema) (31). In the present study, we demonstrated that itch and vasodilatation are signicantly reduced after pretreatment with the selective CB1 receptor agonist, HU210. In addition, coadministration of HU210 with histamine, administered through the microdialysis ber, markedly reduced the axon reex are response. HU210 itself did not induce an increase of skin blood ow nor itch, as revealed in control experiments. The HU210-mediated reduction of histamine-evoked responses (i.e., increase in skin blood ow and are size) may be achieved by the attenuation of the release of neuropeptides from terminal endings of histamine-sensitive nerve bers. It has been shown that CGRP is released inside the axon reex are (21,22), which might be responsible for the maintenance of the longlasting axon reex are. Accordingly, attenuation of CGRP release will lead to a reduction in are size. Additionally, the generation of nitric oxide, which causes local vasodilatation, may be reduced because its release is facilitated by CGRP (32). However, we demonstrated that coadministration of HU210 with histamine did not absolutely abolish the increase in local blood ow, but distinctively prevented the vasodilatation and axon reex are, and therefore assumed that HU210 preferentially inhibits the CGRP release rather than the NO release, possibly due to an interaction of HU210 with CB1/CB2 receptors colocated on the activated nerve bers. Supporting this hypothesis is the nding that capsaicin-induced CGRP release in the rat hindpaw skin is signicantly reduced by coadministration with the endogenous cannabinoid, anandamide (33). Although other studies revealed some contradictory ndings, demonstrating the release of NO in invertebrates (i.e., mollusc) (34) and CGRP in isolated rat arteries (35) following the administration of ananda-

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mide, it has been shown that the induction of CGRP and NO release by anandamide is apparently not mediated by cannabinoid receptors. Crossbinding studies revealed that anandamide binds to vanilloid receptors (VR1) in both rat (35) and human (36,36a) tissues, and the authors suggested that the anandamide-evoked release of neuropeptides, particularly CGRP, is mediated by VR1 receptors in the rat (35). Given the apparent contradiction in these observations and considering the results of the present study, we suggest that the HU210-evoked attenuation of histamine-induced inammatory responses is mediated by the activation of cannabinoid receptors expressed on either nerve bers and/or blood vessels. This assumption was derived from the observation that, rstly, HU210 has been shown to be inactive on VR1 receptors (35), and secondly, it binds primarily to cannabinoid receptors (17). Additionally, cannabinoid receptors are expressed on peripheral neurons (6) and nerve terminals (36), and these ndings suggest that cannabinoid receptors might be involved in the amelioration of itch and inammation. Although there is evidence that HU210 preferentially binds to the cannabinoid type 1 receptor, as it has a CB1:CB2 receptor anity of 40:1 (17), further receptor-binding studies are necessary to elucidate which particular receptor subtype might be involved in the analyzed anti-inammatory responses. Investigations performed with microdialysis revealed that HU210induced eects are not due to an imitation of an antihistaminergic activity. Dermal microdialysis is a sophisticated tool for the study of neurogenic inammation (37) and the measurement of the amount of plasma proteins released in the interstitium in vivo due to chemical stimuli (23,38). Employing this technique, we demonstrated that histamine induced a signicant increase of protein extravasation, whereas the administration of HU210 alone had no impact. Interestingly, coadministration of the cannabinoid receptor agonist with histamine augmented the histamine-evoked plasma protein extravasation. Apparently, this altered vascular response depends on the coactivation of both histamine and cannabinoid receptors, but their interaction and supplemental eects on the vascular tone require further investigation. While the mechanism of such an eect is enigmatic, it demonstrated that the HU210-provoked anti-inammatory and antipruritic eects are not due to an antihistaminergic activity of the cannabinoid agonist, as we should expect in such case an attenuation of the histamine-evoked extravasation of plasma protein. We assume that the analyzed anti-inammatory eects of HU210 are rather mediated by the activation of peripheral cannabinoid receptors being expressed on the terminal endings of thin unmyelinated nerve bers, possibly on itch-specic subunits, subsequently attenuating itch and vasodilatation. Recent ndings indicate that mechanoinsensitive C-bers rather than polymodal C-units mediate the axon reex (39). Interestingly, mechanoinsensitive C-bers have also been shown to mediate itch in human skin (21,22) and it

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can be hypothesized that these itch bers are a subgroup of families mediating the axon reex are. We propose that the cannabinoid receptor agonist, HU210, might act by attenuating the histamine-induced generation of action potentials of C-bers, particularly of the mechanoinsensitive C-units, and thereafter decreasing the release of CGRP with subsequent reduction of vasodilatation, together with the decrease in their conveyance of itch. Having demonstrated that these agonists are not ligands at the H1 receptors and do not indicate antihistaminergic activities, these ndings might lead to an entirely new strategy of treatment of sensitive, itchy, and/or inamed skin. In the present study, it was of further interest to investigate putative antinociceptive eects of cannabinoids. Several studies revealed that cannabinoid agonists exert central antinociceptive eects in both human (40,41) and animal models (42), whereas possible peripheral antinociceptive actions have been demonstrated in animal models only (43,44). For decades, the administration of capsaicin has been used to experimentally induce pain and inammation in these models. Peripheral application of capsaicin evokes activation of a number of C-ber subpopulations and, consequently, intense burning pain. This is accompanied by hyperalgesia to heat at the site of administration (primary zone), which is also mediated by small, unmyelinated primary aerent units (45). These primary responses are accompanied by hyperalgesia to mechanical stimuli in the surrounding skin area (secondary zone). This secondary hyperalgesia has been attributed to sensitization of spinal neurons by noxious input of chemosensitive C-bers (46). The sensitized spinal neurons then respond more vigorously to the input from A-beta (allodynia) and A-delta bers (pinprick hyperalgesia) (47), whereas the maintenance of allodynia requires the continuous activity of aerent C-bers (48). Using the capsaicin model, we observed a signicant reduction of burning pain at the skin sites pretreated with the cannabinoid receptor agonist, HU210. Additionally, we recorded the absence of primary hyperalgesia to heating, measured 5 min after the administration of capsaicin. We further observed that application of HU210 signicantly reduced the secondary response, as estimated by measuring the area of touch-evoked allodynia. The eect was restricted to the rst 10 min after the application of capsaicin and gradually diminished throughout the experiment. Such dynamics could be due to the increasing sensitization in response to the continual C-ber input and/or washout of HU210. However, our investigations of pinprick-induced secondary hyperalgesia revealed no signicant eect of HU210 on capsaicininduced punctate hyperalgesia. It has been demonstrated that punctate hyperalgesia is more enduring than allodynia, has a larger area, and is less dependent on the input from the sensitized area (49). Perhaps to attenuate pinprick hyperalgesia, the concentration of administered HU210 would have to be increased.

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Previous ndings have described antinociceptive properties of a putative endocannabinoid, anandamide, in a capsaicin superfusion model of a rat skin in vitro preparation (33), and our present study reveals that the cannabinoid, HU210, alleviates pain in human skin in vivo. By use of a selective agonist of CB1 and CB2 receptors, we postulate an antinociceptive eect of HU210 that is mediated via cannabinoid receptors expressed on capsaicin-sensitive unmyelinated C-bers. In contrast, attenuation of allodynia by HU210 might implicate a functional expression of cannabinoid receptors on large myelinated mechanoreceptive units because activation of these nerve bers is essential to mediate this particular type of secondary hyperalgesia. However, we demonstrated in the control experiments that HU210 does not modify the sensitivity to touch, as the magnitude of the pressure detection thresholds was not altered by the application of this cannabinoid receptor agonist. Therefore, the antiallodynic eect can be attributed most probably to a reduction of capsaicin-induced activation of C-nociceptors. We showed in the present study antipruritic, anti-inammatory, and antinociceptive eects of a cannabinoid receptor agonist administered peripherally to human skin. It will be of particular interest to elucidate the distribution of cannabinoid receptors and their functions in specic primary aerent units in human skin, particularly with respect to various subclasses of nociceptors with dierent mechanosensitive and chemosensitive attributes. Selective blocking of the cannabinoid receptors, as well as their immunohistochemical localization, will provide additional insight into the cannabinoidmediated responses in human skin. The demonstrations that a peripheral cannabinoid receptor agonist modulates pain at spinal level without the psychomimetic side eects and without the impediment of the sensory function of the skin, combined with the attenuation of itch and lacking antihistaminergic properties, make these compounds candidates for the therapeutic alleviation of a variety of pathophysiological syndromes that are unresponsive to conventional treatments.

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13
Itch Models in Animals, with Special Emphasis on the Serotonin Model in Rats
Jens Schiersing Thomsen
Gentofte University Hospital, Copenhagen, Denmark

I.

OBSERVATIONS IN ANIMALS

Itch is a subjective phenomenon, and itch models in animals are restricted by the fact that animals cannot express whether they scratch themselves due to itch or due to other sensations, such as pain or discomfort, or for no special reason at all (1,2). Therefore, scratching in animals has been regarded as an indirect correlate to itch. So far, only a few valid animal models for pruritus have been established. Spontaneous scratching in rats is probably a cerebral phenomenon or otherwise explained as a general behavior, rather than as a reaction to skin stimuli (3). Feeding rats a diet low in magnesium induces a skin rash, which may share features with atopic dermatitis (4,5). The rash is attributed to lowered serum Mg2+ and described in the literature as extremely pruritic (6). Sometimes, the diet is also low in fat (7), but dietary lipid depletion probably does not play any signicant role in the pathogenesis of the hypomagnesic dermatitis rat model (8). Moreover, injections of dierent chemical substances have been performed in rodents to provoke scratching. Hairless mice were typically used in studies involving intradermal injections, whereas studies with intrathecal
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and intracisternal injections have been conducted on animals with fur (9). Injections into the central nervous system showed dose-dependent reproducible scratching (1016). In the study of peripherally (from the skin) induced itch, scratching was elicited by substances injected into the skin of mice (17 23), guinea pigs (24), and rats (1,19,2527). Among these species, various reactions to injected chemical substances were observed. Intradermal injections of prostaglandin E2 induced a strong itchscratch response in guinea pigs (24), but did not elicit scratching in mice (17). In humans, histamine is the best-characterized pruritogen, but it did not induce scratching in guinea pigs (24). In mice, Kuraishi et al. (21) found no involvement of histamine in scratching behavior, while Inagaki et al. (20), reported the involvement of both histamine H1 and histamine H2 receptors in passive, cutaneous, anaphylaxis-induced scratching behavior in mice. Reaction to the substances varies greatly from animals to humans and also among animal species. This clearly makes it dicult to suggest a valid model for screening dierent mediators in rodents, because the experimental results may not be relevant to humans. In animal models of pruritus, it is therefore necessary to use chemical substances known to induce itch in humans. Scratching in dierent species is then recorded. When trying to dierentiate between scratching due to itch or pain, both pruritogenic and algesiogenic agents have been injected in mice. Only the pruritogenic agents induced scratching behavior (21). Scratching behavior in rats can be attributed to pain (1). Nevertheless, serotonin is able to elicit dose-dependent scratching behavior in rats after intradermal injectionbut when a very high concentration was injected (leading to skin necroses), only little scratching was observed (28).

II.

THE SEROTONIN MODEL FOR SCRATCHING IN RATS

A model for peripherally induced scratching in rats in response to intradermal injections of serotonin was recently developed (28). Because scratching decreases after daily repeated injections of serotonin in the same rat, each rat only received one injection. Injections were given in the neck, as rats can reach this skin area only with their hind paws. After intradermal injections, the rats were transferred to cages and video recorded for 2.5 hr (29) (Fig. 1). Itch prole curves were obtained from viewing the videotapesthe number of scratch sequences was registered in 5-min intervals. In this way, a prole of itch intensity for each rat is recorded. An example of proles for two selected concentrations and saline are shown in Figure 2. Typically, itch prole curves show an increasing number of scratch sequences until

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Figure 1 Set-up for studying rats. The rats were recorded with two black and white videocameras (Topica model TP 606 A/3). These were placed above the cages, so that they could record the rats from above. Recordings were made in authentic real-time speed and videotaped on a time-lapse videotape recorder, Sony model SVT-L230P. They were evaluated visually at triple speed. In night recordings infrared lamps (Imax=940 nm, spectral bandwidth **=50 nm) were used. The lamps were placed behind the cages and induced no signicant lighting of the cages or the animals.

maximum at about half an hour, followed by a decline. When the concentration of injected serotonin is increased from 0.01 mg/mL, the area under curve (AUC) of the itch prole curves also increases, primarily as a result of longer duration of scratching (Fig. 2). Usually, there was a lag time of 510 min before scratching began. This could represent the time for local distribution and absorption of serotonin into the bloodstream, or the lag time could simply be a transient neuronal disturbance as a result of the injection trauma. The lag time could also be a result of metabolism of serotonin (i.e., serotonin in the skin being metabolized into a more active pruritogenic substance). The AUC for each itch prole curve can be obtained, and can be used for investigations of the doseresponse relationship. As mentioned, dierent concentrations of serotonin also produce dierent itch prole curves. It is

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Figure 2 Itch prole curves of scratching in response to dierent concentrations of serotonin injected into the neck of rats. Scratching was registered in 5-min intervals. (Modied curve from Ref. 25.)

seen from Figure 3 that when the concentration of serotonin rises, the AUC also increases. In contrast to injections in the neck, injections of serotonin above the tail root elicited no scratching at all, neither on the site of injection, nor elsewhere. Thus scratching of the neck in this model is ascribed to a local stimulus from the injected skin area, and not as a response to systemic absorption of serotonin into the bloodstream. No indication of a systemic eect of serotonin was found in this model. Serotonin is a known histamine liberator, but neither histamine itself nor the histamine releasing compound 48/80 induced scratching in Sprague Dawley rats used in this model. Thus scratching in the rat due to injections of serotonin is probably elicited in a histamine-independent way. In humans, serotonin is a local pruritogen and has its own pruritogenic potency, not only acting over histamine containing mast cells (30). It is very dicult to know if scratching is a result of itch, pain, or some other sensation. The question is very central to itch research in animals. In a study by De Castro-Costa et al. (1), both morphine and acetylsalicylate, but not the antihistamine drug astemizole, depressed scratching behavior in

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Figure 3 The doseresponse relationship of scratching as a function of the concentration of serotonin injected in the rostral back. The number of scratch sequences (mean scratch) is the area under the curve (AUC) of all the itch curves of serotonin concentrations tested. The data tted a sigmoid curve as a function of log10 to the concentration injected. Error bars represents F 2 S.E.M., n =10. (Modied curve from Ref. 25.)

arthritic rats, and it was concluded that scratching was due to pain. On the other hand, Kuraishi et al. (21) induced scratching behavior in mice by pruritogenic (compound 48/80 and substance P) but not algesiogenic agents (capsaicin and dilute formalin). In the present study, we found no indications of histamine being crucial to scratching behavior in rats, not even in a concentration of 10 mg/mL, so H1-receptor antagonists would hardly be able to reduce scratching behavior in rats (28). Furthermore, scratching activity was greatly reduced in the present study when necroses developed on the injection site (Fig. 3). If serotonin-induced scratching in rats was due to pain, then one would expect that necrosis of the skin would lead to very intense scratching and not very little scratching. Therefore, we believe that scratching in the present study was due to a pruritic sensation.

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In conclusion, when using the serotonin model for pruritus in rats, serotonin is a reproducible local pruritic substance eliciting scratching. The model may be especially useful in research and development of topical antipruritics of the nonhistaminic type. Furthermore, the model appears relevant since serotonin is already recognized as a weak local pruritogen in humans, as well as for various other purposes in pruritus research.

III.

EXAMPLE OF DRUG TESTING USING THE SEROTONIN MODEL

The above-mentioned model was used to test the antipruritic potential of four salicylic compounds, all with dierent skin penetration characteristics (31). There is a strong need for antipruritic substances for treating itch in clinical dermatology, and in one recent human study, topically applied acetylsalicylic acid has been described to rapidly decrease histamine-induced itch (32). Eighteen rats were studied for 6 weeks. Prior to serotonin injections (2 mg/mL, 50 AL), 10 AL of test substances were applied to a circular area 18 mm in diameter. The four substances were all solubilized to a concentration of 5% w/w. Skin penetration of the salicylic compounds had previously been characterized by using the microdialysis technique. After serotonin injections, scratching was monitored by video recordings. Compared to the vehicle, a lower number of scratch sequences were seen after application of slow penetrating salicylic compounds. After application of fast penetrating drugs, no dierence was observed. Furthermore, the number of scratch sequences was lower than with vehicle throughout the 1.5-hr study period. From the above-mentioned study, it can be concluded that topical application of diethylamine salicylate and salicylamide could suppress serotonin-induced scratching in rats. Furthermore, the antipruritic eect seems to be related to slow drug release of the two substances. The results may be clinically relevant because serotonin induces itch in humans.

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16.

17. 18.

Maibach HI, Lowe NJ, eds. Models in Dermatology. Basel: Karger, 1985:187 197. Thomsen JS, Benfeldt E, Serup J. Suppression of spontaneous scratching in hairless rats by sedatives but not by antipruritics. Skin Pharmacol Appl Skin Physiol 2002; 15:218224. Chavaz P, Faucher F, Saurat JH. Dermatosis of hairless rats fed a hypomagnesic dietpathology and immunology. Dermatologica 1984; 169: 105111. Neckermann G, Bavandi A, Meingassner JG. Atopic dermatitis-like symptoms in hypomagnesaemic hairless rats are prevented and inhibited by systemic or topical SDZ ASM 981. Br J Dermatol 2000; 142:669679. Claverie-Benureau A, Lebel B, Gaudin-Harding F. Magnesium deciency allergy-like crisis in hairless rats. A suggested model for inammation studies. J Physiol 1980; 76:173175. Bavandi A, Meingassner JG, Becker S. Diet-induced dermatitis response of hairless rats to systemic treatment with cyclosporin A (Sandimmun), cyclosporin H and FK506. Exp Dermatol 1992; 1:199205. Thomsen JS, Nielsen PL, Serup J. The hypomagnesic rat model: dermatitis prone hairless rats with mild Magnesium depletion fed a diet low in lipids did not develop pruritic dermatitis. Skin Pharmacol Appl Skin Physiol 2002. Submitted. Kuraishi Y, Yamaguchi T, Miyamoto T. Itchscratch responses induced by opioids through central mu opioid receptors in mice. J Biomed Sci 2000; 7: 248 252. Bergasa NV, et al. Plasma from patients with the pruritus of cholestasis induces opioid receptor-mediated scratching in monkeys. Life Sci 1993; 53:12531257. Gmerek DE, Cowan A. An animal model for preclinical screening of systemic antipruritic agents. J Pharmacol Methods 1983; 10:107112. Sakurada T, et al. Nociceptin-induced scratching, biting and licking in mice: involvement of spinal NK1 receptors. Br J Pharmacol 1999; 127:17121718. Takahashi H, et al. Mechanism of pruritus and peracute death in mice induced by pseudorabies virus (PRV) infection. J Vet Med Sci 1993; 55:913920. Thomas DA, Hammond DL. Microinjection of morphine into the rat medullary dorsal horn produces a dose-dependent increase in facial scratching. Brain Res 1995; 695:267270. Tohda C, Yamaguchi T, Kuraishi Y. Intracisternal injection of opioids induces itch-associated response through mu-opioid receptors in mice. Jpn J Pharmacol 1997; 74:7782. Yamaguchi T, Kitagawa K, Kuraishi Y. Itch-associated response and antinociception induced by intracisternal endomorphins in mice. Jpn J Pharmacol 1998; 78:337343. Andoh T, Kuraishi Y. Intradermal leukotriene B4, but not prostaglandin E2, induces itch-associated responses in mice. Eur J Pharmacol 1998; 353:9396. Andoh T, et al. Substance P induction of itch-associated response mediated by cutaneous NK1 tachykinin receptors in mice. J Pharmacol Exp Ther 1998; 286:11401145.

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19. Hayashi I, Majima M. Reduction of sodium deoxycholic acid-induced scratching behaviour by bradykinin B2 receptor antagonists. Br J Pharmacol 1999; 126:197204. 20. Inagaki N, et al. Participation of histamine H1 and H2 receptors in passive cutaneous anaphylaxis-induced scratching behavior in ICR mice. Eur J Pharmacol 1999; 367:361371. 21. Kuraishi Y, et al. Scratching behavior induced by pruritogenic but not algesiogenic agents in mice. Eur J Pharmacol 1995; 275:229233. 22. Rojavin MA, et al. Antipruritic eect of millimeter waves in mice: evidence for opioid involvement. Life Sci 1998; 63:L251L257. 23. Sugimoto Y, et al. Eects of histamine H1 receptor antagonists on compound 48/80-induced scratching behavior in mice. Eur J Pharmacol 1998; 351:15. 24. Woodward DF, et al. Characterization of a behavioral model for peripherally evoked itch suggests platelet-activating factor as a potent pruritogen. J Pharmacol Exp Ther 1995; 272:758765. 25. Berendsen HH, Broekkamp CL. A peripheral 5-HT1D-like receptor involved in serotonergic induced hindlimb scratching in rats. Eur J Pharmacol 1991; 194: 201208. 26. Khasabov SG, et al. Modulation of aerent-evoked neurotransmission by 5HT3 receptors in young rat dorsal horn neurones in vitro: a putative mechanism of 5-HT3 induced anti-nociception. Br J Pharmacol 1999; 127:843852. 27. Kubota K, et al. Pharmacological characterization of capsaicin-induced body movement of neonatal rat. Jpn J Pharmacol 1999; 80:137142. 28. Thomsen JS, et al. Scratch induction in the rat by intradermal serotonin: a model for pruritus. Acta Derm-Venereol 2001; 81:250254. 29. Thomsen JS. Itch models and eect of topical antipruritic substances. PhD thesis, University of Copenhagen, 2001. 30. Weisshaar E, Ziethen B, Gollnick H. Can a serotonin type 3 (5-HT3) receptor antagonist reduce experimentally-induced itch? Inamm Res 1997; 46:412416. 31. Thomsen JS, et al. The eect of topically applied salicylic compounds on serotonin-induced scratching behaviour in hairless rats. Exp Dermatol 2002; 11:370375. 32. Yosipovitch G, et al. Topically applied aspirin rapidly decreases histamineinduced itch. Acta Derm-Venereol 1997; 77:4648.

14
Human Itch Models, with Special Emphasis on Itch in SLS-Inflamed and Normal Skin
Jens Schiersing Thomsen
Gentofte University Hospital, Copenhagen, Denmark

I.

OBSERVATIONS IN HUMANS

Experimental itch studies have, until now, focused on eliciting itch by one or two mediators. In clinical dermatology, itch is typically seen in inammatory dermatoses, containing a whole orchestra of inammatory mediators. Consequently, several research groups have provided information about inammatory mediators, such as prostaglandins and opiates, as being potentiators of conventional itch mediators (1,2). In this way, dierent mediators may contribute to itch sensation (3), and in particular, injection of two dierent mediators in normal skin has been studied (4), with synergy demonstrated (1,5,6). The alternative to eliciting itch with concomitant experimental mediators has been to induce itch in patients with dierent kinds of pruritic or inammatory dermatoses [e.g., urticaria (7), itching psoriasis (7), and unclassied pruritus (7)]. Itch in patients has typically been compared with healthy volunteers (8,9). In recent years, patients suering from atopic dermatitis (AE), in particular, have been studied in experimental itch studies (10,11). Histamine,
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acetylcholine, and other itch inducers have been used to induce itch in AE patients and healthy volunteers in the same studies (7,10,12). One study included both AE patients suering from acute eczema and AE patients during a symptom-free period (12). However, comparison between patients and healthy volunteers is problematic when assessing the inuence of inammation on experimentally induced itch, because the two groups do not match each other. Dierences in itch sensation between the groups could be attributed to factors other than the inamed skin (e.g., cerebral mechanisms, or dierences in Baseline State). Typically, itch is scored by using a 100-mm visual analog scale (VAS) (1214). Both the time interval until itch is perceived (itch latency) (8,15,16) and itch threshold (i.e., the lowest substance concentration eliciting itch) (17,18) are measured. Itch duration (7,8,16), itch magnitude (16), and a combination of these, namely the Total itch index, Tii (or area under the curve, AUC), are often quantied. Scratch intensity has also been used as a more objective measure of itch sensation (1923). However, itch is subjective in nature and scratching can only be a surrogate of self-grading (24). Associated skin symptoms such as wheal (cutaneous edema) and are areas are often quantied in itch studies (2527). Ultraltration from the postcapillary venules creates the wheal (28), while are is a vasodilatation resulting from a local axonal skin reex (28,29). The C-ber-mediated responses (are and itch) often correlate (28,30), while the exclusively vascular wheal typically does not correlate with the two others (28,31). The area of itchy skin can be measured in itch models (32). Alloknesis (or itchy skin) means another sensation, and itch is induced by touching the surrounding area of, e.g., an insect bite (3335). The area of alloknesis can be measured. Changes in skin blood ow have also been quantied in itch studies by laser Doppler owmetry (10,12).

II.

THE SLS-INFLAMED SKIN MODEL FOR PRURITUS IN HUMANS

Instead of mimicking inamed skin seeking for new itch potentiators in a twomediator system, we aimed to establish an itch model in humans comprising both normal and experimentally inamed skin, using volunteers as their own controls (36). The skin of ve selected test sites on one volar forearm was pretreated for 24 hr with large Finn Chambers containing 1% sodium lauryl sulfate (SLS) used as a standard contact irritant to induce inammation.

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After 24 hr, the skin is inamed, and pruritogenic mediators can be intradermally injected into inamed skin (Fig. 1) and normal skin. Dierent pruritic substances can be used in the range 1020 AL, and histamine and saline can be used as positive and negative control substances. All substances are intradermally injected into the inamed test sites, and also into corresponding nontreated sites on the opposite forearm. After injections, the test individuals score itch intensity on a visual analog scale (VAS) for 20 min, and wheal area can then be measured. Flare areas are measured after 5 min (37). In this design, itch can be induced in both normal and inamed skin at the same time in the same volunteer. Because volunteers serve as their own controls, the inuence of skin inammation on dierent itch mediators and antipruritics can be directly assessed. When establishing the model, we could not demonstrate dierences in pruritic potential between mediators injected in inamed and normal skin, because itch was neither signicantly improved

Figure 1 Injection of pruritic substances in sodium lauryl sulfateinamed skin. Extra large Finn Chambers (containing 150 AL of 1% sodium lauryl sulfate) were applied to the forearms for 24 h to induce inammation. Thereafter 10 AL or 20 AL of a pruritic substance was injected in the center of the inamed skin.

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nor signicantly decreased in inamed skin compared with normal skin (36). However, after histamine, the wheal area was much ( p<0.001) larger in the inamed skin when compared with the normal skin. The SLS-inamed skin is closer to a clinically relevant situation compared with the noninamed skin, which is used in conventional itch models. The question of how inammation aects the itch response is of major scientic and clinical interest. Potential antipruritic substances might work dierently in the two situations. Furthermore, the perturbed skin induced by SLS, simulating diseased skin with barrier disruption, may be more sensitive in testing new topical antipruritics simply as a result of better skin penetration of test drugs (38). Thus it is also relevant to determine the eect of a potentially new antipruritic in both inamed and normal skin, to mimic the skin pharmacology of diseased skin. Using this new model, pain should always be scored together with itch. Pain can be scored to distinguish this sensation from itch. However, pain is furthermore able to modify itch sensation, and the inclusion of pain scores is becoming increasingly important in experimental itch studies. This new itch model in humans is important for testing of itch involving both normal and inamed skin. The model has a potential in the evaluation of new topical and systemic treatments of itch.

III.

EXAMPLE OF DRUG TESTING BY USING THE SLS-INFLAMED SKIN MODEL FOR PRURITUS IN HUMANS

In 1997, Yosipovitch et al. (13) reported that topically applied aspirin (acetylsalicylic acid) rapidly decreases histamine-induced itch in humans. We wanted to conrm this observation, and further study the antipruritic ability of topical aspirin in inamed skin by using the abovedescribed model (37). After the inducement of inamed skin with SLS, aspirin 10%, aspirin 1%, mepyramine 5%, and vehicle were applied to the inamed and corresponding noninamed areas 20 min before itch induction with intradermal histamine injection. Itch and pain were scored on a visual analog scale at regular intervals. Wheal and are areas were measured. No dierence in itch intensities was found after the application of test substances. Similar to Yosipovitch et al., we found that itch duration was shorter after aspirin application compared to vehicle. However, more itch was induced when aspirin was applied to inamed skin compared with normal skin. In both skin types, wheals and ares were smaller after application of

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aspirin. We concluded that despite a signicant skin penetration, as measured by the inuence on wheal and are reactions, topically applied aspirin did not decrease histamine-induced itch in the model used. Thus our results are both in accordance, and also in contrast, with the results obtained by Yosipovitch et al. (13).

REFERENCES
1. 2. Greaves MW, McDonald-Gibson W. Itch: role of prostaglandins. Br Med J 1973; 3:608609. Fjellner B, Hagermark O. Potentiation of histamine-induced itch and are responses in human skin by the enkephalin analogue FK-33-824, beta-endorphin and morphine. Arch Dermatol Res 1982; 274:2937. Wallengren J. The pathophysiology of itch. Eur J Dermatol 1993; 3:643647. Lovell CR, et al. Prostaglandins and pruritus. Br J Dermatol 1976; 94:273275. , Strandberg K, Hamberg M. Potentiation of itch and are Ha germark O responses in human skin by prostaglandins E2 and H2 and a prostaglandin endoperoxide analog. J Invest Dermatol 1977; 69:527530. . Pruritus in polycythemia vera: treatment with aspirin Fjellner B, Ha germark O and possibility of platelet involvement. Acta Derm-Venereol 1979; 59:505512. Hagermark O, Rajka G, Bergvist U. Experimental itch in human skin elicited by rat mast cell chymase. Acta Derm-Venereol 1972; 52:125128. Rajka G. Experimental pruritus in the unaected skin of patients with dierent itching dermatoses. Acta Derm-Venereol 1970; 50:270272. Hagermark O, Strandberg K. Comparison of the antihistaminic eects in skin of a tertiary (promethazine) and a quarternary phenothiazine (N-hydroxyethylpromethazine). Acta Allergol 1974; 29:462468. Heyer G, Hornstein OP, Handwerker HO. Skin reactions and itch sensation induced by epicutaneous histamine application in atopic dermatitis and controls. J Invest Dermatol 1989; 93:492496. Groene D, Martus P, Heyer G. Doxepin aects acetylcholine induced cutaneous reactions in atopic eczema. Exp Dermatol 2001; 10:110117. Rukwied R, Heyer G. Cutaneous reactions and sensations after intracutaneous injection of vasoactive intestinal polypeptide and acetylcholine in atopic eczema patients and healthy controls. Arch Dermatol Res 1998; 290:198204. Yosipovitch G, et al. Topically applied aspirin rapidly decreases histamineinduced itch. Acta Derm-Venereol 1997; 77:4648. Darsow U, et al. Skin testing of the pruritogenic activity of histamine and cytokines (interleukin-2 and tumour necrosis factor-alpha) at the dermalepidermal junction. Br J Dermatol 1997; 137:415417. . Inuence of antihistamines, sedatives, and aspirin on experHa germark O imental itch. Acta Derm-Venereol 1973; 53:363368.

3. 4. 5.

6. 7. 8. 9.

10.

11. 12.

13. 14.

15.

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16. Simone DA, Alreja M, LaMotte RH. Psychophysical studies of the itch sensation and itchy skin (alloknesis) produced by intracutaneous injection of histamine. Somatosens Motor Res 1991; 8:271279. 17. Shuttleworth D, et al. Relief of experimentally induced pruritus with a novel eutectic mixture of local anaesthetic agents. Br J Dermatol 1988; 119:535540. 18. Davies MG, et al. The ecacy of histamine antagonists as antipruritics in experimentally induced pruritus. Arch Dermatol Res 1979; 266:117120. 19. Ebata T, et al. The characteristics of nocturnal scratching in adults with atopic dermatitis. Br J Dermatol 1999; 141:8286. 20. Endo K, et al. Evaluation of scratch movements by a new scratch-monitor to analyze nocturnal itching in atopic dermatitis. Acta Derm-Venereol 1997; 77:432 435. 21. Ebata T, et al. Use of a wrist activity monitor for the measurement of nocturnal scratching in patients with atopic dermatitis. Br J Dermatol 2001; 144:305 309. 22. Rees JL, Laidlaw A. Pruritus: more scratch than itch. Clin Exp Dermatol 1999; 24:490493. 23. Daly BM, Shuster S. Eect of aspirin on pruritus. Br Med J (Clin Res Ed) 1986; 293:907. 24. Wahlgren CF. Measurement of itch. Semin Dermatol 1995; 14:277284. 25. Weisshaar E, et al. Eect of topical capsaicin on the cutaneous reactions and itching to histamine in atopic eczema compared to healthy skin. Arch Dermatol Res 1998; 290:306311. 26. Jorizzo JL, et al. Vascular responses of human skin to injection of substance P and mechanism of action. Eur J Pharmacol 1983; 87:6776. 27. Fuller RW, et al. Sensory neuropeptide eects in human skin. Br J Pharmacol 1987; 92:781788. 28. Darsow U, et al. Correlations between histamine-induced wheal, are and itch. Arch Dermatol Res 1996; 288:436441. 29. Schmelz M, Petersen LJ. Neurogenic inammation in human and rodent skin. News Physiol Sci 2001; 16:3337. 30. Bromm B, et al. Eects of menthol and cold on histamine-induced itch and skin reactions in man. Neurosci Lett 1995; 187:157160. 31. Lischetzki G, et al. Nociceptor activation and protein extravasation induced by inammatory mediators in human skin. Eur J Pain 2001; 5:4957. 32. Heyer G, et al. Histamine-induced itch and alloknesis (itchy skin) in atopic eczema patients and controls. Acta Derm-Venereol 1995; 75:348352. 33. Weisshaar E, et al. Experimentally induced pruritus and cutaneous reactions with topical antihistamine and local analgesics in atopic eczema. Skin Pharmacol 1997; 10:183190. 34. Weisshaar E, Ziethen B, Gollnick H. Can a serotonin type 3 (5-HT3) receptor antagonist reduce experimentally-induced itch? Inamm Res 1997; 46:412416. 35. Heyer G, et al. Opiate and H1 antagonist eects on histamine induced pruritus and alloknesis. Pain 1997; 73:239243. 36. Thomsen JS, et al. Experimental itch in sodium lauryl sulphate-inamed and

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normal skin in humans: a randomized, double-blind, placebo-controlled study of histamine and other inducers of itch. Br J Dermatol 2002; 146:792800. T. Topically applied aspirin 37. Thomsen JS, Jensen SB, Benfeldt E, Serup J, Menne decreases histamine-induced wheal and are reactions in SLS inamed and normal skin, but does not decrease itch. A randomized, double-blind and placebocontrolled human study. Acta Derm Venereol 2002; 82:3035. 38. Benfeldt E, Serup J, Menne T. Eect of barrier perturbation on cutaneous salicylic acid penetration in human skin: in vivo pharmacokinetics using microdialysis and non-invasive quantication of barrier function. Br J Dermatol 1999; 140:739748.

15
Microdialysis in Itch Research
Martin Schmelz
University of Heidelberg, Mannheim, Germany

Intradermal microdialysis has been used successfully as an elegant tool to study the interaction of mediators, nociceptors, inammatory cells, and vasculature in human skin in vivo. The main advantage of this technique is given by the combination of atraumatic delivery of exogenous mediators and analysis of released endogenous mediators with noninvasive techniques to assess the vascular responses and psychophysical methods to measure quality and intensity of sensation.

I.

TECHNIQUE

Microdialysis is a minimally invasive technique that was originally developed for use in the central nervous system (1), but has also been adapted for dermal use (2). A semipermeable capillary is inserted into the tissue of interest and is perfused at a constant ow rate of a few microliters per minute. According to the concentration gradient, mediators will diuse from the tissue into the lumen of the capillary and can then be analyzed in the dialysate, which is collected after the tissue passage. If the perfusing medium contains substances at a concentration exceeding the tissue concentration, they will be delivered into the tissue by diusion. The molecular cuto of the capillaries is chosen according to the size of the molecules of interest. For small molecules like histamine, a molecular cuto of 5 kDa has been
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successfully used, whereas for large proteins like mast cell tryptase, a molecular cuto of 3 MDa is required. A. Measurement of Local Mediator Concentration

Microdialysis has been used to assess local histamine concentrations in human skin under control conditions (35). However, the main results in the arena of itch research were gained by measuring the histamine release in response to exogenous mediators. A multitude of studies has been conducted to assess the histamine concentrations in response to various mediators in controls and patients (2,621). Studies investigating the role of neuropeptides and mast cells for itch will be dealt with in detail below. Histamine release could be assessed in parallel to the itch sensation in type 1 allergy and urticaria (17,22,23). These results mainly conrm the role of mast cell-derived histamine in these conditions. The use of high-molecular cuto membranes has enabled the analysis of macromolecules with microdialysis. Thereby, cell activation markers like mast cell tryptase (6), eosinophilic cationic protein (ECP), and myeloperoxidase (24) could be measured. In the later study, cell activation markers were analyzed during the development of a delayed type 1 reaction following allergen prick for 7 hr. The increase of ECP matched the histologically observed inltration by eosinophil granulocytes. Rather than providing data on single mediators, these studies illustrate that microdialysis can be successfully employed to investigate the complex interactions of various inammatory cells in vivo. B. Simultaneous Assessment of Biological Responses

The use of microdialysis can be largely improved by the combination with noninvasive techniques to assess the biological response of the tissue. In Figure 1, the experimental setup of a standard microdialysis study is shown. As described above, stimulatory mediators or their antagonists can be delivered via the capillary, while, simultaneously, the released endogenous mediators are measured in the dialysate. In addition, the vascular response, which might result directly from a local eect of the applied mediator, from secondary local release, or from activation of nociceptors and subsequent release of vasodilatory neuropeptides in their innervation territory (axon reex), can be assessed by laser Doppler imaging. It should be noted that diusion in the tissue is very limited; thus the local vasodilatation is restricted to the immediate vicinity of the membrane. Even for the small and water-soluble histamine, molecule diusion in the skin is restricted to less than 3 mm (16). In contrast, the axon reex erythema can spread for

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Figure 1 Schematic illustration of the experimental setup. The muscle relaxant was delivered by diusion via plasmapheresis hollow bers inserted intracutaneously, causing mast cell degranulation. Mediator release, vascular reactions, and sensory eects were determined.

several centimeters from the stimulation site, as maximum diameters of chemonociceptors in human skin have been found to be 9 cm (25). As the mechanisms of local and axon reex vasodilatation are dierent, they have to be analyzed separately. As an example, mast cell degranulation by the muscle relaxant rocuronium is shown. At lower concentrations, the muscle relaxant induces local vasodilatation without mast cell degranulation and nociceptor activation; accordingly, no axon reex erythema can be assessed. At higher concentrations, rocuronium directly activates nociceptors and additionally degranulates mast cells; thus, in addition to local vasodilatation, an axon reex erythema is provoked (Fig. 2). Provocation of an axon reex erythema indicates the activation of nociceptors; however, these nociceptors could be involved in pain or in itch processing. Therefore, psychophysical assessment of quality and intensity of the induced sensation is necessary for the interpretation. The conrmation of mast cell degranulation by a mediator does not suce to prove its pruritic eect. As shown in Figure 3, the application of two dierent muscle relaxants may induce either pain or itch, although their mast cell degranulating eect is virtually identical as can be judged from the doseresponse curve for histamine release and protein extravasation (26) (Fig. 3). While rapa-

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Figure 2 Local vasodilatation (upper panels) and axon reex vasodilatation (lower panels) as assessed by laser Doppler imaging are shown in response to intraprobe delivery of dierent concentrations of rocuronium. Note that the nonneurogenic vasodilatation is restricted to the stimulatory membrane (upper left panel), whereas the axon reex erythema spreads several centimeters (lower left panel). (Modied from Ref. 26.)

curonium causes mast cell degranulation only, rocuronium also directly activates nociceptors involved in pain processing (27), and thus the pain sensation suppresses the itch as discussed in Chapter 3.

II.

NEUROPEPTIDES

Neuropeptides, especially substance P (SP), have been implicated in the mechanism of itch for decades (2832). There is no doubt that at high concentrations, SP degranulates mast cells by a nonreceptor-mediated mech-

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Figure 3 Doseresponse relations for nociceptor activation (itch or pain; upper panel), histamine release (center panel), and protein extravasation (lower panel) following intraprobe delivery of two dierent muscle relaxants via intradermal microdialysis bers are shown. (Modied from Ref. 27.)

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anism. However, even at high stimulatory concentrations of up to 105 M, SP did not evoke any sensation or axon reex, although protein extravasation and vasodilatation can be elicited at a concentration of 108 M, without any histamine release (33). In contrast to rodents, physiological concentrations of endogenously released SP are obviously too low to provoke mast cell degranulation (33,34) or even protein extravasation (35) in human skin. Thus, it can be concluded that SP-induced vasodilatation and wheal formation are mast cell-independent (36). In addition, there is probably no direct role for SP as pain or itch mediator in the periphery. This does not exclude a major role of the released neuropeptides for the inammatory process. Trophic and immunomodulatory eects of neuropeptides were observed at concentrations of about 1011 M (3739), which might reect their major function under physiological conditions. In addition, in the disease state, the concentrations of neuropeptides in the skin might well be increased and play a major role in the pathophysiological mechanisms as shown in chronic pain patients (40).

III.

MAST CELLS

As described above, exogenously applied neuropeptides degranulate dermal mast cells in humans, whereas endogenously released neuropeptides do not cause protein extravasation, histamine, or mast cell tryptase release even under conditions of intense nociceptor activation (6,1214,35,41). Despite the absence of acute degranulation, there is evidence for stimulatory eects of neuropeptides on mast cells. Picomolar concentrations of SP have been shown to prime mast cells for subsequent degranulation (42). In addition, SP can act on its specic receptor (NK1) on mast cells to induce increased tumor necrosis factor a (TNF a) expression in mast cells (43,44). Thus, there might well be a pathophysiological role of SP to enhance skin inammation and thereby indirectly promote itching, for example, in atopic dermatitis. A. Proteinase-Activated Receptors

While previous research has mainly focused on histamine as the main pruritic mediator in itch patients, microdialysis has also provided evidence for histamine-independent mechanism by which mast cells can induce itch. In atopic dermatitis patients, mast cell degranulation by compound 48/80 provokes itch, which is not suppressed by antihistamines (45) (Fig. 4). Mast cell-derived tryptase has been hypothesized as a possible candidate for this eect, as it specically activates proteinase-activated receptors (PAR-2). While proteinases like papain were identied as histamine-

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Figure 4 Maximum pruritus ratings (A), maximum are size (B), and wheal diameter (C) following stimulation with histamine (0.01% w/v), C48/80 (0.05% w/v), and C48/80 co-perfused with cetirizine (200 Ag/mL perfusate). Values are given as mean F S.E.M.; signicant dierences are marked by asterisks ( p < 0.05, MannWhitney Utest). Note that cetirizine reduces C48/80-induced wheal and are reactions; however, itch sensation is abolished in controls only (A). (Modied from Ref. 45.)

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independent itch mediators several decades ago (46,47), they did not receive much attention during the last years. However, the identication of specic proteinase-activated receptors on aerent nerve bers (48) has initiated various successful studies investigating the role of PAR-2 in the pain pathway (4951). Meanwhile, there is convincing evidence for an involvement of PAR-2 for activation and sensitization of both somatic (48,52) and visceral aerent nerve bers (5355). Apart from the involvement in the pain pathway, recent results from PAR-2 knockout mice indicate a role of PAR-2 also in itchy skin diseases including atopic dermatitis (56). The latest microdialysis result suggests that tryptase concentration is elevated in atopic dermatitis patients as could be expected from the higher percentage of tryptasepositive mast cells (57) and that activation of PAR-2 receptors may induce itch in these patients (57a). The importance of PAR-2 signaling for the induction of dermatitis has recently been shown by a markedly decreased contact dermatitis in PAR-2 knockout mice (56). As PAR-2 is expressed by various inammatory cells including mast cells (58) and T cells (59), one may speculate that PAR-2 is critically involved in both neurogenic and nonneurogenic inammation of human skin.

B.

Opioids

Activation of mast cells by opioids has been used to explain their pruritic eects. It is well known that morphine and codeine given in therapeutical concentrations degranulate mast cells. Microdialysis provides an elegant tool to investigate doseresponse relations for this eect. In Figure 5, mast cell tryptase increase following intraprobe delivery of morphine is shown. In contrast, the highly potent A-opioid agonist fentanil does not provoke any mast cell degranulation, even if applied at concentrations far exceeding the A-agonistic eect of morphine (Fig. 5). Thus, one can conclude that morphine-induced mast cell degranulation is not mediated by A-opioid receptors (10). On the other hand, fentanilinduced pruritus cannot be linked to mast cell degranulation, but instead central mechanisms have also to be assumed as discussed in Chapter 26.

C.

Other Mediators

There is a large body of evidence that histamine, the main pruritic in urticaria, is not the key factor for pruritus in atopic eczema (60). Prostaglandins are known to be weak pruritics upon intradermal injection. Interestingly, topical application of prostaglandin E2 (PGE2) in the conjunctiva seems

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Figure 5 Time course of tryptase concentration following intraprobe delivery of morphine and dierent concentrations of fentanil (black bar) is shown. Note that only morphine provokes mast cell tryptase release.

to be even more potent (61). In addition to its weak pruritic action, PGE2 has been shown to enhance histamine-induced itch (62,63). Recent investigations on local application of cyclooxygenase inhibitors suggest that there might be a role of prostanoids in histamine-induced itch (64) and pruritus in allergic conjunctivitis (65). However, oral cyclooxygenase inhibitors did not prove to be eective in the treatment of pruritus in AD patients (66) or experimentally induced itch (46), although they alleviate pruritus in polycythemia vera (67). Recent work on microdialytically applied PGE2 in atopic dermatitis patients and controls conrmed its pruritic activity, but did not provide evidence for increased PGE2 sensitivity in AD (68). In summary, microdialysis is an elegant tool that complements traditional approaches of itch research like psychophysics and behavioral tests. It provides unique information if used in combination with psychophysics and objective assessment of the biological responses. Therefore, in the context of itch research, the technique has been mainly used as a clinical research tool, which can be applied in patients. The future development might show two main directions: it will be important to link this approach to the results of basic research. On the other hand, the application of microdialysis should be

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extended to the sites of interest, namely, the symptomatic skin sites (7,8), which do not always coincide with the traditionally used volar forearm skin, but instead might involve dierent body regions such as scalp skin (69).

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1. 2. 3. Ungerstedt U, Hallstrom A. In vivo microdialysisa new approach to the analysis of neurotransmitters in the brain. Life Sci 1987; 41:861864. Groth L. Cutaneous microdialysis. Methodology and validation. Acta DermVenereol Suppl (Stockh) 1996; 197:161. Petersen LJ. Quantitative measurement of extracellular histamine concentrations in intact human skin in vivo by the microdialysis technique: methodological aspects. Allergy 1997; 52:547555. Krogstad AL, Lonnroth P, Larson G, Wallin BG. Increased interstitial histamine concentration in the psoriatic plaque. J Invest Dermatol 1997; 109:632 635. Anderson C, Andersson T, Andersson RG. In vivo microdialysis estimation of histamine in human skin. Skin Pharmacol 1992; 5:177183. Schmelz M, Zeck S, Raithel M, Rukwied R. Mast cell tryptase in dermal neurogenic inammation. Clin Exp Allergy 1999; 29:652659. Krogstad AL, Lonnroth P, Larson G, Wallin BG. Capsaicin treatment induces histamine release and perfusion changes in psoriatic skin. Br J Dermatol 1999; 141:8793. Krogstad AL. Neurogenic control of blood ow and histamine release in psoriatic skin. Acta Derm-Venereol (Stockh) Suppl 1999; 203:143. Clough G. Experimental models of skin inammation. Clin Exp Allergy 1999; 29(suppl 3):105108. Church MK, Clough GF. Human skin mast cells: in vitro and in vivo studies. Ann Allergy Asthma & Immun 1999; 83:471475. Odum L, Petersen LJ, Skov PS, Ebskov LB. Pituitary adenylate cyclase activating polypeptide (PACAP) is localized in human dermal neurons and causes histamine release from skin mast cells. Inamm Res 1998; 47:488492. Petersen LJ, Church MK, Skov PS. Histamine is released in the wheal but not the are following challenge of human skin in vivo: a microdialysis study. Clin Exp Allergy 1997a; 27:284295. Petersen LJ, Winge K, Brodin E, Skov PS. No release of histamine and substance P in capsaicin-induced neurogenic inammation in intact human skin in vivo: a microdialysis study. Clin Exp Allergy 1997b; 27:957965. Hultunen M, Harvima IT, Ackermann L, Harvima RJ, Naukkarinen A, Horsmanheimo M. Neuropeptide- and capsaicin-induced histamine release in skin monitored with the microdialysis technique. Acta Derm-Venereol (Stockh) 1996; 76:205209. Horsmanheimo L, Harvima IT, Harvima RJ, Ylonen J, Naukkarinen A,

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Horsmanheimo M. Histamine release in skin monitored with the microdialysis technique does not correlate with the wheal size induced by cow allergen. Br J Dermatol 1996; 134:94100. Petersen LJ, Church MK, Skov PS. Mapping of histamine release in the wheal and are reaction by skin microdialysis technique. J Allergy Clin Immunol 1995a; 95:255. Andersson T, Wardell K, Anderson C. Human in vivo cutaneous microdialysis estimation of histamine release in cold urticaria. Acta Derm-Venereol (Stockh) 1995; 75:343347. Petersen LJ, Nielsen HJ, Skov PS. Codeine induced histamine release in intact human skin monitored by skin microdialysis technique comparison of intradermal injections with an atraumatic intraprobe drug delivery system. Clin Exp Allergy 1995b; 25:10451052. Petersen LJ, Skov PS. Methacholine induces wheal-and-are reactions in human skin but does not release histamine in vivo as assessed by the skin microdialysis technique. Allergy 1995; 50:976980. Okahara K, Murakami T, Yamamoto S, Yata N. Skin microdialysis: detection of in vivo histamine release in cutaneous allergic reactions. Skin Pharmacol 1995; 8:113118. Petersen LJ, Poulsen LK, Sondergaard J, Skov PS. The use of cutaneous microdialysis to measure substance P- induced histamine release in intact human skin in vivo. J Allergy Clin Immunol 1994; 94:773783. Petersen LJ, Mosbech H, Skov PS. Allergen-induced histamine release in intact human skin in vivo assessed by skin microdialysis technique: characterization of factors inuencing histamine releasability. J Allergy Clin Immunol 1996; 97:672679. Petersen LJ, Skov PS, Bindslev Jensen C, Sondergaard J. Histamine release in immediate-type hypersensitivity reactions in intact human skin measured by microdialysis. A preliminary study. Allergy 1992; 47:635637. Nielsen PN, Skov PS, Poulsen LK, Schmelz M, Petersen LJ. Cetirizine inhibits skin reactions but not mediator release in immediate and developing latephase allergic cutaneous reactions. A double-blind, placebo-controlled study. Clin Exp Allergy 2001; 31:13781384. Schmelz M, Schmidt R, Bickel A, Handwerker HO, Torebjo rk HE. Specic Creceptors for itch in human skin. J Neurosci 1997b; 17:80038008. Koppert W, Blunk JA, Petersen LJ, Skov P, Rentsch K, Schmelz M. Dierent patterns of mast cell activation by muscle relaxants in human skin. Anesthesiology 2001; 95:659667. Blunk J, Seifert F, Schmelz M, Reeh PW, Koppert W. Injection pain of rocuronium and vecuronium is evoked by direct activation of nociceptive nerve endings. Eur J Anaesthesiol 2003; 20:245253. Andoh T, Nagasawa T, Satoh M, Kuraishi Y. Substance P induction of itchassociated response mediated by cutaneous NK1 tachykinin receptors in mice. J Pharmacol Exp Ther 1998; 286:11401145. Wallengren J, Akesson A, Scheja A, Sundler F. Occurrence and distribution of

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peptidergic nerve bers in skin biopsies from patients with systemic sclerosis. Acta Derm-Venereol (Stockh) 1996; 76:126128. 30. Heyer G, Hornstein OP, Handwerker HO. Reactions to intradermally injected substance P and topically applied mustard oil in atopic dermatitis patients. Acta Derm-Venereol 1991; 71:291295. 31. Giannetti A, Girolomoni G. Skin reactivity to neuropeptides in atopic dermatitis. Br J Dermatol 1989; 121:681688. 32. Ha germark O, Hokfelt T, Pernow B. Flare and itch induced by substance P in human skin. J Invest Dermatol 1978; 71:233235. 33. Weidner C, Klede M, Rukwied R, Lischetzki G, Neisius U, Skov PS, Petersen LJ, Schmelz M. Acute eects of substance P and calcitonin gene-related peptide in human skina microdialysis study. J Invest Dermatol 2000; 115:10151020. 34. Schmelz M, Petersen LJ. Neurogenic inammation in human and rodent skin. News Physiol Sci 2001; 16:3337. 35. Sauerstein K, Klede M, Hilliges M, Schmelz M. Electrically evoked neuropeptide release and neurogenic inammation dier between rat and human skin. J Physiol 2000; 529:803810. 36. Cappugi P, Tsampau D, Lotti T. Substance P provokes cutaneous erythema and edema through a histamine-independent pathway. Int J Dermatol 1992; 31:206209. 37. Parenti A, Amerini S, Ledda F, Maggi CA, Ziche M. The tachykinin NK1 receptor mediates the migration-promoting eect of substance P on human skin broblasts in culture. Naunyn-Schmiedebergs Arch Pharmacol 1996; 353:475481. 38. Noveral JP, Grunstein MM. Tachykinin regulation of airway smooth muscle cell proliferation. Am J Physiol 1995; 269:L339L343. 39. Lambert RW, Granstein RD. Neuropeptides and Langerhans cells. Exp Dermatol 1998; 7:7380. 40. Weber M, Birklein F, Neundorfer B, Schmelz M. Facilitated neurogenic inammation in complex regional pain syndrome. Pain 2001; 91:251257. 41. Schmelz M, Luz O, Averbeck B, Bickel A. Plasma extravasation and neuropeptide release in human skin as measured by intradermal microdialysis. Neurosci Lett 1997a; 230:14. 42. Janiszewski J, Bienenstock J, Blennerhassett MG. Picomolar doses of substance P trigger electrical responses in mast cells without degranulation. Am J Physiol 1994; 267:C138C145. 43. Cocchiara R, Lampiasi N, Albeggiani G, Bongiovanni A, Azzolina A, Geraci D. Mast cell production of TNF-alpha induced by substance P evidence for a modulatory role of substance P-antagonists. J Neuroimmunol 1999a; 101:128 136. 44. Cocchiara R, Lampiasi N, Albeggiani G, Bongiovanni A, Azzolina A, Geraci D. Mast cell production of TNF-alpha induced by substance P evidence for a modulatory role of substance P-antagonists. J Neuroimmunol 1999b; 101:128136.

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45. Rukwied R, Lischetzki G, McGlone F, Heyer G, Schmelz M. Mast cell mediators other than histamine-induced pruritus in atopic dermatitis patients: a dermal microdialysis study. Br J Dermatol 2000; 142:11141120. 46. Ha germark O. Inuence of antihistamines, sedatives, and aspirin on experimental itch. Acta Derm-Venereol 1973; 53:363368. 47. Rajka G. Latency and duration of pruritus elicited by trypsin in aged patients with itching eczema and psoriasis. Acta Derm-Venereol 1969; 49:401403. 48. Steinho M, Vergnolle N, Young SH, Tognetto M, Amadesi S, Ennes HS, Trevisani M, Hollenberg MD, Wallace JL, Caughey GH, Mitchell SE, Williams LM, Geppetti P, Mayer EA, Bunnett NW. Agonists of proteinaseactivated receptor-2-induced inammation by a neurogenic mechanism. Nat Med 2000; 6:151158. 49. Fiorucci S, Distrutti E. Role of PAR2 in pain and inammation. Trends Pharmacol Sci 2002; 23:153155. 50. Vergnolle N, Bunnett NW, Sharkey KA, Brussee V, Compton SJ, Grady EF, Cirino G, Gerard N, Basbaum AI, Andrade-Gordon P, Hollenberg MD, Wallace JL. Proteinase-activated receptor-2 and hyperalgesia: a novel pain pathway. Nat Med 2001a; 7:821826. 51. Vergnolle N, Wallace JL, Bunnett NW, Hollenberg MD. Protease-activated receptors in inammation, neuronal signaling and pain. Trends Pharmacol Sci 2001b; 22:146152. 52. Kawabata A, Kawao N, Kuroda R, Tanaka A, Itoh H, Nishikawa H. Peripheral PAR-2 triggers thermal hyperalgesia and nociceptive responses in rats. NeuroReport 2001; 12:715719. 53. Corvera CU, Dery O, McConalogue K, Gamp P, Thoma M, Al Ani B, Caughey GH, Hollenberg MD, Bunnett NW. Thrombin and mast cell tryptase regulate guinea-pig myenteric neurons through proteinase-activated receptors-1 and -2. J Physiol (Lond) 1999; 517:741756. 54. Coelho AM, Vergnolle N, Guiard B, Fioramonti J, Bueno L. Proteinases and proteinase-activated receptor 2: a possible role to promote visceral hyperalgesia in rats. Gastroenterology 2002; 122:10351047. 55. Hoogerwerf WA, Zou L, Shenoy M, Sun D, Micci MA, Lee-Hellmich H, Xiao SY, Winston JH, Pasricha PJ. The proteinase-activated receptor 2 is involved in nociception. J Neurosci 2001; 21:90369042. 56. Kawagoe J, Takizawa T, Matsumoto J, Tamiya M, Meek SE, Smith AJ, Hunter GD, Plevin R, Saito N, Kanke T, Fujii M, Wada Y. Eect of proteaseactivated receptor-2 deciency on allergic dermatitis in the mouse ear. Jpn J Pharmacol 2002; 88:7784. 57. Jarvikallio A, Naukkarinen A, Harvima IT, Aalto ML, Horsmanheimo M. Quantitative analysis of tryptase- and chymase-containing mast cells in atopic dermatitis and nummular eczema. Br J Dermatol 1997; 136:871877. 57a. Steinho M, Neisius U, Ikoma A, et al. Proteinase-activated receptor-2 mediates itch: a novel pathway for pruritus in human skin. J Neurosci 2003; 23:61766180. 58. DAndrea MR, Rogahn CJ, Andrade-Gordon P. Localization of protease-

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Schmelz activated receptors-1 and -2 in human mast cells: indications for an amplied mast cell degranulation cascade. Biotech Histochem 2000; 75:8590. Bar-Shavit R, Maoz M, Yongjun Y, Groysman M, Dekel I, Katzav S. Signalling pathways induced by protease-activated receptors and integrins in T cells. Immunology 2002; 105:3546. Klein PA, Clark RA. An evidence-based review of the ecacy of antihistamines in relieving pruritus in atopic dermatitis. Arch Dermatol 1999; 135:15221525. Woodward DF, Nieves AL, Hawley SB, Joseph R, Merlino GF, Spada CS. The pruritogenic and inammatory eects of prostanoids in the conjunctiva. J Ocul Pharmacol Ther 1995; 11:339347. Greaves MW, McDonald-Gibson W. Itch: role of prostaglandins. Br Med J 1973; 3:608609. Ha germark O, Strandberg K, Hamberg M. Potentiation of itch and are responses in human skin by prostaglandins E2 and H2 and a prostaglandin endoperoxide analog. J Invest Dermatol 1977; 69:527530. Yosipovitch G, Ademola J, Lui P, Amin S, Maibach HI. Topically applied aspirin rapidly decreases histamine induced itch. Acta Derm-Venereol (Stockh) 1997; 77:4648. Woodward DF, Nieves AL, Friedlaender MH. Characterization of receptor subtypes involved in prostanoid-induced conjunctival pruritus and their role in mediating allergic conjunctival itching. J Pharmacol Exp Ther 1996; 279:137142. Daly BM, Shuster S. Eect of aspirin on pruritus. Br Med J (Clin Res Ed) 1986; 293:907. Fjellner B, Ha germark O. Pruritus in polycythemia vera: treatment with aspirin and possibility of platelet involvement. Acta Derm-Venereol 1979; 59:505512. Neisius U, Olsson R, Rukwied R, Lischetzki G, Schmelz M. Prostaglandin E2 induces vasodilatation and pruritus, but no protein extravasation in atopic dermatitis and controls. J Am Acad Dermatol 2002; 47:2832. Rukwied R, Zeck S, Schmelz M, McGlone F. Sensitivity of human scalp skin to pruritic stimuli investigated by intradermal microdialysis in vivo. J Am Acad Dermatol 2002; 47:245250.

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66. 67.

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16
Measuring Nocturnal Scratching in Atopic Dermatitis
Toshiya Ebata
Jikei University School of Medicine, Tokyo, Japan

I.

INTRODUCTION

Itching is the major symptom of atopic dermatitis (AD), and the resultant scratching apparently worsens the skin lesions. Scratching causes further itch, and a vicious itchscratch cycle is created. Patients tend to scratch more during the night. Therefore, it is clinically important to evaluate the nature and the amount of nightly scratching in AD and try to treat it, as well as use standard anti-inammatory therapies. The amount of scratching is also regarded as a quantitative reection of the sensation of itch. In the majority of studies, scratching during the night has been chosen for analysis because scratching during daytime is aected by daily activities and psychological factors. In this chapter, the methods and the eects of the measurement of scratching in AD are reviewed.

II.

MEASUREMENT OF NOCTURNAL SCRATCHING

Measurement of scratching dates back to the early 1970s when Savin et al. (1,2) pioneered measuring scratching during sleep by measuring muscle potentials from both forearms generated by the act of scratching. They eval161

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uated nocturnal scratching by counting the number and length of scratch bouts in pruritic skin diseases such as AD, dermatitis herpetiformis, lichen planus, urticaria, and psoriasis. By the simultaneous measurement of polysomnography (PSG), they demonstrated that scratching occurs during all stages of sleep but is more frequent during stages 1 and 2 than in stages 3 and 4. The results indicate that conscious aspects have some inuence on nocturnal scratching, which had been regarded as a mere reex action. Felix and Shuster (3) modied self-winding wrist watches to measure limb movements in the act of nocturnal scratching in various pruritic skin diseases. They demonstrated that nocturnal scratching correlated well with the subjective assessment of the severity of the itching. They also measured scratch movements on the bed with proximity vibration transducers attached to the bed legs, which gave qualitative and quantitative information about scratching and served as a reference for the measurement with limb meters. Summereld and Welch (4) developed an electromagnetic movement detector as a later version of the limb meter, which increased sensitivity and could record cumulative time spent on scratching. They measured nocturnal scratching of patients with itchy and nonitchy liver diseases. Aoki et al. (5) measured scratching by using paper strain gauges attached to the backs of the hands. By simultaneous measurements with the PSG, they showed that deep orthodox sleep is seriously deprived in patients with severe AD (6). They also observed that sleep tends to lighten after scratching bouts and suggested that scratching itself can lead to lightening of sleep. Endo et al. (7) developed a pressure sensor that is attached to the backs of the hands. It is a portable device and can be used by outpatients. Ebata et al. (8) used an infrared video camera to directly record and measure nocturnal scratching in AD. It was capable of recording in the complete darkness of the ward and it needed no patient connection to the device. In addition to the quantication of the amount of scratching expressed in terms of scratching time, the patterns and locations of scratching were successfully observed. One disadvantage is that it is a time-consuming task to play back the video to measure scratching time. All the devices for scratch measurement enumerated above are used only by a few researchers with specialized interest in the eld. Some dermatologists applied wrist activity monitors (Fig. 1) for the measurement of nocturnal scratching. They are commercially available wristwatch-shaped devices and contain a piezoelectric sensor to record physical motions, and have already been used in sleep studies and neurology. Laidlaw and Rees (9) used an ActigraphR (Ambulatory Monitoring Inc., Ardsley, NY) attached to the wrists and ankles of the subjects, and found that itchy patients signicantly moved their hands but not their legs as compared to the controls, and assumed that these movements were due to scratching. Ebata et al. (10) used

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Figure 1 Wrist activity monitors.

an ActiTracR (IM Systems, Baltimore, MD) in patients with AD and demonstrated a signicant positive correlation between activity counts of the wrists motions, as measured by the ActiTrac, and scratching time, as measured simultaneously by an infrared video camera. By using these commercially available devices, the measurement of nocturnal scratching can come within the reach of any research group that acquires the devices. However, because they are not specically designed to pick up scratching motions exclusively, there is room for the development of more specic monitors for scratching.

III.

CHARACTERISTICS OF NOCTURNAL SCRATCHING IN AD

Using the techniques described above, several investigators measured nocturnal scratching in patients with AD mainly for the purpose of estimating itch intensity to objectively evaluate the eects of treatment. In general, nocturnal scratching has been reported during 220% of time asleep. The

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severity of AD is reported to correlate with the amount of scratching (7,10). As a result of 112 infrared video recordings of 36 adult patients, patients with severe AD were shown to spend, on average, 15% of the time in bed on scratching, those with moderate AD spent 6% and those with mild AD spent 0.7%, respectively. Patients tended to scratch the head, face, and neck longer than other parts of the body. Patients with severe AD scratched vigorously and longer. The mean duration of scratching bout was more than a minute in this group of patients (11). Although a quantitative assessment of nocturnal scratching is possible with other devices, the infrared video pictures of the patients with severe AD quite impressively conveyed the true images of vigorous scratching behavior and its impact on sleep to the observers. The actual conditions of severe nocturnal scratching in children have been documented by a report on the experience of mothers caring for a child with severe AD (12).

IV.

EVALUATION OF TREATMENT EFFICACY

Felix and Shuster (3) showed that nocturnal scratching, as measured by limb meters, decreased toward a normal level as the sensation of itch disappeared after successful treatment with topical corticosteroids in 18 inpatients with eczema. Infrared video techniques also demonstrated that nocturnal scratching time decreased by, on average, 15% as the dermatitis markedly improved after standard treatment, which consisted of topical corticosteroids, emollients, and oral antihistamines (11). The eect of oral antihistamines in relieving the pruritus of AD has been a controversial issue. There are some reports suggesting that histamine does not play a major role as a pruritogen in AD (13,14). Placebo-controlled studies of the antipruritc eects of oral antihistamines, as judged by subjective evaluation such as the visual analogue scale (VAS), have shown conicting results. Some have shown positive eects (1517), whereas others have shown negative results (1820). To date, there seems to be no report that is considered to be a grade A trial (large, randomized, double-blind, placebocontrolled clinical trial) to support or refute the antipruritic eects of oral antihistamines (21). Demonstration of changes in nocturnal scratching in response to oral antihistamines may help to solve this problem. Endo et al. (22) found that azelastine chloride, an antihistamine with a mildly sedative action, signicantly reduced nocturnal scratching in 40 adult patients with AD. However, there is the possibility that the decrease in nocturnal scratching achieved by sedative antihistamines is due to their sedative eect, which may prolong the period of deep sleep stages when the number of scratch bouts is small. Savin et al. (23) showed this to be the case by measuring PSG while giving patients trimeprazine and trimipramine. There is also a report

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showing that nitrazepam, a hypnotic without any antihistamine activity, reduced itch and nocturnal scratching in itchy dermatoses including AD (24). However, a placebo-controlled study using infrared video recordings showed that the total duration of nocturnal scratching was not aected although the frequency of scratch bouts decreased by taking 10 mg of nitrazepam (25).

V.

FUTURE PROSPECTS

In spite of the considerable eorts made to measure nocturnal scratching so far, it is necessary to further clarify the relationship between nocturnal scratching and itch because itch may be experienced in silent immobility without scratching (26). Although it has been proven that itch intensity is greatest at night in AD (27) and other itchy skin diseases (28,29), there are not enough data to show that it is applicable in every kind of pruritic disease. Indeed, some patients who complain of severe itch during the daytime do not appear to feel itch during the night. Taking that into account, scratching during the daytime should also be evaluated. Talbot et al. devised a transducer, which is a small piece of piezoelectric lm that is attached to the patients ngernail. When the ngernail vibrates as it traverses the skin in the act of scratching, the lm produces a signal. The signal is telemetered to a signal processor where the signals above a preset threshold level and within the preset frequencies are chosen as scratching activity index. They succeeded in discriminating scratching motions from other motions, which enables monitoring during the daytime as well (30). Bergasa et al. (31) applied this system for 24-hr measurement of scratching in inpatients with cholestatic pruritus and successfully demonstrated that patients scratched more during the daytime and that opioid A-antagonists worked to reduce scratching. A portable version of this device was developed by Molenaar et al. (32). Furthermore, Bijak et al. (33) recently developed a portable recording system of scratching using a ngernail vibration sensor and a microcontroller the size of a wristwatch. With such advanced technologies, a number of clinical studies are expected to be performed in the near future to better understand the nature of itch and scratching in AD and to lead to better methods to eectively treat itching.

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21. Klein PA, Clark RAF. An evidence-based review of the ecacy of antihistamines inrelieving pruritus in atopic dermatitis. Arch Dermatol 1999; 135:1522. 22. Endo K, Sano H, Fukuzumi T, et al. Objective scratch monitor evaluation of the eect of an antihistamine on nocturnal scratching in atopic dermatitis. J Dermatol Sci 1999; 22:54. 23. Savin JA, Paterson WD, Adam K, et al. Eects of trimeprazine and trimipramine on nocturnal scratching in patients with atopic eczema. Arch Dermatol 1979; 115:313. 24. Krause L, Shuster S. Mechanism of action of antipruritic drugs. BMJ 1983; 287:1199. 25. Ebata T, Izumi H, Aizawa H, et al. Eects of nitrazepam on nocturnal scratching in adults with atopic dermatitis: a double-blind placebo-controlled crossover study. Br J Dermatol 1998; 138:631. 26. Bernhard JD. Itch, Mechanisms and Management of Pruritus. New York: McGraw-Hill, 1994:95. 27. Yosipovitch G, Goon ATJ, Wee J, et al. Itch characteristics in Chinese patients with atopic dermatitis using a new questionnaire for the assessment of pruritus. Int J Dermatol 2002; 41:212. 28. Yosipovitch G, Goon A, Wee J, et al. The prevalence and clinical characteristics of pruritus among patients with extensive psoriasis. Br J Dermatol 2001a; 143: 969. 29. Yosipovitch G, Zucker I, Boner G, et al. A questionnaire for the assessment of pruritus: validation in uremic pruritus. Acta Derm-Venereol (Stockholm) 2001a; 81:108. 30. Talbot TL, Schmitt JM, Bergasa NV, et al. Application of piezo lm technology for the quantitative assessment of pruritus. Biomed Instrum Technol 1991; 25:400. 31. Bergasa NV, Alling DW, Talbot TL, et al. Eects of naloxone infusions in patients with the pruritus of cholestasis. Ann Intern Med 1995; 123:161. 32. Molenaar HA, Oosting J, Jones EA. Improved device for measuring scratching activity in patients with pruritus. Med Bil Eng Comput 1998; 36:220. 33. Bijak M, Mayr W, Rafolt D, et al. Pruritometer 2: portable recording system for the quantication of scratching as objective criterion for the pruritus. Biomed Tech 2001; 46:137. 34. Savin JA. The measurement of scratching. Semin Dermatol 1995; 14:285.

17
Itch Questionnaires as Tools for Itch Evaluation
Gil Yosipovitch
Wake Forest University School of Medicine, Winston-Salem, North Carolina, U.S.A.

Itch is the primary symptom of inammatory skin disease and an important symptom as well in several systemic diseases such as chronic renal failure and hepatic failure. Itch, like pain, is a subjective symptom. When itch is chronic, it can have a signicant eect on the quality of life with a complex network of suering that involves depression, somatic preoccupation, sleep disturbance, physical limitation, and eect on work. This is very similar to the eect of chronic pain on a patients life. Pain measurement with questionnaires is an important part of patient monitoring and evaluation. The ability to quantify the relevant dimensions of chronic pain is of prime importance for successful management of pain (1). The success of treatment can be observed within certain dimensions and not in others. Several questionnaires became part of the armamentarium of pain evaluation. The McGill Pain Questionnaire (MPQ) is the most extensively tested multidimensional scale available. It has been used worldwide, translated into many languages, and validated in dierent cultures. Little dermatological research has been devoted to evaluation of itch in relation to quality of life. Visual analog scales (VAS) have been the main technique of evaluation of itch for many years. The subjective perception of itch, like pain, is a complex emotional experience. It is inuenced by many factors, not only by a stimulus intensity or
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severity of skin disease, and therefore assessing it only with a visual analog scale has signicant limits. Chronic itch has an impact on several dimensions, including functional, psychosocial, and behavioral. Therefore, both the sensory and emotional aspects of itch are important and must be assessed. Recently, two itch questionnaires have been developed based on the MPQ. One is based on the long form and another is based on the short form (2,3). In the current chapter, we will describe the two questionnaires recently developed.

I.

THE SHORT-FORM ITCH QUESTIONNAIRE

This questionnaire [based on the short form of the McGill pain questionnaire (3)] has been developed and tested in several populations in Israel, Singapore, the United States, and Japan. It has been translated into several languages and has been validated (4). With this questionnaire, clinical characteristics of itch, its severity, and its impact on quality of life have been demonstrated in pruritic skin diseases such as psoriasis (5), atopic eczema (6), and chronic urticaria (7). In addition, it has been used to assess itch in several systemic diseases: in hemodialysis patients (4), in hyperthyroidism (Yosipovitch and Lee unpublished results), and in hospitalized schizophrenic patients (see Chapter 35). The questionnaire (see Appendix A) contains the following 10 sections: 1. 2. Personal data including demographic data, medical history, and current drug treatment. Pruritus history: duration, frequency, circumstances of onset and cessation, and accompanying symptoms such as pain, sweating, headache, heat sensation, and cold sensation. Circadian changes in the appearance and pattern of pruritus. Current antipruritic medications and their short-term eect (less than 24 hr) or long-term eect (more than 24 hr) on pruritus. Pruritus characteristics: questions on location, symmetry, pattern of pruritus, whether episodic or continuous. The patient is asked to mark on a body diagram the areas where he or she usually itches so that the percentage of area aected by pruritus can be calculated by the rule of nines for burn assessment (8). Description of itch sensation constructed from a list of six words used to describe pruritus. Aective descriptors commonly mentioned by patients suering from itch (see Appendix A). The

3. 4.

5.

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171

6.

7. 8. 9.

10.

descriptors were selected based on a set of words in more than 80 historical cases of patients suering from generalized pruritus describing their itch sensation. Each descriptor was ranked on an intensity scale of 0 = none, 1 = mild, 2 = moderate, and 3 = severe. A sensory and aective score was calculated as the sum of all parameters divided by the maximum possible number. Intensity of pruritus assessed by visual analog scale of 10 cm anchored at one end by the label no itch and at the opposite end by the label very strong itch. In addition, a verbal intensity scale was used: 1 = no itch; 2 = weak itch; 3 = moderate itch; 4 = strong itch; 5 = very strong itch. The examinees were asked to score their pruritus using both methods for four dierent temporal states: at present, i.e., at the time when the patient has been examined; at the time of the worst pruritus; at the time when the condition was in the best state; and at the time of the strongest itch after a mosquito bite as a reference point. Eect of pruritus on daily life activities and habits: a list of 16 activities/physical factors. The eects of pruritus on sleep and the use of sleeping medications. Coping with pruritus and quality-of-life measures: includes questions on mood change, eating habits, and sexual desire and function. Open-ended questions on ways the patient had found to relieve his or her pruritus and the techniques used to scratch.

A.

Validation of the Questionnaire

The questionnaire was repeated after 2 weeks in a random sample of uremic patients and there were no signicant dierences in regard to VAS in all temporal states and in the site of itch. The test reliability was high (r = 0.72, p < 0.01) (4). This questionnaire provides categorical scales, which assess the impact of pruritus upon the daily life of the aected patient: for example, How do the 16 life activities aect (or not) pruritus, e.g., increase itching, decrease itching? In addition, this questionnaire provides continuous scales. The VAS is the most common example: this tool allows subjects to describe their pruritus sensations without limitation to a few categories. It enables us to produce continuous data for analysis with parametric statistics and is a very sensitive way to assess itch intensity (9). The questionnaire also addresses issues related to quality of life, which have been addressed in other

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dermatology health-related quality-of-life tests such as the Dermatology Life Quality Index (DLQI) and Skindex (10,11).

II.

EPPENDORF ITCH QUESTIONNAIRE

The Eppendorf itch questionnaire (EIQ) is based on items of the long form of the McGill pain questionnaire (12). It has a large le of 40 descriptive adjectives describing the itch sensation and 40 descriptors of more aective and emotional items of itch (see Appendix B). Every item is scored within the range of 04: 0 = not true; 4 = describes exactly the itch sensation. The left side of the rst form of the EIQ consists of descriptors of the itch sensation itself; on the right side, descriptors with emotional value are summarized. The second form comprises descriptors of time, scratching behavior, a visual analog scale, and the area of distribution. This questionnaire was rst evaluated in a controlled laboratory environment with experimental histamine itch in 15 volunteers (13). As with the McGill pain questionnaire, it was possible to establish correlations of the questionnaire outcome with VAS of the investigated sensation during the interview. The next step was the use of the German version of this questionnaire in a higher number (n = 108) of patients with acute atopic eczema and correlating it to the SCORAD index used for evaluation of atopic eczema (14).

III.

COMPARISON BETWEEN BOTH QUESTIONNAIRES

The Eppendorf questionnaire is more informative in itch descriptors as it has 80 adjectives for sensation and aect relating to itch, while in the short form of the itch questionnaire, there are only 10. However, the short questionnaire provides data on measures of quality of life, which are not mentioned in the Eppendorf questionnaire. The short questionnaire evaluates itch intensity in four temporal states, while the EIQ does so only at the time of the interview.

IV.

CONCLUSION

The information provided by these tools and their usefulness as judged by various investigators in patients from dierent cultures may enable us to assess the clinical severity of itch and how patients cope with the disease. Furthermore, they will be useful tools for multicenter studies assessing the

Itch Questionnaires as Tools for Itch Evaluation

173

ecacy of new treatments which are currently in the pipeline for this troublesome symptom.

APPENDIX A: SHORT FORM OF QUESTIONNAIRE FOR PRURITUS ASSESSMENT Date: ____________________ Personal Information Subject No: ____________ Sex: Age: Male Female S M D W

Family Status:

Years of Education: __________ Ethnicity: _____________ Handedness: Right Left Both

Profession: _________________________________ Currently Working: Medical Background Diagnosis (es): ___________________________________________________ ___________________________________________________ ___________________________________________________ Medications: _____________________________________________________ 1. Pruritus History Subject currently suers from pruritus Subject suered from pruritus in the past (more than 12 year ago) When? _______________________ Yes/No

Yes Yes

No No

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Yosipovitch

Pruritus duration (current or previous) _______________________ Pruritus frequency 1. Almost every day 2. Every week 3. Every month 4. Seldom Circumstances of pruritus onset: _______________________ Circumstances surrounding the end of pruritus (if applicable): ________ ________________________________________________________________ _ Symptoms accompanying pruritus: 1. Pain in the pruritic area 2. Sweating 3. Headache 4. Heat sensation 5. Cold sensation 6. Other ________

CURRENT TREATMENT OF PRURITUS Systemic 1. 2. 3. 4. 5. 6. antihistamine tricyclics serotonin antagonist morphine antagonist cholestyramine aspirin
Local

j j j
Physical
1. 2. 3. 4. 5. 6. 7. 8. 9. emollients menthol counterirritants antihistamine topical anesthetic crotamiton steroids capsaicin doxepin

Other

1. TENS 2. UVB 3. PUVA

Eect of current treatment: 1. No eect 2. Short-term eect (less than 24 hr) 3. Long-term eect (more than 24 hr) In your opinion, why do you suer from pruritus? __________________ _____________________________________________________________

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2. Pruritus Characteristics A. Location Which areas of the subjects body are involved? ___________________ ___________________ Percent of subjects body surface area involved: ___________________ Is the pruritus symmetrical? Yes No

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Yosipovitch

*B. CHARACTER OF SENSATION To what extent do the following descriptions match your pruritus?

Tickling Stinging Crawling (like ants) Stabbing Pinching Burning Bothersome Annoying Unbearable Worrisome

j
jj jj jj jj j

not at all

jj jj jj jj j

to a small extent

jj jj jj jj j

to a moderate extent

jj jj jj jj j

to a great extent

*3. THE DAILY CHANGES OF THE PRURITUS For each part of the day please indicate: 1. The frequency of appearance a) Not itching b) Occasional c) Often d) Always present 2. The time pattern a) Continuous b) Episodic c) Momentary

Time Morning Noon Evening Night

j
j j

Frequency

j j

Time pattern

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177

Pruritus and sleep Please indicate frequency of the following: 1. Almost always 2. Sometimes 3. Never

Diculty falling asleep Awakening by pruritus Use of sleeping medications

j
Hot water Cold water Dryness Sweat

Inuences on pruritus Please indicate how each item aects your pruritus: 1. Increases 2. Does not aect 3. Relieves

Sleep Rest Activity Lying Sitting Stress Fatigue Eating Physical eort Specic fabrics

jj j
Cold Heat

4. Intensity of Pruritus Please indicate below the intensity of the pruritus as follows: 1. No itching 2. Weak

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3. 4. 5.

Moderate Strong Very strong

State of pruritus Now In its worst state In its best state Itch after a mosquito bite

j j
Intensity

VAS

Visual Analog Scale


Please mark on the lines below the intensity of itching that you experience in the following states: 1. 2. 3. 4. Now None ____________________________ Pruritus in its worst state None ____________________________ Pruritus in its best state None ____________________________ Itch after a mosquito bite None ____________________________ Very strong Very strong Very strong Very strong

5. Coping with the pruritus Has your mood changed because of the pruritus? 1. No change 2. Depressed 3. More agitated 4. Diculty in concentration 5. Anxious 6. Other Have your eating habits changed because of the pruritus? Did you start a special diet because of the pruritus? Sexual desire 1. No change 2. Decreased 3. Nonexistent

Yes No Yes No

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179

Sexual function 1. No change 2. Decreased 3. Nonexistent Did you nd a way to relieve the pruritus? Yes No How? ___________________________________________________________ With what do you scratch (e.g., hand, legs, brush, etc.)? ____________________________________________________________

APPENDIX B: EPPENDORF ITCH QUESTIONNAIRE Emotional descriptors are found on the right side of Form 1. Form 2 comprises topographical, diurnal and reaction items, and the visual analog scale (12).
EPPENDORF ITCH QUESTIONNAIRE Patient Form 1

Name:

Date:
No Yes

The following descriptions apply:


0 1 2 3 4 painful pulsating throbbing pricking piercing hurting dragging tickling biting stinging warm penetrating burning cold feels antlike acute more when cold

ID No: Please check for every item from 0 to 4.


No Yes

0 1 23 4 unbearable annoying physical urge to scratch awful rumbling terrible cruel bothersome no room for other feelings torturing merciless exciting inaming excruciating numbing tormenting wearing

180
No less when cold more when warm less when warm palpable dull soft sharp tingling comes in waves pointed sore high-pitched pinprick-like hot itching like sunburn pinching prickling stroking vibrating squeezing mosquito bite-like goes right through me Yes unpleasant pleasurable disgusting confusing tiresome tiring pleasant restricting my life disturbing my sleep dreadful churning up bothering grim unmanageable I only feel the itch My only desire: no itch stubborn frightful oppressive insistent severe uncontrollable compulsive

Yosipovitch
No Yes

0 1 2 3 4

01234

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REFERENCES
1. 2. 3. 4. 5. Melzack R, Katz J. Pain measurement in persons in pain. In: Wall PD, Melzack R, eds. Textbook of Pain. Edinburgh: Churchill Livingstone, 1994:339347. Melzack R. The McGill Pain Questionnaire: major properties and scoring methods. Pain 1975; 1:277299. Melzack R. The short form McGill Pain Questionnaire. Pain 1987; 30:191197. Yosipovitch G, Zucker I, Boner G, et al. A questionnaire for the assessment of pruritus: validation in uremic patients. Acta Derm Venereol 2001; 81:108111. Yosipovitch G, Goon A, Wee J, et al. The prevalence and clinical characteristics of pruritus among patients with extensive psoriasis. Br J Dermatol 2000; 143:969973. Yosipovitch G, Goon A, Wee J, et al. Itch characteristics in Chinese patients with atopic dermatitis using a new questionnaire for the assessment of pruritus. Int J Dermatol 2002; 41:212216. Yosipovitch G, Ansari N, Goon A, et al. Clinical characteristics of pruritus in chronic idiopathic urticaria. Br J Dermatol 2002; 147:3236. Goodwin CL, Finkelstain JI, Madden MR. Burns. In: Shwartz SI, Shires GT, Spencer FC, eds. Principles of Surgery. New York: McGraw-Hill, 1994:230. Wahlgren CF. Itch and atopic dermatitis: clinical and experimental studies. Acta Derm Venereol Suppl 1991; 165:153. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI), a simple practical measure for routine clinical use. Clin Exp Dermatol 1994; 132:942 949. Chren MM, Lasek RJ, Quinn LM, et al. Skindex, a quality-of-life measure for patients with skin disease: reliability, validity, and responsiveness. J Invest Dermatol 1996; 107:707713. Darsow U, Mautner V, Scharein E, Bromm B, Ring J. Der Eppendorfer Juckreizfragebogen. Hautarzt 1997; 48:730733. Darsow U, Ring J, Scharein E, Bromm B. Correlations between histamineinduced wheal, are and itch. Arch Dermatol Res 1996; 288:436441. Darsow U, Scharein E, Simon D, et al. New aspects of itch pathophysiology: component analysis of atopic itch using the Eppendorf Itch Questionnaire. Int Arch Allergy Immunol 2001; 124:326331.

6.

7. 8. 9. 10.

11.

12. 13. 14.

18
Epidemiology of Itching in Skin and Systemic Diseases
Gil Yosipovitch
Wake Forest University School of Medicine, Winston-Salem, North Carolina, U.S.A.

It is reasonable to assume that all humans itch at some point in their lives, but the incidence and prevalence of itching remains unknown. The discussion in this chapter will be limited to several skin diseases and systemic diseases where itch is an important factor, or where itch has not been well described before. We will present highlights and will not discuss all the itchy dermatoses. The reader is referred to complete textbooks for indepth discussion. (1) Atopic dermatitis: Itch is the hallmark symptom. The prevalence of atopic dermatitis has increased in the last 40 years and reached a worldwide percentage of 17% (1). There is much variation in the prevalence in dierent countries, only partly explained by nonvalidated translations of questionnaires. (2) Senile xerosis: Within the elderly population, itching is a common symptom associated with dry skin, experienced by 3060% of that population within any 1-week period (2). (3) Urticaria: The actual prevalence of urticaria, which is usually intensely itchy, is unavailable, but 1523% of the U.S. population may have had this condition at least once in their lifetime (3,4).
183

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(4) Contact dermatitis: It is frequently associated with itch. It is estimated that 210% of the general population is aected by hand dermatitis (5). In a recent large epidemiological study in Germany, the estimated prevalence of contact sensitization to nickel, a common allergen, was 1.94.5 million individuals (6). Plant dermatitis: Poison ivy dermatitis causes severe pruritus. In endemic areas in the United States, poison ivy dermatitis should be suspected in any individual with a severe contact dermatitis. It has been estimated that at least 70% of the population of the United States is sensitive to poison ivy and other members of this plant family (7). (5) Psoriasis and itch: Generalized itch is a common symptom in patients with extensive psoriasis (8). In a large U.S. study where 40,350 questionnaires were mailed out, itch was identied as the second most common symptom, experienced by 79% of respondents (9). (6) Papulosquamous diseases and itch: Many of the papulosquamous diseases of the skin have an itch component: lichen planus, pityriasis rosea, and pityriasis rubra pilaris, to name a few. Pityriasis rosea is a common papulosquamous disorder. The largest population-based epidemiologic study of pityriasis rosea was performed more than 20 years ago by Chuang et al. (10), who reported a yearly incidence of 172 per 100,000 person-years. (7) Neurodermatitis: It encompasses a large group of eczematous disorders, some of which belong to atopic eczema. Included in this group are lichen simplex chronicus, prurigo nodularis, prurigo simplex, chronic prurigo of adults, and lichen amyloidosis (see Chapter 25). (8) Seborrheic dermatitis: The prevalence of seborrheic dermatitis is around 13% in the general population of the United States (11). Localized itch is a common manifestation of seborrheic dermatitis, especially in the scalp. (9) Itch in hypertrophic scars and keloids: Keloids and scars, especially those which are growing, can cause itch (12). In a recent survey of 60 Asians who suered from keloids of 2 cm and above, 90% of the patients complained of itch. The itch occurs frequently in the borders of the keloid (Yosipovitch and Lee, unpublished results). (10) Postburn itch: It is a major problem aecting patients after burn injury at wound sites. The incidence ranges between 57% and 100% for children and between 25% and 87% for adults (see Chapter 24). (11) Bullous disease and itch: Dermatitis herpetiformis is a rare, intensely pruritic, chronic papulovesicular disease. Its incidence varies by dierent regions. For instance, it is evident in 588 per million in Ireland as compared to 110 per million in Scotland (13). Itch has been reported in patients with bullous pemphigoid, especially those with urticarial lesions. Pemphigoid gestation, which causes severe itch, is a rare autoimmune bullous disease that occurs in pregnancy. It is estimated to occur in 40,00060,000 pregnancies annually worldwide (13a).

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185

(12) Itch in cutaneous T cell lymphoma: It has been associated with persistent generalized pruritus, especially the erythrodermic type of mycosis fungoides and Sezary syndrome. Interestingly, a new subtype of mycosis fungoides has been described where generalized pruritus was the only cutaneous manifestation of the disease. This subtype was coined invisible mycosis fungoides (14,15). (13) Itch in rheumatic skin diseases Dermatomyositis and itch: Itch is a prominent feature in dermatomyositis noted by clinicians, but not well discussed in the literature. A case review of 20 patients with juvenile dermatomyositis showed that 38% had a complaint of pruritus (16). A recent survey at the Department of Dermatology at Wake Forest University School of Medicine among 70 patients with dermatomyositis had a similar prevalence of itch of 37% (Shirani et al., unpublished results). grens syndrome and itch: Recalcitrant itch has been reported with Sjo Sjo grens disease and was attributed to the skin dryness associated with this syndrome (17,18). (14) Infectious skin diseases: Many viral, fungal, and parasitic diseases cause itch. Bacterial diseases, except folliculitis, do not cause itch. Among viral diseases, varicella infection occurs throughout the world and its yearly incidence in 1996 was reported to be 4 million cases a year, equivalent to the annual U.S. child birth rate (19). The Centers for Disease Control and Prevention (CDC) is conducting a large epidemiologic study on the incidence of varicella; it seems that the incidence may have fallen in part due to prophylaxis with a vaccine. Itch in HIV patients: In HIV patients, itch is the most common dermatologic symptom (see Chapter 21). Supercial fungal infections and itch: Tinea versicolor infections and pityrosporum folliculitis are associated with itch, which is exacerbated in humid and hot temperatures. Tinea corporis has a strong itch component. Parasitic skin disease and itch: Parasitic diseases, such as scabies, are common causes of itch. Onchocerciasis, which occurs mainly in Africa, has an estimated 18 million infected patients and 6 million of them have severe itching (20). (15) Itch in venous insuciency: It is well known to vascular surgeons that patients suering from varicose veins and venous insuciency without any signs of eczema complain of itch in the lower legs, especially after prolonged standing. However, there is no published data on this topic. Venous eczema is a gravitational eczema which is occasionally itchy. It is related to venous hypertension, which appears later in life, usually in middle-aged or elderly females (11). (16) Itchy dermatosis of pregnancy: There are several pruritic dermatoses in pregnancy in addition to the pemphigoid gestations mentioned

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Yosipovitch

above. Polymorphic eruption of pregnancy is the most common, aecting about 1 in 160 pregnancies (21). Papular and pruritic dermatoses of pregnancy encompass mainly two disease entities: (a) prurigo of pregnancy aecting about 1 in 300 pregnancies (22); (b) pruritic folliculitis of pregnancy initially reported in 1981 by Zoberman and Farmer (23). Its prevalence is unknown, but it is much less common than the other dermatoses of pregnancy. Tables 1 and 2 summarize major skin diseases associated with itch.

Table 1

Itch in Skin Diseases Estimated prevalence of itch 17% of the population 210% of U.S. population 70% of the U.S. population is sensitized to this plant 3060% of adult population 1523% in U.S. population 80% of 40,350 psoriatics 172 per 100,000 person years a year Not known Not known (1) (5) (7) (2) (4) (9) (10) References

Skin disease Atopic dermatitis Contact dermatitis Hand dermatitis Poison ivy Senile xerosis Urticaria Psoriasis Pityriasis rosea Seborrheic dermatitis Neurodermatitis: lichen simplex chronicus, prurigo nodularis, lichen amyloidosis Pityriasis rubra pilaris Cutaneous T cell lymphoma: mycosis fungoides and Sezary syndrome Dermatitis herpetiformis Bullous pemphigoid Rheumatic skin disease: dermatomyositis Sjo grens syndrome Itch in keloid scars Postburn itch

Not known Not known

110588 per million per year Not known 38% Not known 90% 57100% for children 2587% for adults

(13)

(16)

(see Chapter 24)

Epidemiology of Itching in Skin and Systemic Diseases Table 2 Disease Varicella Itch in Infectious Skin Diseases Prevalence 4 million cases of varicella occur in the United States each year (equivalent to the annual birth rate in the United States) 2550% of HIV 1146% 6 million have severe itching Not known Not known

187

References (19)

HIV HIV-associated folliculitis Nonspecic pruritic eruption Onchocerciasis Scabies Supercial fungal infections

(24) (25) (20)

I.

EPIDEMIOLOGY OF ITCH IN SYSTEMIC DISEASES

Itch in uremic disease: The prevalence of uremic pruritus varies widely and ranges between 25% and 85% of patients with end-stage renal failure. Mettang (see Chapter 19) described a lower prevalence of 25% which was attributed to better ecacy of the dialysis. We examined the prevalence of itch in hemodialysis patients from two large centers and found that the prevalence is rather high (70%) and was not related to the type of dialysis membrane nor to the dialysis ecacy. Itch in hepatobiliary disease: Itch occurs in 2025% of patients with cholestatic jaundice (26). Pruritus occurs in 100% of patients with primary biliary cirrhosis and is the presenting symptom of PBC in 50% of patients (27). Hepatitis C as a cause of pruritus was initially reported in 1994. The prevalence of hepatitis C is rapidly increasing all over the world and recent studies have shown that a large number of patients suer from severe generalized pruritus (see Chapter 20). Cholestasis of pregnancy is the second most common cause of jaundice in pregnant women. Itch in hematopoietic disorders: Itch occurs in 48% of patients suering from polycythemia vera. It occurs classically after hot showers and baths. It may precede the diagnosis of the disease by years (28). Itch associated with Hodgkins disease develops in approximately 30% of patients. Interestingly, those who had severe pruritus, about 6%, had a statistically shorter survival rate than those with mild pruritus (29). In other hematopoietic malignancies, the prevalence of itch is not reported. Itch has been reported in mastocytosis and multiple myeloma.

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Yosipovitch

Itch has long been associated with iron-deciency anemia. Adams (30) presented results of a case study in 50 patients with generalized pruritus, where 20 patients had low ferritin as a measure of low iron stores.

II.

ENDOCRINE DISEASE AND ITCH

Thyroid disease: Itch in hyperthyroidism is common and the last study done on this topic showed that the prevalence in thyrotoxic patients was 411% (31). In a recent study in a large out-patient clinic, we found that itch in hyperthyroid patients was much more prevalent than the previous report

Table 3 Systemic Disease Associated with Pruritus Disease Chronic renal failureend stage Hepatic Cholestatic jaundice Primary biliary cirrhosis Hepatitis C Cholestasis of pregnancy Hematopoietic Polycythemia vera Iron deciency anemia Mastocytosis Multiple myeloma Hodgkins disease Endocrine Hyperthyroidism Hypothyroidism Diabetes mellitus Carcinoid syndrome Anorexia nervosa Neurological disease Multiple sclerosis Stroke Brain tumors Jakob-Creutzfeldt disease Postherpetic neuralgia Hydroxyethyl starch Notalgia parasthetica Prevalence 6090% 2025% 100% 4% ? 48% ? ? ? 30% 60% ? ? ? 58% 4% ? ? ? 48% 50% ? References (37) (26) (27)

(38)

(29) (unpublished)

(34) (39)

(40) (41)

Epidemiology of Itching in Skin and Systemic Diseases

189

and was observed in 60% of 120 patients (Lee and Yosipovitch, unpublished results). Itch in hypothyroidism: Although skin dryness is common in hypothyroidism, there are few reports on itch related to hypothyroidism. In a recent retrospective study of pruritus of unknown origin among 11 patients with a systemic cause for their itch, only one patient had hypothyroidism (32). Itch in diabetes mellitus: Localized itch has been well reported in diabetes, particularly related to vulvovaginal candidiasis. However, no statistical link has been shown between generalized itch and diabetes (33). Itch in anorexia nervosa: A recent study has shown that 58% of 19 hospitalized patients with anorexia nervosa suered from severe generalized pruritus (34). Itch in carcinoid syndrome: Itch is one of the symptoms associated with carcinoid syndrome (35) although burning sensation is more commonly noted. There is no data on the prevalence of itch in carcinoid syndrome. Itch in neurological diseases: Itch has been described in multiple neurological diseases involving the central nervous system, such as after cerebral stroke, brain tumors, multiple sclerosis, and prion disease, and peripheral neuropathies, such as postherpetic neuralgia and itch related to hydroxyethyl starch in peripheral nerves. For in-depth discussion on neuropathic itch, the reader is referred to Chapter 22. Itch in psychiatric diseases: A high prevalence of psychiatric disorders was reported in patients suering from pruritus (36). A recent study has shown that 30% of the in-patient population in a psychiatric institute were suering from itch (see Chapter 35). Table 3 summarizes the major systemic diseases associated with itch and the prevalence of itch.

REFERENCES
1. 2. 3. 4. Williams HC. Epidemiology of atopic dermatitis. Clin Exp Dermatol 2000; 523528. Beauregard S, Gilchrest BA. A survey of skin problems and skin care regimens in the elderly. Arch Dermatol 1987; 123, 16381643. Greaves MW. Chronic urticaria. N Engl J Med 1995; 332:17671772. Soter NA. Urticaria and angioedema. In: Freedberg IM, et al., ed. Dermatology in General Medicine. 5th ed. New York: McGraw Hill, 1998:1409 1419. Elston DM, Ahmed DD, Watsky KL, Schwarzenberger K. Hand dermatitis. J Am Acad Dermatol 2002; 47:291299. Schnuch A, Uter W, Geier J, et al. Epidemiology of contact allergy: An

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Yosipovitch estimation of morbidity employing the clinical epidemiology and drug utilization research (CE-DUR) approach. Contact Dermatitis 2002; 47:3239. Fisher A. Poison Sumac Rhus Family in Contact Dermatitis. In: Fisher A, ed. 3d ed. Philadelphia: Lea Febiger, 1986:405417. Yosipovitch G, Goon A, Wee J, Chan YH, Goh CL. The prevalence and clinical characteristics of pruritus among patients with extensive psoriasis. Br J Dermatol 2000; 143:969973. Krueger G, Koo J, Lebwohl M, Menter A, SternRS, RolstadT. The impact of psoriasis on quality of life: results of a 1998 National Psoriasis Foundation patient-membership survey. Arch Dermatol 2001; 137:280284. Chuang TY, Ilstrup DM, Perry HO, Kurland LT. Pityriasis rosea in Rochester, Minnesota, 1969 to 1978. J Am Acad Dermatol 1982; 7:8089. Burton JL, Holden CA. Eczema, lichenication and prurigo. In: Champion RH, Burton JL, Burns DA, Brethnach SM, eds. Rook/Wilkinson and Ebling Textbook of Dermatology. 6th ed. Blackwell Science, 1998:629660. Herman LE. Itching in scars. In: Bernhard J, ed. Itch Mechanisms and Management of Pruritus. McGraw Hill, 1994:156160. Fry L. Dermatitis Herpetiformis. London: Chapman and Hall, 1990. Jenkins RE, Shornik JK, Black MM. Pemphigoid Gestationes. J Eur Acad Dermatol Venereol 1993; 2:163173. Pujol RM, Gallardo F, Llistosella E, et al. Invisible mycosis fungoides: a diagnostic challenge. J Am Acad Dermatol 2000; 42:324328. Hwong H, Nicholas T, Duvic M. Invisible mycosis fungoides. J Am Acad Dermatol 2001; 45:318. Peloro TM, Miller OF III, Hahn TF, et al. Juvenile dermatomyositis: a retrospective review of a 30-year experience. J Am Acad Dermatol 2001; 45:2834. Feuerman EJ. Sjo grens syndrome presenting as recalcitrant generalized pruritus. Dermatologica 1968; 137:7486. Aso K. Senile dry skin type Sjo grens syndrome. Int J Dermatol 1994; 33:351 355. Arvin AM. Varicella zoster virus. In: Long S, Picekring LK, Proben CG, eds. Principles and Practice of Pediatric Infectious Disease. Churchill Livingstone, 1997:11441146. WHO fact sheets on onchocerciasis N-95, 2000. Black MM. Polymorphic eruption of pregnancy. In: Black M, McKay M, et al., eds. Obstetric and Gynecologic Dermatology. London: Mosby, 2002:39 44. Nurse DS. Prurigo of pregnancy. Aust J Dermatol 1968; 9:849855. Zoberman E, Farmer ER. Pruritic folliculitis of pregnancy. Arch Dermatol 1981; 117:2022. Majors M, Berger T, Blauvelt A, et al. HIV related eosinophilic folliculitis: a panel discussion. Semin Cutan Med Surg 1997; 16:219223. Liautaud B, Pape J, deHovitz J, et al. Pruritic skin lesions; a common initial presentation of acquired immunodeciency syndrome. Arch Dermatol 1989; 125:629632.

7. 8.

9.

10. 11.

12. 13. 13a. 14. 15. 16. 17. 18. 19.

20. 21.

22. 23. 24. 25.

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26. Botero F. Pruritus as a manifestation of systemic disorders. Cutis 1978; 21:873880. 27. Prince MI, Jones DE. Primary biliary cirrhosis: new perspectives in diagnosis and treatment. Postgrad Med J 2000; 76:199206. 28. Gerlini G, Prignano F, Pimpinelli N. Acute leucocytoclastic vasculitis and aquagenic pruritus long preceding polycythemia rubra vera. Eur J Dermatol 2002; 12:270271. 29. Gobbi PG, Attardo-Parrinello G, Lattanzio G, et al. Severe pruritus should be a B symptom in Hodgkins disease. Cancer 1983; 15:19341936. 30. Adams SJ. Iron deciency and other hematological causes of generalized pruritus. In: Bernhard JD, ed. Itch Mechanisms and Management of Pruritus. New York: McGraw-Hill, 1994:243250. 31. Caravati CM Jr, Richardson DR, Wood BT, Cawley EP. Cutaneous manifestations of hyperthyroidism. South Med J 1969; 62:11271130. 32. Zirwas MJ, Seraly MP. Pruritus of unknown origin; a retrospective study. J Am Acad Dermatol 2001; 45:892896. 33. Neilly JB, Martin A, Simpson N, MacCuish AC. Pruritus in diabetes mellitus: Investigation of prevalence and correlation with diabetes control. Diabetes Care 1986; 9:273275. 34. Morgan JF, Lacey JH. Scratching and fasting: a study of pruritus and anorexia nervosa. Br J Dermatol 1999; 140:453456. 35. Bruner W. Pruritusalso a challenge in internal medicine. Schweiz Med Wochenschr 1995; 125:22442250. 36. Picardi A, Abeni DMelchi CF, et al. Psychiatric morbidity in dermatological outpatients: an issue to be recognized. Br J Dermatol 2000; 143:983991. 37. Schwartz IF, Iaina A. Uraemic pruritus. Nephrol Dial Transplant 1999; 14: 834839. 38. Diehn F, Teeri A. Pruritus in polycythemia vera: prevalence, laboratory correlates and management. Br J Haematol 2001; 115:619621. 39. Matthews WB, Compston A, Allen IV, Martin CN. McAlpines Multiple Sclerosis. Edinburgh: Churchill Livingstone, 1991:68. 40. Oaklander AL, Bowsher D. Post herpetic itch (PHI), a common neuropathic complication after shingles (herpes zoster). J Pain 2001; 2S1:18. 41. Metze D, Reimann S, Szepfalusi Z, Bohle B, Kraft D, Luger TA. Persistent pruritus after hydroxyethyl starch infusion therapy: a result of long-term storage in cutaneous nerves. Br J Dermatol 1997; 136:553559.

19
Uremic Pruritus: New Perspectives and Insights from Recent Trials
Thomas Mettang and Dominik Mark Alscher
Robert-Bosch Hospital, Stuttgart, Germany

Christiane Pauli-Magnus
University Hospital Zurich, Zurich, Switzerland

I.

INTRODUCTION

Uremic pruritus (UP) remains a frequent and sometimes tormenting problem in patients with advanced or end-stage renal disease (1). Many attempts have been made to relieve this bothersome symptom in aected patients, but with only limited success. Whenever a new treatment option is reported to be eective, only little time elapses until conicting results are published. In the meantime, patients and physicians moods change from euphoria to disillusionment. This happened with erythropoietin (2,3) and naltrexone (4,5) as the last propagated treatment modalities in this respect. The main obstacle in the eort to create eective treatment modalities is the incomplete knowledge of the underlying pathophysiological mechanisms. Furthermore, given the great clinical heterogeneity of UP, systematically performed studies are hard to perform and therefore sparse.
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II.

CLINICAL FEATURES OF UREMIC PRURITUS

Intensity and spatial distribution of pruritus varies signicantly over time and patients are aected to a varying intensity throughout the duration of their renal disease. The intensity of UP ranges from sporadic discomfort to complete restlessness during daytime and nighttime. Initially, patients with uremic pruritus do not show any changes in skin appearance. As secondary phenomena, excoriation by scratching with or without impetigo can occur and, rarely, prurigo nodularis can be observed. (Fig. 1 ad). There are interindividual dierences in spatial distribution of UP: 2550% of the aected patients complain about generalized pruritus (6,7). In the remaining patients, UP seems to aect predominantly the back, the face, and the shunt

Figure 1 Skin aects observed in patients with uremic pruritus: (a) scratches on the arm hosting the stula; (b) deep scars on the shoulders and the back of a female patient on hemodialysis; (c) prurigo nodularis with excoreations and superinfection on the forearm of a patient on peritoneal dialysis; (d) Kyrles disease on the back of a patient on hemodialysis.

Uremic Pruritus: New Perspectives and Insights Table 1 Prevalence of Uremic Pruritus Reported in the Literature Prevalence, % (n) Author Young et al. (9) Altmeyer et al. (11) Gilchrest et al. (8) Bencini, (35) Matsumoto, (36) Parfrey, (38) Sta hle-Ba ckdahl, 1988 (37) Mettang et al. (10) Albert, (40) Balaskas, (39) Pauli-Magnus, (18) HD 86 78 37 41 57 49 66 64 54 54 22 (86) (28) (237) (54) (51) (29) (28) (71) (76) (378) CAPD Anamnestic UP, % (n) HD CAPD

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Statistical Relevance

41 (237) 16 (19) 50 (97) 50 (26) 48 (79) 62 43 (44) 17 (28) 21 (26) HD > CAPD n.s. n.s. n.s. n.s. CAPD>HD

arm, respectively (8). In about 25% of patients, UP is most severe during or immediately after dialysis (8).

III.

INCIDENCE OF UREMIC PRURITUS

Whereas at the beginnings of dialysis treatment UP was a very common problem, the incidence has declined over the past 20 years. In the early 1970s, Young et al. (9) reported that about 85% of patients were aected by UP. This number decreased to 5060% in the late 1980s (10). A recent investigation in Germany showed that only 22% of all patients on dialysis complained about pruritus at the time they were questioned (5). Some of the representative studies are shown in Table 1. Interestingly, substantial pruritus is very rare in pediatric patients on dialysis. This could be shown by a systematic review of all German pediatric dialysis centers involving 199 children, where only 9.1% of the children on dialysis complained about pruritus and the intensity was not very severe in the patients aected (12) (Fig. 2).

IV. A.

PATHOPHYSIOLOGICAL CONCEPTS OF UREMIC PRURITUS The Immuno-Hypothesis

With regard to several observations and information from other studies, there is increasing evidence that UP is rather a systemic than a skin disease

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Figure 2 Prevalence of uremic pruritus in children on dialysis (18 years or younger) and in adult dialysis patients (older than 18 years). Prevalence of uremic pruritus in children is signicantly lower than in adult patients (chi-square test). (From Ref. 12.)

and that derangements of the immune system with a proinammatory pattern may be involved in the pathogenesis of UP. This hypothesis is reinforced by several lines of evidence as follows: 1. Gilchrest et al. (13) showed that exposing patients to ultraviolet B (UVB) radiation was accompanied by relief of UP in a considerable number of patients. This eect could be demonstrated even when only half of the body was irradiated. This observation led to the assumption that there is a systemic eect of UVB radiation. Interestingly, UVB exposure was shown to be a pronounced modulator of Th1 and Th2 lymphocyte dierentiation and to attenuate TH1 expression (14). 2. Some studies have shown that increasing the eciency of dialysis leads to an improvement of UP (15). Consequently, the lower incidence of UP over the last decades has been linked to the improvement of dialysis modalities. The increased eectiveness of dialysis

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and Kt/V, which measures the clearances of small molecules or creatinine clearance-guided dialysis regimens, might have contributed to the decrease of UP incidence. Additionally, dialysis ecacy has increased following the use of high-ux membranes with larger surfaces, and dialysis biocompatibility has improved by the introduction of synthetic bers, mostly polysulfone or amylnitrile. These new materials activate complement and leukocytes to a much lower degree than the conventional materials such as cuprophane. Consequently, lower levels of secreted proinammatory cytokines are generated (16). 3. It has been shown that oral thalidomide and topical tacrolimus are eective in the therapy of UP, at least to a certain degree (17,18). Thalidomide, which is currently used as an immunomodulator to treat graft-vs.-host reactions, suppresses TNF-a production and leads to a predominant dierentiation of Th2 lymphocytes with suppression of interleukin 2 (IL-2)-producing Th1 cells (19). A similar eect can be observed with tacrolimus, which also suppresses dierentiation of Th1 lymphocytes and ensuing IL-2 production (20). 4. Patients after kidney transplantation almost never complain about UP as long as immunosuppressive therapy, including cyclosporine, is continued although a substantial loss of transplant function has occurred (11). These observations point to an important role of immunological mechanisms in the pathogenesis of UP. Several factors might be involved, but the most likely culprit is interleukin 2, which is secreted by activated Th1 lymphocytes. Patients receiving IL-2 for treatment of malignant disease frequently report tormenting pruritus (21). Additionally, it has been shown that intradermally applied IL-2 had a rapid, but weak pruritogenic eect (22). The hypothesis that interleukin-2 is causatively linked to UP cytokine should be further investigated, and T cell dierentiation patterns should be determined in patients with and without UP. Additionally, T-cell dierentiation and cytokine pattern should be investigated in children on dialysis who rarely complain about UP. It has been reported that older individuals are more likely to dierentiate T helper cells in favor of Th1 than younger people (23). B. The Opioid Hypothesis

The pathogenetic concept that changes in the opioidergic system might be involved in the pathophysiology of pruritus was rst developed for cholestatic pruritus and is supported by dierent lines of evidence: First, several A-

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receptor-agonistic drugs are known to induce pruritus, particularly after central administration (24,25); second, it could be demonstrated in animal studies that cholestasis is associated with an increased opioidergic tone (26,27); and, third, administration of opiate antagonists was successful in treatment of cholestatic pruritus (28,29). It was suggested that cholestatic pruritus may be mediated by pathological changes in the central nervous system. This hypothesis was supported by the ndings that a global downregulation of A receptors occurred in the brain of cholestatic rats (30) and that in patients with chronic cholestasis, an opiate withdrawal-like syndrome was precipitated by administration of an oral opiate antagonist (31). In 1985, there was a rst case report, describing successful treatment of uremic pruritus by intravenous administration of the opiate-antagonist naloxone (32). The therapeutical use of opiate antagonists in patients with uremic pruritus was based on the assumption that endogenous opiate peptides may also be involved in the pathogenesis of uremic pruritus. A subsequent placebo-controlled clinical trial by Peer et al. (4) showed that administration of the oral A-receptor-antagonist naltrexone is associated with a signicant decrease in pruritus perception in all of the treated patients with severe uremic pruritus (4). However, the number of patients studied was small and the treatment period (1 week) was short. It therefore remains to be established whether the opioidergic system plays a signicant role in the pathophysiology of uremic pruritus.

V.

THERAPEUTIC OPTIONS

As stated above, therapeutic options are sparse in UP. Most of the success stories turned into failure reports. Based on the aforementioned pathophysiological concepts, we will focus on two recent modalities, which were extensively studied by our group: 1. Local treatment with tacrolimus ointment. 2. Systemic treatment with naltrexone, a A-receptor antagonist. A. Local Treatment with Tacrolimus Ointment

Being helpless to alleviate severely tormented patients with UP led us to take some experimental approaches. It has been shown previously that administering tacrolimus ointment to the skin of patients with atopic dermatitis leads to complete or partial resolution of illness-related symptoms (33). Three patients on peritoneal dialysis with severe UP and unsuccessfully treated earlier with other potentially eective modalities were recruited. The patients documented pruritus by a visual analog scale (VAS) ranging from 0

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to 10 and a detailed pruritus score 3 days prior to and during the treatment phase. Patients were instructed to apply a 0.03% tacrolimus ointment twice daily to the areas most aected by UP for a period of 7 days. In all three patients, UP was reduced dramatically right from the start of treatment (Fig. 3). Two days after discontinuation of treatment, pruritus slowly recurred. No side eects could be monitored during or after the treatment period (18). Tacrolimus ointment seems to be a safe and highly eective short-term treatment option for patients suering from severe UP. However, considering the potential carcinogenic eect of systemically administered tacrolimus, one should be cautious to treat patients over a longer period of time. Systemic Treatment with Naltrexone, a M-Receptor Antagonist

B.

We undertook a placebo-controlled, double-blind, crossover study in patients on hemodialysis and peritoneal dialysis with persistent, treatment-resistant pruritus. Of 422 patients screened between December 1997 and June 1998, 93 suered from pruritus and 23 were eligible for the study. Patients started either with a 4-week naltrexone sequence (50 mg/day) or matched placebo. There was a 7-day washout between the two periods. Pruritus intensity was

Figure 3 Treatment of uremic pruritus with tacrolimus ointment in three patients with otherwise refractory pruritus. (From Ref. 18.)

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scored daily by visual analog scale (VAS) and weekly by a detailed score assessing scratching activity, distribution of pruritus, and frequency of pruritus-related sleep disturbance. Sixteen of 23 patients completed the study. During the naltrexone sequence, pruritus decreased by 29.2% on the visual analog scale and by 17.6% on the detailed score. In comparison, pruritus decreased by 16.9% on the visual analog scale and by 22.3% during the placebo period. The dierence between the naltrexone and the placebo treatment periods was not statistically signicant (Fig. 4). Nine of 23 patients complained about gastrointestinal adverse events during the naltrexone period in comparison to only 1 of 23 patients during the placebo period ( p<0.005). The results of Peer et al. are in sharp contrast to the results of our study and cannot be explained by dierences in patients compliance, in naltrexone dose, or study design as both studies were randomized, placebo-controlled, double-blind, crossover trials. As in the study of Peer, subjects included in our trial had long-lasting, treatment-resistant pruritus and no evidence of coexisting dermatologic disease. To exclude factors possibly aggravating uremic pruritus such as inadequate dialysis and anemia, only patients considered well dialyzed and with a hemoglobin >10 g/L were included in our trial. We also included patients with evidence of hyperparathyroidism and hyperphosphatemia because the pathogenetical role of these factors in uremic pruritus are controversial (34). However, to exclude a relevant inuence of these factors on the eect of naltrexone treatment, we performed a subgroup analysis examining data separately for those with hyperparathyroidism or hyperphospha-

Figure 4 Response of uremic pruritus in 23 patients with refractory pruritus during treatment with either 50 mg naltrexone or placebo for 4 weeks. No statistically signicant dierence between the two treatment phases could be seen. (From Ref. 5.)

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temia and those without these laboratory ndings. Naltrexone treatment was ineective in all subgroups. Pathogenesis of uremic pruritus may be inuenced by dierences in management of dialysis patients and regional dierences in lifestyle and eating habits in distinct parts of the world. In the study of Peer, there are no details given on dialysis modalities. Possibly, the involvement of such additional pathogenetic factors led to a higher incidence of severe pruritus and to dierences in naltrexone eectiveness in this investigation. In summary, UP remains a clinically important problem in patients on dialysis. The pathogenesis of this bothersome and sometimes tormenting symptom is still obscure. There are hints that derangement of either the opioidergic and/or the immune system is involved. Safe and eective therapeutic modalities are still lacking. Probably, immunomodulatory drugs may prove helpful in the most severe cases.

REFERENCES
Mettang T, Fischer FP, Kuhlmann U. Ura mischer Pruritus pathophysiologische und therapeutische Konzepte. Dtsch Med Woschenschr 1996; 121:1025 1031. 2. De Marchi S, Cecchin E, Villalta D, Sepiacci G, Santini G, Bartoli E. Relief of pruritus and decreases in plasma histamine concentrations during erythropoietin therapy in patients with uremia. N Engl J Med 1992; 326:969974. 3. Balaskas EV, Uldall RP. Erythropoietin does not improve uremic pruritus. Perit Dial Int 1992; 12:330331. 4. Peer G, Kivity S, Agami O, Fireman E, Silverberg D, Blum M, Iaina A. Randomised crossover trial of naltrexone in uraemic pruritus. Lancet 1996; 348:15521554. 5. Pauli-Magnus C, Mikus G, Alscher DM, Kirschner T, Nagel W, Gugeler N, Risler T, Berger ED, Kuhlmann U, Mettang T. Naltrexone does not relieve uremic pruritus: results of a randomized, placebo-controlled crossover-study. J Am Soc Nephrol 2000; 11:514519. 6. Morvay M, Marghescu S. Hautvera nderungen bei Haemodialysepatienten. Med Klin 1988; 83:507510. 7. Ponticelli C, Bencini PL. Uremic pruritus: a review. Nephron 1992; 60:15. 8. Gilchrest GA, Stern RS, Steinman TI, Brown RS, Arndt KA, Anderson WW. Clinical features of pruritus among patients undergoing maintenance hemodialysis. Arch Dermatol 1982; 118:154156. 9. Young AW, Sweeney EW, David DS, Cheigh J, Hochgelerent EL, Sakai S, Stenzel KH, Rubin AL. Dermatologic evaluation of pruritus in patients on hemodialysis. NY State J Med 1973; 73:26702674. 10. Mettang T, Fritz P, Weber J, Machleidt C, Hu bel E, Kuhlmann U. Uremic 1.

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Mettang et al. pruritus in patients on hemodialysis or Continuous Ambulatory Peritoneal Dialysis (CAPD). The role of plasma histamine and skin mast cells. Clin Nephrol 1990; 34:136141. Altmeyer P, Kachel HG, Scha fer G, Fahbinder W. Normalisierung der ura mischen Hautvera nderungen nach Nierentransplantation. Hautarzt 1986; 37:217 221. Schwab M, Mikus G, Mettang T, Pauli-Magnus C, Kuhlmann U. Arbeitsgemeinschaft fu diatrische Nephrologie: Ura mischer Pruritus im Kindes- und r Pa Jugendalter. Monatsz Kinderheilk 1999; 147:232. Gilchrest BA, Rowe JW, Brown RS, Steinman TI, Arndt KA. Ultraviolet phototherapy of uremic pruritus. Long-term results and possible mechanisms of action. Ann Intern Med 1979; 91:1721. Garssen J, Vandebriel RJ, DeGruijl FR, Wolvers DA, Van Dijk M, Fluitman A, Van Loveren H. UVB exposure-induced systemic modulation of Th1- and Th2-mediated immune responses. Immunology 1999; 97:506514. Hiroshige K, Kabashima N, Takasugi M, Kuroiwa A. Optimal dialysis improves uremic pruritus. Am J Kidney Dis 1995; 25:413419. Rousseau Y, Haener-Cavaillon N, Poignet JL, Meyrier A, Carreno MP. In vivo intracellular cytokine production by leukocytes during hemodialysis. Cytokine 2000; 12:506517. Silva SRB, Viana PCF, Lugon NV, Hoette M, Ruzany F, Lugon JR. Thalidomide for the treatment of uremic pruritus: a crossover randomized doubleblind trial. Nephron 1994; 67:270273. Pauli-Magnus C, Klumpp S, Alscher D, Kuhlmann U, Mettang T. Short-term ecacy of tacrolimus ointment in severe uremic pruritus. Perit Dial Int 2000; 6:802803. McHugh SM, Rifkin IR, Deigghton J, Wilson AB, Lachmann PJ, Lockwood CM, Ewan PJ. The immunosuppressive drug thalidomide induces T helper cell type 2 (Th2) and concomitantly inhibits Th1 cytokine production in mitogenand antigen-stimulated human peripheral blood mononuclear cell cultures. Clin Exp Immunol 1995; 99:160167. Suthanthiran M, Strom TB. Renal transplantation. N Engl J Med 1994; 331: 365376. Call TG, Creagan ET, Frytak S, Buckner JC, van Haelst-Pisani C, Homburger HA, Katzmann JA. Phase I trial of combined interleukin-2 with levamisole in patients with advanced malignant disease. Am J Clin Oncol 1994; 17:344347. Darsow U, Scharein E, Bromm B, Ring J. Skin testing of the pruritogenic activity of histamine and cytokines (interleukin-2 and tumour necrosis factoralpha) at the dermo-epidermal junction. Br J Dermatol 1997; 137:415417. Sakata-Kaneko S, Wakatsuki Y, Matsunaga Y, Usui T, Kita T. Altered Th1/ Th2 commitment in human CD4+ T cells with ageing. Clin Exp Immunol 2000; 120:267273. Reiz S, Westberg M. Side eects of epidural morphine. Lancet 1980; 2:203204. Cousins MJ, Mather LE. Intrathecal and epidural administration of opioids. Anesthesiology 1984; 62:276310.

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26. Bergasa NV, Jones EA. The pruritus of cholestasis: potential pathogenic and therapeutic implications of opioids. Gastroenterology 1995; 108:15821588. 27. Bergasa NV, Alling DW, Vergalla J, Jones EA. Cholestasis in the male rat is associated with naloxone-reversible antinociception. J Hepatol 1994; 20:8590. 28. Bergasa NV, Alling DW, Talbot TL, et al. Eects of naloxone infusion in patients with the pruritus of cholestasis: a double-blind randomised controls trial. Ann Intern Med 1995; 123:161167. 29. Bergasa NV, Schmitt JM, Talbot TL, et al. Open-label trial of oral nalmefene therapy for the pruritus of cholestasis. Hepatology 1998; 27:679684. 30. Bergasa NV, Rothman RB, Vergalla J, Xu H, Swain MG, Jones EA. Central mu-opioid-receptors are down-regulated in a rat model of acute cholestasis. J Hepatol 1992; 15:220224. 31. Thornton JR, Losowsky MS. Opioid peptides and primary biliary cirrhosis. Br Med J 1988; 297:15011504. 32. Andersen LW, Friedberg M, Lokkegaard N. Naloxone in treatment of uremic pruritus: a case history. Clin Nephrol 1984; 21:355356. 33. Gianni LM, Sulli MM. Topical tacrolimus in the treatment of atopic dermatitis. Ann Pharmacother 2001; 35:943946. 34. Cho YL, Liu HN, Huang TP, Tamg DC. Uremic pruritus: roles of parathyroid hormone and substance P. J Am Acad Dermatol 1997; 36:538543. 35. Bencini PL, Montagnino G, Citterio A, Graziani G, Crosti C, Ponticelli C. Cutaneous abnormalities in uremic patients. Nephron 1985; 40(3):316321. 36. Matsumoto M, Ichimaru K, Horie A. Pruritus and mast cell proliferation of the skin in end stage renal failure. Clin Nephrol 1985; 23(6):285288. 37. Sta hle-Backdahl M, Haegermark O, Lins LE. Clinical and experimental pruritus in chronic renal failure. Kidney Int 1988; 33:759. 38. Parfrey PS, Vavasour HM, Henry S, Bullock M, Gault MH. Clinical features and severity of nonspecic symptoms in dialysis patients. Nephron 1988; 50(2):121 128. 39. Balaskas EV, Chu M, Uldall RP, Gupta A, Oreopoulos DG. Pruritus in continuous ambulatory peritoneal dialysis and hemodialysis patients. Perit Dial Int 1993; 13(suppl 2):S527S532. 40. Albert C, Michel C, Ikeni A, Bindi P, Viron B, Mentre F, Mignon F. Pruritus in patients on hemodialysis (HD) and peritoneal dialysis (PD) Perit Dial Int 1991; 11(suppl):5.

20
Pruritus Complicating Liver Disease
Nora V. Bergasa
College of Physicians and Surgeons, Columbia University, New York, New York, U.S.A.

E. Anthony Jones
Academic Medical Center, Amsterdam, The Netherlands

I.

THE CHALLENGE OF PRURITUS COMPLICATING LIVER DISEASE

Pruritus is a complication of certain liver diseases, particularly those associated with cholestasis, such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (1). The pruritus due to liver disease tends to be generalized and is not adequately relieved by scratching. Itching commonly occurs in the palms of the hands and soles of the feet. Intractable pruritus complicating liver disease may be a serious clinical problem; it may result in interference with normal activities, sleep deprivation, depression, and even suicidal ideation. Because of its marked negative impact on the quality of life, intractable pruritus due to liver disease may, alone, be an indication for liver transplantation (2); thus, the provision of eective medical therapy is needed. Many patients with liver disease report that pruritus is worse when they go home at the end of a working day. Dermatologists may be the rst physicians to evaluate patients with pruritus secondary to liver disease. This type of pruritus is not associated with a primary rash, although lesions secondary to scratching activity may develop
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(e.g., excoriations and prurigo nodularis). Liver disease has to be considered in all patients who present with generalized pruritus and no primary rash. When evaluating such patients, it is mandatory to request routine serum biochemical liver tests. The intensity of pruritus in patients with liver disease does not seem to correlate with biochemical indices of liver disease or cholestasis. When pruritus complicates cholestatic diseases, such as PBC, the serum alkaline phosphatase level is typically elevated, but serum bilirubin may or may not be increased. Noncholestatic liver diseases, which may be complicated by pruritus, include, notably, chronic hepatitis C and, also rarely, chronic hepatitis B and chronic alcoholic liver disease; in patients with these diseases, plasma indices of cholestasis (e.g., elevated serum alkaline phosphatase level) may be normal, but increased serum activity of transaminases is usually present. In cholestatic and chronic noncholestatic parenchymal liver diseases, elevated fasting serum total bile acid concentrations are usually present; an increase in fasting serum total bile acid concentrations is a sensitive index of cholestasis. The etiology of the pruritus of cholestasis is unknown. It has been postulated that in patients with liver disease who experience pruritus, there is impaired secretion of putative pruritogens into bile, as a consequence of which they accumulate in plasma. A certain level of hepatocellular function appears to be necessary for pruritus complicating liver disease to be perceived; as a chronic hepatocellular disease progresses and hepatocellular failure supervenes, pruritus typically resolves spontaneously (3). Thus, in patients with pruritus secondary to liver disease, pruritogens may be synthesized by the liver (e.g., see Ref. 4). In addition, the reported rapid disappearance of pruritus in patients with large duct biliary obstruction, when the obstruction is relieved, is consistent with the hypothesis that the liver is a source of pruritogen(s) in this condition (5,6). Bile acids accumulate in the plasma, interstitial uid, and dermis in patients with cholestasis, and the intracutaneous injection of bile acids has been reported to induce a local itching sensation in normal volunteers (7). These observations have led to the hypothesis that bile acids are pruritogenic and contribute to pruritus complicating liver disease. However, an intracutaneous injection of bile acids does not simulate the pathophysiology of cholestasis or noncholestatic liver disease, and no neuroelectrophysiological data that indicate that bile acids are pruritogenic have been reported. When considering a possible pruritogenic role for bile acids, two clinical observations should be taken into account: (a) high serum concentrations of bile acids are not always associated with pruritus (8,9), and (b) relief of pruritus complicating liver disease is not consistently associated with a decrease in serum bile acid levels (10).

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II.

EMPIRICAL THERAPEUTIC APPROACHES

Several therapeutic interventions, other than opiate antagonists (see below), have been used empirically in the treatment of pruritus complicating liver disease. These approaches lack a clear scientically sound rationale and the ecacy of none of them has been established in well-designed clinical trials using an objective quantitative primary ecacy endpoint. Some of these empirical therapeutic approaches are considered briey in this section. Cholestyramine and colestipol are anion exchange resins that bind anions (including bile acids) in the intestines and decrease their enterohepatic circulation. Pruritus in some patients with liver disease appears to respond to treatment with one of these resins. An improvement, if it occurs, tends to be transient. When administered, a dose (e.g., a 4-g packet) before and after breakfast has been advocated in order to enhance the binding of hypothetical pruritogenic substance(s) in the small bowels after the delivery of food and bile into the intestine when the fast is broken. It is recommended that a dose of 16 g/day not be exceeded (11). Antihistamines do not appear to decrease the pruritus of cholestasis; the sedative properties of some antihistamines may help patients to sleep (12). There is no evidence that histamine is implicated in the pathogenesis of the pruritus of cholestasis. In two clinical trials, in which a subjective primary ecacy endpoint was used, the antibiotic, rifampicin, which induces enzymes of the hepatic P450 system at doses of 300450 mg/day, appeared to be associated with an improvement of the pruritus of cholestasis (13,14). Interestingly, single doses of rifampicin (900 mg) signicantly increased the 2-hr postprandial level of total serum bile acids in patients with cirrhosis (15), and rifampicin therapy has been associated with an opiate withdrawal reaction in patients receiving methadone (16). This reaction suggests that rifampicin may ameliorate pruritus in patients with liver disease by decreasing increased central opioidergic tone (see below). Invasive therapeutic procedures that aim to remove hypothetical pruritus-inducing compound(s) from the circulation have been used in the management of the pruritus of cholestasis. These procedures include charcoal hemoperfusion (17), plasmapheresis (18), partial external diversion of bile (19,20), and ileal diversion (21). Studies of these procedures have been inadequately controlled and have employed subjective ecacy endpoints. Thus, the ecacy of such procedures, which is dicult to assess in controlled clinical trials, has not been established. The fact that such maneuvers have been applied in attempts to treat pruritus complicating liver disease emphasizes how serious this complication of liver disease can be and the urgency of establishing ecacious medical therapies for it.

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III. A.

THE OPIOID NEUROTRANSMITTER SYSTEM The Pruritogenic Effects of Opiate Agonists

For decades, it has been assumed that the origin of pruritus complicating liver disease is peripheral in the skin due to increased levels of putative pruritogens interacting with cutaneous nerve endings. However, the lack of convincing scientic data to support this hypothesis has prompted a consideration of a nonperipheral origin of pruritus complicating liver disease, in particular a central origin in the brain. Opiate agonists, such as morphine, particularly when administered centrally, induce an increase in opioidergic neurotransmission in the brain, generalized pruritus, and scratching activity in both laboratory animals (2225) and human beings (2628). The generalized pruritus induced by opiate agonists is reversed by an opiate antagonist (2628), indicating that it is opioid receptor-mediated. Thus, increased opioidergic tone in the brain is a cause of generalized pruritus. It follows that, if central opioidergic neurotransmission is increased in cholestasis (and noncholestatic liver disease), enhanced opioidergic tone may contribute to pruritus complicating liver disease. B. The Opioid System in Cholestasis

The rst observation consistent with central opioidergic tone being increased in cholestasis was the observation by Thornton and Losowsky of an adverse reaction in patients with chronic cholestasis following the oral administration of the opiate antagonist, nalmefene. This reaction was characterized by anorexia, colicky abdominal pain, an increase in blood pressure, visual and auditory hallucinations, nausea, and insomnia. It subsided after about 23 days in spite of continued administration of the drug (29). In human opiate addicts, an opiate withdrawal reaction is precipitated by an abrupt interruption of ingestion of opiates, or by the administration of an opiate antagonist. Opiate antagonists compete with opioid agonists for occupancy of opioid receptors, at which opioid agonists mediate their intrinsic activity (30). The opiate withdrawal-like reaction experienced by patients with chronic cholestasis, who had not been taking opiate drugs, after the oral administration of an orally bioavailable opiate antagonist strongly suggested that central opioidergic tone was increased in the patients. Opioid withdrawal-like phenomena have also been reported in patients with chronic cholestasis in other studies following the administration of nalmefene (31,32) or another opiate antagonist, naltrexone (3335). That increased opioidergic tone is a component of the pathophysiology of cholestasis is also supported by the nding of antinociception (analgesia) (i.e., stereoselectively reversed by naloxone) in rats with acute cholestasis secondary to bile duct resection (36).

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The mechanism of increased opioidergic tone in cholestasis is not known. Increased availability of endogenous opioids at opioid receptors may be one factor. In support of this notion is the nding of downregulation of opioid receptors in brain membranes of rats with cholestasis secondary to bile duct resection (37). The high concentrations of the endogenous opioids, Met-enkephalin and Leu-enkephalin, in the plasma of an animal model of cholestasis (38) and patients with chronic cholestasis (29) may be responsible for the downregulation of central opioid receptors in cholestasis (37), if endogenous opioids in plasma can cross the bloodbrain barrier and reach central opioid receptors in the brain. However, it is not yet possible to implicate specic opioid peptides, found in high concentrations in plasma in cholestasis (29,38), in the pathogenesis of the pruritus of cholestasis. The available data support an opioid receptor-mediated mechanism in the mediation of the pruritus of cholestasis. However, data on the nature of the endogenous opioid receptor ligand(s) that contribute to pruritus in cholestatic patients are not yet available. It seems possible that the liver in cholestasis may be a source of endogenous opioids. We have shown that in cholestasis in the adult rat, the liver expresses the gene that codes for enkephalins and enkephalin-containing peptides, and also strongly expresses Met-enkephalin immunoreactivity (4). Met-enkephalin immunoreactivity was also detectable in the liver of patients with chronic cholestasis due to PBC (39). These ndings suggest that the liver in cholestasis reacquires its fetal ability to express and produce endogenous opioids. However, whether these ndings are relevant to the presumed increase in endogenous opioid-mediated opioidergic tone in the brain in cholestasis is not known. A major problem in studying the pruritus of cholestasis (or chronic noncholestatic liver disease) is the lack of an animal model of the syndrome. In monkeys (23,24) and rats (25), the administration of drugs with agonist activity at opioid receptors into the medullary dorsal horn (MDH) results in dose-dependent facial scratching activity. The model in monkeys has been used to assess the ability of plasma extracts from patients with chronic cholestasis to induce scratching activity. In this experiment, in contrast to the injection of plasma extracts from patients without pruritus or normal saline, the injection of plasma extracts from patients with pruritus into the MDH of monkeys was followed by facial scratching activity, which could be reversed or prevented by naloxone (40). These ndings suggest that the plasma of cholestatic patients with pruritus contains a substance(s) with opioid agonist properties and that this substance(s), by interacting with opioid receptors in the brain, can induce opioid receptor-mediated scratching activity. The hypothesis that increased central opioidergic tone contributes to the pruritus of cholestasis was originally proposed in 1990 (41).

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There may be a range of increased central opioidergic tone associated with generalized pruritus in patients with liver disease. In such patients, a drug that reduces opioidergic tone to a level below the lower limit of this range (e.g., an opiate antagonist) may ameliorate pruritus; conversely, a drug that increases opioidergic tone to a level above the upper limit of this range (e.g., morphine) may also ameliorate pruritus.

C.

Efficacy Endpoints in Clinical Trials

A major problem with clinical trials of treatments for pruritus is the need to incorporate into their design an objective quantitative primary ecacy endpoint. Pruritus, being an inherently subjective perception, cannot be quantitated. Accordingly, visual analogue scores of pruritus do not constitute an adequate endpoint in clinical trials (42). In contrast, scratching activity, which in this context can be dened as the behavioral consequence of pruritus, can be quantitated. A scratching activity monitoring system that measures scratching activity independent of gross body movements has been designed (43). This device has enabled controlled clinical trials of opiate antagonists for the pruritus of cholestasis to be conducted, using a welldened objective quantitative primary ecacy endpoint. The prototypic scratching activity monitoring system (43), which involves telemetering the electrical signal from a scratch transducer on a nger nail over a distance of a few meters to a receiver for processing and storage of data, requires the patient to be conned to a hospital room during the recording of scratching activity. This disadvantage has been overcome by storing data on scratching activity in a computer chip attached to the patients body during a recording. At the end of the period of the recording, the data in the chip are downloaded into a personal computer (44). Thus, this improved device enables data on scratching activity to be recorded while the patient is in a normal nonhospital environment.

D.

Efficacy of Opiate Antagonists in Ameliorating Pruritus Complicating Liver Disease

Bernstein and Swift (45) were the rst to report that the intravenous administration of the opiate antagonist, naloxone, but not saline, was associated with relief of pruritus in a patient with PBC. Thornton and Losowsky subsequently reported that oral administration of the opiate antagonist, nalmefene, for a period of 6 months was also associated with a marked amelioration or disappearance of pruritus in patients with chronic cholestasis

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(29). These investigators suggested that the improvement of pruritus in their patients might have resulted from inhibition of the release of pruritogenic substances by the opiate antagonist (29). A major disadvantage of these two reports was that the ecacy endpoint used was subjective. Using the prototypic scratching activity monitoring system (43), intravenous infusions of naloxone in two placebo-controlled trials have been shown to reduce scratching activity signicantly in cholestatic patients (46,47), and oral administration of nalmefene, in two additional controlled trials, has also been shown to reduce scratching activity signicantly in patients with cholestasis and pruritus (31,32) (Table 1). These ndings provide further support for the hypothesis that in cholestasis, there is increased opioidergic tone in the brain mediated by endogenous opioids, and that pruritus complicating cholestasis (or noncholestatic liver disease) is, at least in part, secondary to increased central opioid-mediated neurotransmission. The use of an opiate antagonist as a treatment for the pruritus of cholestasis is not empirical, but is based on a hypothesis (41) that is supported by scientic data (31,32,46,47). Two controlled trials of naltrexone for the pruritus of cholestasis, in which a subjective endpoint was used, have suggested that that this orally bioavailable opiate antagonist also ameliorates this type of pruritus (33,48). In Table 1, details on one of the trials are given (33). Naltrexone, which is used in the treatment of alcoholism and drug addiction, has been reported to be hepatotoxic at high doses (49). Accordingly, it is prudent to monitor routine biochemical liver tests when this drug is prescribed. In addition, its pharmacokinetics are aected by hepatocellular dysfunction (50). In Table 1, some details from four clinical trials of opiate antagonists for the pruritus of cholestasis are given. E. Prevention of Opiate Antagonist-Precipitated Opiate Withdrawal-Like Reactions

One concern regarding the use of orally bioavailable opiate antagonists for the treatment of the pruritus of cholestasis in practice is the possible precipitation of a clinically signicant opioid withdrawal-like reaction, when initiating therapy with an orally administered opiate antagonist. Such reactions can be prevented or minimized by starting therapy with low doses of an opiate antagonist. For example, therapy can be started with a slow ineective intravenous infusion of naloxone (e.g., 0.002 Ag/kg/min). The infusion rate can be slowly increased over hours to a pharmacologically ecacious rate (e.g., 0.2 Ag/kg/min). The infusion can then be stopped and small oral doses of an orally bioavailable opiate antagonist can be administered (e.g., naltrexone 12.5 or 25 mg, twice or thrice daily) (35,51).

212

Table 1 Some of the Studies of Opiate Antagonists for the Pruritus of Cholestasis Number of patients Methodology Scratching activity monitoring system Dose Results HSA geometric mean 34% lower on naloxone than on placebo solution 29 References 47

Naloxone

Nalmefene

Visual analog scale

97% decrease in mean visual analog scale score 75% decrease in mean HSA 4993% decrease in visual analog scale score

29 32 33 Bergasa and Jones

Naltrexone

16

Scratching activity monitoring system Visual analog scale

0.4 mg intravenous bolus followed by continuous infusions at doses of 0.2 Ag/kg/min 520 mg twice a day, orally 20120 mg per day, orally 50 mg/day

HSA=hourly scratching activity.

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IV.

OTHER NEUROTRANSMITTER SYSTEMS

The sensation or perception of itch may be associated with altered neurotransmission in the brain aecting more than one neurotransmitter system. Because pruritus and nociception share neural pathways, in this context, neurotransmitters involved in the mediation of nociception may be relevant. The serotonin system, like the opioid system, is involved in the mediation of nociception (52). To date, there are no reports documenting altered serotoninergic neurotransmission in patients with cholestasis and pruritus. However, experimental data suggest that increased central opioidergic tone can result in increased serotoninergic tone (53). Preliminary subjective observations suggest that ondansetron, an antagonist of type 3 serotonin receptors (5HT3), which are found on central nervous system and peripheral neurons, may ameliorate the pruritus of cholestasis (5457). One study involved the treatment of 10 patients with liver disease and pruritus. An intravenous bolus injection of ondansetron (4 or 8 mg) was reported to induce a decrease in pruritus, which lasted for several hours (56). This study had a placebocontrolled design, but it was not conducted double-blind and the endpoint was subjective. A short-term study, in which an objective quantitative ecacy endpoint (measurements of scratching activity) was used, did not conrm that ondansetron had a benecial eect on pruritus complicating liver disease (58). Another uncontrolled subjective observation relating to the serotonin neurotransmitter system in liver disease has been published in abstract form. In this report, the use of sertraline, a serotonin reuptake inhibitor, which was administered for depression to some patients with PBC and pruritus, was apparently associated with a decrease in pruritus (59). This observation has to be considered in relation to the apparent eect of ondansetron on pruritus in patients with liver disease. Ondansetron would tend to reduce serotoninergic tone, whereas sertraline would tend to increase it. It may be that there is a range of increased serotoninergic tone associated with pruritus, and that drugs that decrease or increase serotoninergic tone to values outside of this range ameliorate pruritus associated with increased serotoninergic tone. Further appropriately designed clinical trials, which include the use of an objective quantitative primary ecacy endpoint, are necessary to determine denitively whether ondansetron or sertraline decrease the pruritus of cholestasis. Recent uncontrolled subjective observations suggested that dronabinol, a cannabinoid agonist, may have improved intractable pruritus in three patients with liver disease (60). The use of dronabinol to treat pruritus was prompted by the experience of a patient who reported relief of her pruritus after smoking marijuana. We suggested that dronabinol, by increasing the threshold to nociception, such as the sensation of pruritus, may have de-

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creased the ability of the patients to experience this symptom (61). We tested this hypothesis in an animal model of cholestasis and showed that the pharmacological increase in cannabinoidergic neurotransmission does increase the threshold to experience nociception, as measured by the tail ick latency assay (62). Thus, it appears that there is a rationale to study drugs, such as dronabinol, that increase the nociception threshold as potential treatments for pruritus complicating liver disease in appropriately designed clinical trials.

V.

CONCLUDING PERSPECTIVES

The lack of application of objective methodology to study pruritus in patients with liver disease has retarded progress in establishing ecacious therapies for this form of pruritus. Opiate agonists, such as morphine, induce increased central opioidergic tone and centrally mediated generalized pruritus. The pruritus of cholestasis is associated with increased central opioidergic tone mediated by endogenous opioid agonist peptides. Thus, there is a rationale for administering opiate antagonists in the treatment of the pruritus of cholestasis. The development of methodology for the quantitation of scratching activity, independent of gross body movements, has enabled an objective quantitative primary ecacy endpoint to be incorporated into the design of clinical trials of opiate antagonist therapy for the pruritus of cholestasis. The results of four such trials indicate that opiate antagonists decrease scratching activity in patients with the pruritus of cholestasis. Because central opioidergic tone is increased in patients with the pruritus of cholestasis, oral administration of an orally bioavailable opiate antagonist may precipitate a transient, but nevertheless clinically signicant, opioid withdrawal-like reaction. Such reactions can be avoided by an initial slow intravenous infusion of naloxone followed by small oral doses of an orally bioavailable opiate antagonist.

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59. 60.

61.

62.

21
Itch in HIV-Infected Patients
Maria I. Duque, Gil Yosipovitch, and P. Samuel Pegram
Wake Forest University School of Medicine, Winston-Salem, North Carolina, U.S.A

I.

INTRODUCTION

Human immunodeciency virus (HIV) infection leads to a state of CD4 lymphopenia and generalized immune activation with the subsequent development of opportunistic infections and malignancies. The use of highly active antiretroviral therapy (HAART) has dramatically improved the clinical outcome for HIV-infected patients, but exposes the patients to multiple drugs and can be associated with immune restoration phenomena. Itching is a very common symptom in this population and can have multiple etiologies. Although generally tolerable and controllable, it can be a serious problem for the individual patient, greatly diminishing the quality of life and, in extreme cases, leading to suicidal ideation (1). The spectrum of pruritic conditions associated with HIV reects not anergy, but an inammatory state indicating signicant disruption of the normal cytokine and cell populations in the immune system of the HIV-infected patient (2). In advanced HIV infection, there is a shift in cytokines from a Th1predominant to a Th2-predominant state. Hypereosinophilia and increased levels of IgE can occur (1,3,4), and generalized itch and pruritic skin disease may become more prominent (5).
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II.

POSSIBLE PATHOGENESIS OF ITCH IN HIV INFECTION

HIV can infect cells other than those of the lymphoreticular system including Langerhans cells, broblasts, and neurons (6). The infection of peripheral nerves could lead to stimulation of pathways associated with itch directly or indirectly (1). There is also evidence for a direct excitatory eect of the HIV coat protein, gp120, on nociceptive neurons (7), and it is also linked to inammatory axonal damage (8). Interestingly, substance P, which is an important neuropeptide in itch as well as pain transmission, and its receptor, neurokinin 1, are present in lymphocytes and monocyte-derived macrophages and can modulate HIV infection. HIV-seropositive men have a signicantly higher plasma substance P level than uninfected controls (9). Another possible explanation for itch in patients with HIV is impaired barrier function of the stratum corneum, leading to skin dryness, which can enhance and aggravate itch (1). Dierent causes of itch in HIV-infected patients can be divided into the following categories: specic HIV itching eruptions, pruritic diseases exacerbated by HIV, drug reactions, and generalized idiopathic pruritus (see Table 1).

Table 1 Causes of Itch in HIV-Infected Patients Diseases Pruritic papules of HIV HIV-associated folliculitis Insect bite hypersensitivity Nonspecic pruritic papular eruption Xerosis Lichenoid dermatitis Pruritic diseases exacerbated by HIV Seborrheic dermatitis Psoriasis Infections and infestations Scabies Folliculitis Supercial fungal infections Acute and chronic urticaria Photosensitivity reactions Lichenoid photo eruptions Others Drug eruptions Generalized idiopathic pruritus Prevalence 2550% Not known 1146% Not known Not known 85% 1% Not known 25% 54% Not known Not known Not known Not known Not known References (11) (19)

(2) (12)

(23) (5)

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A.

Specific HIV Pruritic Eruptions

1. Papular Pruritic Eruptions This category contains the most common cutaneous manifestations seen in HIV-infected patients. It includes eosinophilic folliculitis, insect bite hypersensitivity, and nonspecic papular pruritic eruptions. The prevalence varies between 11% and 50%, and these conditions may be one of the earliest manifestations of HIV disease; however, the majority of the patients have advanced disease with CD4 counts below 50 cell/mm3. Papular pruritic eruptions can be regarded as a cutaneous marker of advanced HIV infection and can be used to predict the CD4 count of these patients (10). HIV-Associated Eosinophilic Folliculitis. Eosinophilic folliculitis is a common pruritic eruption in HIV-infected patients. It is considered as a distinct dermatosis associated with advanced HIV infection and accounts for 2550% of the pruritic papular eruptions in these patients (11). Generally, the patient presents with erythematous, urticarial follicular papules, and pustules and/or papules with pinpoint vesicles or pustules. Most are located on the forehead, cheeks, upper chest, back, and proximal upper extremities, characteristically above the nipple line (2,11,12). Pruritus usually is severe and unrelieved by antihistamines; it tends to be chronic with occasional periods of remission. The cause is unknown, but some authors (1,13) believe that there is an immuneinammatory response to late-stage HIV disease. The immune response shifts from CD4-type Th1 to Th2, which is then directed against follicular antigen. Others have found Demodex in aected hair follicles at the center of the follicle inltrate (11). This entity occurs in association with progressive HIV infection (CD4 count <250300 cells/mm3) (14). However, some patients experience eosinophilic folliculitis when their CD4 counts increase with HAART as part of an immune reconstitution eect (2). Laboratory tests may reveal elevated IgE and peripheral eosinophilia. Diagnosis is conrmed by biopsy. Early lesions show perifollicular inammation with lymphocytes and eosinophils at the isthmus and sebaceous duct, and small numbers of macrophages and neutrophils. There is follicular epithelial spongiosis, generally greatest at the follicular isthmus. The older lesions show intrafollicular pustules with eosinophils. Routine fungal and bacterial cultures are negative (11,12,15). Follicular rupture is uncommon. Eosinophilic abscesses and ame gures may be seen (12). Other follicle inammatory conditions are in the dierential diagnosis and include alopecia mucinosa, fungal or dermatophytic folliculitis, eosinophilic pustular folliculitis of childhood, acne, rosacea, insect bites (15), and eosinophilic folliculitis

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of Ofuji. This latter entity was described by Ofuji and diers from HIVassociated eosinophilic folliculitis clinically by the recurrence of crops of pruritic follicular sterile papulopustules, which appear over the face, trunk, and extremities in Japanese men (11). If untreated, HIV-associated eosinophilic folliculitis waxes and wanes over a period of months. Mild cases are controlled with potent topical steroids, oral antihistamines, and 5% permethrin applied every day until the lesions disappear (2). In addition, ultraviolet (UV) B light therapy (16) and phototherapy with UVA can produce substantial improvement after 46 weeks. In cases refractory to these therapies, itraconazole can be useful. The mechanism of action is believed to be distinct from itraconazoles antifungal properties because no fungus has been identied in lesions. The initial dose is 200 mg/day, but this can be increased to 300400 mg/day if there has not been a response after 2 weeks of treatment (13). For resistant cases, isotretinoin has been used with good responses usually noted after 68 weeks of treatment. Isotretinoin and some antiretrovirals (especially protease inhibitors) increase triglycerides and may lead to problems in an individual patient (2). Severe acute ares are treated with prednisone ( >0.5 mg/kg/day), which induces rapid remissions. Patients with lesions on the face respond best to oral metronidazole, whereas truncal lesions respond best to itraconazole. Some authors recommend long-term topical permethrin treatment to eliminate Demodex mites from the follicles (11), as well as ivermectin (12). Daily applications may prevent new lesions but have no eect on established lesions, and require at least 34 weeks of treatment (11). Insect Bite Hypersensitivity Reaction. HIV-infected patients (particularly those with CD4 lymphocyte counts below 200 cells/mm3) experience intensied skin reactions to mosquito and ea bites (2,13). Even with a detailed history, patients may not provide any history of known exposure to insect bites, pets, or drugs. Penneys et al. (17) hypothesized that this phenomenon represents a form of chronic recall reaction to an antigen present in the insects salivary glands. This could be related to a nonspecic B-cell activation so common in HIV-infected patients. The clinical presentation is of urticarial papules, which become excoriated and spontaneously resolve in 23 weeks. They are located most commonly over the legs (ea bites) or on exposed areas (mosquito bites). Pruritus may be persistent and give rise to prurigo nodularis. A skin biopsy may be required to conrm the diagnosis. The treatment consists of topical highpotency steroids applied to individual lesions and oral antihistamines at regular doses. Topical or oral doxepin at night may relieve the itch probably secondary to its sedative antihistamine eect (2,13).

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Pruritic Papules Dierent from HIV-Associated Folliculitis and Insect Bite Hypersensitivity. Pruritic papules distinct from eosinophilic folliculitis and insect bites have been described. Their clinical presentation is not signicantly dierent but, histologically, they do not have the features of the two latter entities. Initially, there are skin-colored (18) macules or papules on the forearms, which then spread symmetrically to the legs, face, and trunk with the absence of other denable causes of pruritus (10,19). The cause of the pruritus is unknown (18), but it is intense. These pruritic papules have been associated with insomnia and severe excoriations with subsequent scarring. This condition was the major complaint in 46% of 134 HIV-infected patients in a study by Liautaud et al. (19) a similar percentage was noted in other studies (20). Biopsies reveal acute polymorphonuclear leukocyte inltrates with predominance of eosinophils (mostly perivascular), extending deep into the dermis with occasional destruction of the pilosebaceous unit and sweat glands. The epidermis is acanthotic, with hypergranulosis, hyperkeratosis, spongiosis, and vacuolization of keratinocytes. Neither bacteria nor fungi have been identied in lesions (19). Treatments used have included topical steroids, topical antiparasitic drugs, antihistamines, oral antibiotics, emollients, phototherapy with PUVA, dapsone (18), and phototherapy UVB (21). 2. Xerosis

Xerosis is common in HIV-infected patients. It is especially prominent on the anterior aspects of the lower legs (2), but may be seen on the back of lower legs and arms, or even in a generalized distribution (13). The impairment of the barrier function may contribute to this dryness and itch. The use of antibacterial soaps to prevent folliculitis can further dry the skin and compromise the water barrier (12). Clinically, patients complain of pruritus with no skin ndings, which worsens 5 minutes to a few hours after bathing (13). The recommended treatment is with emollient creams, topical steroids, and antihistamines, but xerosis often persists regardless of therapy (1). Unfortunately, dry skin (and associated pruritus) tends to worsen as HIV progresses (12,13). 3. Lichenoid Dermatitis

This skin condition, induced by drugs and ultraviolet radiation, is extremely resistant to treatment and may are following minimal ultraviolet exposure (1).

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B. 1.

Common Pruritic Diseases Exacerbated by HIV Seborrheic Dermatitis

Seborrheic dermatitis is a common but generally mild disorder in HIVinfected patients aecting up to 85% of patients at some time (2). It may be a marker for early HIV disease before any other sign of immunosuppression with CD4 counts >500 cells/mm3 (12). It may be mild or quite severe, involving the face, trunk, underarms, groin, scrotum, and penis. Lesions in the scalp are particularly pruritic. This entity is believed by some authors to be an allergic reaction to the yeast Pityrosporum (13); others believe that HIV-related seborrheic dermatitis may be an entity distinct from classic seborrheic dermatitis and the overgrowth of Pityrosporum organisms does not play a role in pathogenesis (1,2). Standard therapy with topical antifungals is usually eective, but in severe cases, oral antifungal therapies are indicated. Ultraviolet phototherapy has also been used in resistant cases (2,12,13). 2. Psoriasis

Psoriasis has an increased incidence in HIV-infected patients. It is frequently associated with seborrheic dermatitis, and this presentation of sebopsoriasis on the face (13) has been associated with itch. Psoriasis may be aggravated or exacerbated in HIV-infected patients. The clinical presentation often demonstrates a predominance of involvement of palms, soles, and inverse psoriasis (2). Psoriasis in this population is frequently itchy and has a pattern of acral involvement, sometimes with severe destructive nail changes (12). Standard treatment with topical agents is eective. Eective HAART can also result in improvement of lesions. Although immunosuppressive therapy is generally contraindicated in patients with HIV, the use of cyclosporine and methotrexate may be considered in resistant cases (2,12). PUVA therapy and UVB light therapy are also helpful; these two treatments theoretically may activate HIV replication, but studies have not conrmed any increased HIV activity. 3. Infections and Infestations

Scabies. Scabies is a common infestation and should always be considered in the dierentiation of pruritic dermatitis. It may present as either typical or atypical scabies in the HIV-infected population (13,22). The latter is an exaggerated form and may be widespread (13) and bullous, appearing in atypical areas such as the face. HIV disease is characteristically advanced with a CD4 count below 200 cell/mm3 (2,23). In a third form called crusted or

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Norwegian scabies, there are no papules but widespread thick crusts with high concentration of mites in the scalp, face, and back, and under the nails. Norwegian scabies is extremely contagious, making these patients a potential source of nosocomial scabies (1,23). The itch can be intolerable; however, there are cases with mild or no itch (13). A reason for the development of widespread scabies may be related to the decrease in the number of Langerhans cells in patients with HIV infection (1). Diagnosis requires skin scraping, looking for the mites or eggs. A skin biopsy sometimes is necessary to conrm the diagnosis (13,23). Topical treatment options include permethrin, crotamiton, and lindane in several doses applied to all areas including the head and neck (2). Patients who fail this treatment or patients with crusted scabies can be given a single dose of ivermectin of 1218 mg (200 Ag/kg) (2,23). Frequently, an ID reaction and papular urticaria will follow scabies treatment and can last for several weeks even if the scabies mite was fully eradicated (1). Folliculitis. The pilosebaceous unit is prone to infection in HIVinfected patients. As HIV-related immunosuppression progresses, approximately 25% of patients may have folliculitis (24). HIV-infected patients normally are Staphylococcus aureus nasal carriers (12). These staphylococci may then infect the skin and other parts of the body. Staphylococcal folliculitis is a common infection in HIV-infected patients due to the nasal carriage and impaired neutrophil function (25,26), and it may be confused with eosinophilic folliculitis. The lesions are red papules and pustules located around the hair follicle in the upper trunk, back, groin, and legs, and may be intensely pruritic (13,25). The atypical sites are scalp and under the arms. Diagnosis requires culture from the pustule and, normally, a course of a standard antibiotic is enough for treatment (2,12,13). 4. Superficial Fungal Infections

Supercial fungal infections are common in patients infected with HIV. In some communities where these infections are frequent, they may serve as markers of the stage of HIV infection (27). HIV patients may have widespread lesions, which may or may not be associated with inammation. Clinically, some of the lesions may look atypical, appearing verrucous or as thick plaques. The microorganisms are the same as in immunocompetent patients. The pruritus produced by these lesions resolves following eradication of the fungus. Candidiasis in intertriginous areas may be extremely pruritic due to maceration and irritation (1).

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Acute and Chronic Urticaria. The clinical course of urticaria is similar to that in immunocompetent patients. Some causes of urticaria may be more common in HIV infection including hepatitis B, mononucleosis infection, amoebiasis, strongyloidiasis, drug reactions, and urticarial vasculitis. Urticaria may be more prominent due to the elevated serum levels of IgE in HIVinfected patients and the hyperreleasability of histamine-containing cells. Urticarial eruptions may be extremely refractory to therapy (1). 5. Photosensitivity Reactions

The most common photosensitivity reaction is the lichenoid photo eruption. Others include polymorphous light eruption, chronic actinic dermatitis, photosensitivity, and porphyria cutanea tarda [especially with HIV/hepatitis C virus (HCV) coinfection]. Lichenoid Photo Eruptions. These eruptions tend to occur on the dorsa of the hands, extensor extremities, face, lower lip, and neck, and are associated with severe pruritus. The more predisposed individuals are black patients (12) with CD4 counts below 50 cells/mm3. The most commonly implicated drugs are sulfonamides and nonsteroidal anti-inammatory drugs. The treatment includes sun protection, potent topical steroids, and, if possible, discontinuation of the medication believed to induce the eruption (2,12). C. 1. Others Drug Reactions

Allergic reactions to prescription and over-the-counter medications are very common in HIV patients, and these reactions can be very pruritic. The most common reaction is a generalized morbiliform rash, which develops from 7 to 14 days after the initiation of a drug (13). The most common oending drugs are sulfamethoxazole trimethoprim, clindamycin, cephalexin, and diphenylhydantoin. Hormonal folliculitis may occur in patients taking anabolic steroid for wasting syndrome. It is manifested as papules or pustules over the chest, back, and proximal extremities. It diers from eosinophilic folliculitis of Ofuji in that patients with hormonal folliculitis have a burning sensation and develop lesions within a few months of initiating or increasing the dose of steroids. There is often a history of acne vulgaris in adolescence. The reduction or discontinuation of anabolic steroids as well as the use of topical benzoyl peroxide or oral isotretinoin resolve the folliculitis (2). Rash and itch are major adverse eects of a number of antiretroviral agents. The nonnucleoside reverse transcriptase inhibitor class (nevirapine,

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efavirenz, and delavirdine), the nucleoside reverse transcriptase inhibitor abacavir (which can be associated with a life-threatening hypersensitivity reaction), and the protease inhibitor amprenavir are commonly the etiology of itch/rash. There is a report about itching related to treatment with indinavir (another protease inhibitor), where 40% of 101 patients experienced diuse cutaneous dryness and pruritus (28). Another case report described prolonged cholestatic jaundice and pruritus associated with fosinopril (29). D. Systemic

Rarely HIV-infected patients have itch without any primary skin disease. The laboratory evaluation has to be directed toward patient history, symptoms, and physical examination, and may include blood tests, urinalysis, skin biopsy, x-ray examination, hepatitis serologies, etc. (12,13). There are multiples causes of systemic itching including end-stage renal disease as a result of HIV nephropathy; cholestatic and liver disease; blood malignancies such as polycythemia vera, lymphoma, and leukemia; and hormone dysfunction such as hyperthyroidism and hypothyroidism. E. Generalized Idiopathic Pruritus

This diagnosis is established after ruling out primary skin disease or other systemic causes. For treatment, there are several anecdotal reports on the use of oral antihistamines, oral doxepin, and ultraviolet B therapy. Responses are usual after 48 weeks of treatment. Psoralens plus ultraviolet light A have also been reported as benecial. In anecdotal reports, pentoxifylline and indomethacin were also helpful (12).

REFERENCES
1. Cockerell C. The itches of HIV infection and AIDS. In: Bernhard JD, ed. Itch Mechanisms and Management of Pruritus. New York: McGraw-Hill, 1994:281 298. Rodwell G, Berger T. Pruritus and cutaneous inammatory conditions in HIV disease. Clin Dermatol 2000; 18:479484. Milazzo F, Piconi S, Trabattoni D, et al. Intractable pruritus in HIV infection: immunologic characterization. Allergy 1999; 54:266272. Skiest D, Keiser P. Clinical signicance of eosinophilia in HIV infected individuals. Am J Med 1997; 102:449453.

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Duque et al. Uthayakumar S, Nandwani R, Drinkwater T, et al. The prevalence of skin disease in HIV infection and its relationship to the degree of immunosuppression. Br J Dermatol 1997; 137:595598. Duvic M. Human immunodeciency virus and the skin: selected controversies. J Invest Dermatol 1995; 105:117S121S. Oh SB, Tran PB, Gillard SE, et al. Chemokines and glycoprotein 120 produce pain hypersensitivity by directly exciting primary nociceptive neurons. J Neurosci 2001; 21:50275035. Herzberg U, Sagen J. Peripheral nerve exposure to HIV viral envelope protein gp 120 induces neuropathic pain and spinal gliosis. J Neuroimmunol 2001; 116:2939. Douglas S, Ho WZ, Gettes D, et al. Elevated substance P levels in HIV-infected patients. AIDS 2001; 15:20432045. Boonachai W, Laohasrisakul R, Manonukul J, et al. Pruritic papular eruption in HIV seropositive patients: a cutaneous marker for immunosuppression. Int J Dermatol 1999; 38:348350. Majors M, Berger T, Blauvelt A, et al. HIV-related eosinophilic folliculitis: a panel discussion. Semin Cutan Med Surg 1997; 16(3):219223. Gelfand J, Rudiko D. Evaluation and treatment of itching in HIV infected patients. Mt Sinai J Med 2001; 68(45):298308. Roland M. Itchy skin in HIV AIDS treat news. April 15, 1994. www. aegis.com (accessed on November 2002). Pintanida E, Turiansky G, Kenner J, et al. HIV-associated eosinophilic folliculitis: diagnosis by transverse histologic sections. J Am Acad Dermatol 1998; 38:124126. McCalmont T, Altemus D, Maurer, et al. Eosinophilic folliculitis: the histologic spectrum. Am J Dermatopathol 1995; 17(5):439446. Misago N, Narisawa Y, Hayashi S. HIV-associated eosinophilic pustular folliculitis: successful treatment of a Japanese patient with UVB phototherapy. J Dermatol 1998; 25:178184. Penneys N, Nayar J, Bernstein H, et al. Chronic pruritic eruption in patients with acquired immunodeciency syndrome associated with increased antibody titers to mosquito salivary antigens. J Am Acad Dermatol 1989; 21:421425. Hevia O, Jimenez-Acosta F, Ceballos P, et al. Pruritic papular eruption of the acquired immunodeciency syndrome: a clinicopathologic study. J Am Acad Dermatol 1991; 24:231235. Liautaud B, Pape J, de Hovitz J, et al. Pruritic skin lesions: a common initial presentation of acquired immunodeciency syndrome. Arch Dermatol 1989; 125:629632. Hira SK, Wadhawan D, Kamanga J, et al. Cutaneous manifestation of human immunodeciency virus in Lusaka, Zambia. J Am Acad Dermatol 1988; 19:451 457. Pardo R, Bogaert M, Penneys N, et al. UVB phototherapy of the pruritic papular eruption of the acquired immunodeciency syndrome. J Am Acad Dermatol 1992; 26:423428.

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8.

9. 10.

11. 12. 13. 14.

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22. Schlesinger I, Oelrich M, Tyring S. Crusted (Norwegian) scabies in patients with AIDS. South Med J 1994; 87:352355. 23. Portu J, Santamaria J, Zubero Z, et al. Atypical scabies in HIV positive patients. J Am Acad Dermatol 1996; 34:915917. 24. Ban uls J, Ramon D, Aniz E, et al. Papular pruritic eruption with human immunodeciency virus infection. Int J Dermatol 1991; 30:801803. 25. Scully M. Pruritus, Staphylococcus aureus, and human immunodeciency virus infection. Arch Dermatol 1990; 126:685686. 26. Duvic M. Staphylococcal infections and the pruritus of AIDS-related complex. Arch Dermatol 1987; 123:1599. 27. Aly R, Berger T. Common supercial fungal infections in patients with AIDS. Clin Infect Dis 1996; 22:S128S132. 28. Calista D, Boschini A. Cutaneous side eects induced by indinavir. Eur J Dermatol 2000; 10(4):292296. 29. Nunes AC, Amaro P, Macas F, et al. Fosinopril-induced prolonged cholestatic jaundice and pruritus: rst case report. Eur J Gastroenterol Hepatol 2001; 13(3):279282.

22
Neuropathic Pruritus
Gil Yosipovitch
Wake Forest University School of Medicine, Winston-Salem, North Carolina, U.S.A.

Rashel Goodkin
Lahey Clinic, Burlington, Massachusetts, U.S.A.

Ellen Mary Wingard and Jeffrey D. Bernhard


University of Massachusetts Medical School, Worcester, Massachusetts, U.S.A.

I.

DEFINITION

Neuropathic itch is dened as an itch that arises due to pathology located at any point along the aerent pathway of the nervous system. It has many similarities with neuropathic pain. Just as neuropathic pain may have features such as burning, stinging, or aching neuropathic, itching may have similar paresthetic features. Although burning, pain, paresthesia, and anesthesia are more characteristic features of certain neuropathies (such as diabetic neuropathy or postherpetic neuralgia), itching may occur as a component or sole symptom of various neuropathies as well. It may also occur in passing during recovery from isolated nerve injury. It can reoccur simultaneously with pain such as in postherpetic itch (PHI).
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Neuropathic pruritusin both its generalized and localized forms is not widely recognized, but the evidence supporting its existence is substantial and is reviewed here. We will discuss itch due to nervous system pathology in syndromes of localized pruritus and itch due to central nerve damage.

II. A.

ITCH DUE TO PATHOLOGY IN THE PERIPHERAL NERVOUS SYSTEM Postherpetic Itch

Postherpetic itch can be part of postherpetic neuralgia (14). A recent study reported that among 153 patients with prior shingles, 48% reported itching on the McGill pain questionnaire (3). PHI could occur at the same location and time as PHN. Interestingly, most cases of PHI were on the face. PHN severity was not dierent between patients with and without PHI. Possible mechanisms include: (a) electrical hyperactivity of hypoaerented central itchspecic neurons, (b) preservation of itch-specic C nerve bers originating in neighboring dermatomes, and (c) imbalance between excitation and inhibition of second-order sensory neurons (4). The treatment of PHI is similar to that of PHN; topical anesthetics such as lidocaine patch (4) or capsaicin and oral treatments with neurotropic agents such as gabapentin and tricyclical antidepressants have been reported to be useful (5). B. Direct Deposition of Hydroxyethyl Starch in Peripheral Nerves Produces Pruritus

Persistent pruritus is a well-documented side eect of the infusion of hydroxyethyl starch, a compound that has been used as a plasma substitute (6). More than 50% of 93 patients who received an infusion of hydroxyethyl starch developed generalized pruritus as a result of hydroxyethyl starch (HES) deposition in peripheral nerves. Hot water, friction, and stress exacerbated HES-related itching. Skin biopsies from patients with pruritus revealed HES deposits in cutaneous nerves in the form of intracellular vacuoles in Schwann cells, endoneural cells, and perineural cells. In contrast, skin biopsies from patients who did not develop pruritus revealed HES vacuoles only in histiocytes and not in neural tissues. Biopsies from healthy volunteers did not display HES vacuoles. The improvement of pruritus in HES-treated patients was accompanied by the disappearance of HES vacuoles from the nerves. Thus, HES-induced pruritus arises through a direct eect of HES on peripheral nerves.

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C.

Notalgia Paresthetica

Notalgia paresthetica (NP) is a syndrome of localized pruritus in which patients present with itching of the back in the distribution of T2T6 dermatomes (7). It is usually unilateral. Other sensory symptoms, such as numbness, tingling, and formication, may be present as well. Usually, there is no visible abnormality of the skin, but in chronic cases, secondary changes caused by rubbing and scratching may occur. Some cases of macular amyloidosis of the upper back are related to underlying NP (8). The nerves supplying these dermatomes are unique in that they make a sharp right-angle turn after they exit the spinal cord and thus may be more susceptible to mechanical injury. Compression of posterior rami of spinal nerves roots T2T6 is thought to be involved in NP (9). Many cases of NP are associated with radiographical abnormalities of the spine, which in turn may be related to nerve compression (9,10). These abnormalities correlated precisely with the dermatomal localization of pruritus (10). Changes in sensory innervation may accompany pruritus of NP, such as pain, paresthesia, or hypoesthesia to touch and pinprick, and were present in the same location as pruritus (7). However, a recent study failed to disclose signicant dierence in nerve staining patterns in lesional and nonlesional skin (11). The hypothesis that nerve compression may be one of the etiological factors in NP is further supported by the observation that factors that aect the spinal cord may precipitate NP. Specically, tilting the head to the right and lying with the aected side downward exacerbated NP in one patient (12), and driving a car precipitated symptoms in another patient (7). Reported treatments for NP include physiotherapy (9), paravertebral local anesthetic blocks (13), cervical epidural steroid injection (12), phenytoin (Dilantin) (7), EMLA cream (14), and capsaicin (15). Most of the above treatments exert their eect through actions on the nervous system. This supports the hypothesis that pruritus in NP is of neurological origin.

D.

Brachioradial Pruritus

Brachioradial pruritus (BRP) is a syndrome of localized pruritus in which patients present with itching localized to the brachioradial area of the arm and often seek the advice of a dermatologist. Pruritus sometimes extends across the back and occasionally to the chest (16). BRP has been related to cervical root compression, including a spinal cord tumor involving one or all of C5C8 cervical nerve root segments (1722). Patients suer from altered sensation in the same dermatome where pruritus is present (18,22). In a recent study of 22 patients with BRP, 11 patients

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underwent radiographs of the cervical spine (19). Each of these 11 patients had cervical spine disease that could be correlated with the location of their symptoms. Factors that aect the spinal cord have also been cited as precipitants. Tait et al. (20) described six BRP patients with a history of neck problems and also reported that cervical spine manipulation was helpful in BRP management. Changes in neck position were reported as precipitants (21,22). Heyl (23) suggested that cervical spine x-rays should be obtained in any patient who complains of BRP. Some investigators believe that BRP is a result of solar exposure and have called BRP solar pruritus (16). We believe that both cervical spine disease and sun-induced cutaneous nerve injury are important contributors acting to variable degrees in individual patients (24). We also suspect that the ice packs that many patients report using to relieve itch in this condition may temporarily help, only to make things worse by further cutaneous nerve damage over the long term. There are no controlled studies on treatments for BRP. Reported treatments for BRP include physiotherapy, neck traction and cervical spine manipulation (23), topical capsaicin (25,26), gabapentin (Neurontin) (27), carbamazepine (Tegretol) (20), anti-inammatory drugs (23), and surgical resection of a cervical rib (28). E. Localized Itching at Other Sites

One patient was reported to have a spinal cord tumor at T4T8, producing pruritus of the abdomen at the T6T7 dermatomal area (29). The patients pruritus resolved immediately after resection of the tumor. Itching of the scalp may have a neuropathic origin in some cases (30). F. Other Pruritic Syndromes of Unknown Etiology, Senile Pruritus

Senile pruritus may have a neurological origin (31). In addition to xerosis (which may cause itching by itself), age-related degenerative changes in nerve bers and microstrokes have been proposed as possible entirely separate underlying etiology.

III.

ITCH DUE TO PATHOLOGY IN THE BRAIN

Pruritus has been reported as a manifestation of brain pathology. The list of underlying pathologies includes strokes (3235), tumors (36,37), abscesses (38), and CreutzfeldtJakob disease (39).

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In fact, pruritus can present as the rst and only symptom of a brain tumor (36). It can also be the rst symptom of CreutzfeldtJakob disease (39). Facial and/or nasal pruritus is a particularly interesting manifestation of brain pathology (36,37). A complete resolution of pruritus was observed in some cases once the tumors were treated. Among the 72 patients with brain tumors and dermatological conditions studied by Andreev and Petkov (37), six patients had nasal pruritus. In all six patients, tumor inltrated the base of the fourth ventricle. The degree of pruritus in these patients was so intense that even when unconscious, they scratched their nostrils and, if restrained, tried to rub their noses. Canavero et al. (35) postulated that pruritus might have occurred as a result of the tumor activating either ascending neural tracts from the face, or descending tracts from the brainstem. Pruritus of the ipsilateral side of the nose had also been mentioned as a result of retrogasserian section for intractable trigeminal neuralgia (40).

IV.

PHANTOM ITCH

More than 90 patients with phantom itch have been reported (4143). The phenomenon of phantom pain is well recognized. The phantom sensation originates in the brain (44). The phenomenon of phantom itch is less well known (31). Nail et al. (42) reported that at least one third of 218 women who underwent mastectomy experience phantom breast itch. Thirty-six percent of women did not tell anybody about the phantom sensations, and fewer than 10% (=13) mentioned the sensation to a nurse. Lierman (41) reported 4 of 20 women who developed pruritus of the phantom nipple after mastectomy. Jacome (43) reported one patient who developed severe bilateral phantom foot pruritus as a consequence of bilateral below-the-knee amputations. The patient was able to relieve pruritus by pretending to scratch the area where his feet would normally be located. He was not able to relieve pruritus by scratching the stumps. In some cases, phantom mechanisms may be at play in senile pruritus, as will be discussed later. Sullivan and Drake (38) suggest that, like other sensations, itching may have a homunculus-like representation in the brain. Just as there is a map of sensations from dierent parts of the body in the cerebral cortex, there may be a similar cortical map of itchy sensations from dierent anatomical locations and, similar to phantom pain, if there is no sensory input from a limb to the brain, phantom itch may occur. Thus, if a cutaneous sensory nerve is injured and transmission of normal itch input from the skin to the brain is interrupted, phantom itch may be generated in the area of skin supplied by this

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nerve. Another possibility is that transection of normally inhibitory neurons allows overactivity of itch neurons that would otherwise be tonically inhibited by other sensations such as touch. As is true for phantom pain, the intensity of phantom itch is very strong. Patients suering from phantom itch are not merely recollecting sensations but are feeling them with the full intensity and detail of an ongoing experience (45). The existence of phantom itch phenomena may prove crucial to our understanding of the pathophysiology of pruritus. The evidence presented and reviewed here argues for an association between nerve injury and localized pruritus. One can imagine a scenario in which the cutaneous sensory nerve carrying the itch bers is injured and the brain is thus deprived of its sensory input on pruritus. The brain and spinal cord may, as a result, generate the more intense phantom itch sensation that clinicians have observed as localized itching. Such an itch cannot be dealt with by treating the skin alone. The gate control theory may help explain how localized itch of noncutaneous origin may be produced (44). If a nerve responsible for inhibition of a cutaneous sensory nerve carrying the sensation of pruritus to the central nervous system is injured, suppression of pruritus is lost, and the brain is bombarded with a constant and uninhibited itch message.

V.

PAROXYSMAL ITCHING IN MULTIPLE SCLEROSIS

Paroxysmal itching has been described in 17 of 377 patients with multiple sclerosis (MS) (46). The itching may be in any part of the body and can be very intense. The attacks can last from several seconds to few minutes, and may occur several times a day. Features of these attacks are similar to the wellknown Lhermittes sign of MS described as sudden, transient, electric-like shocks extending down the arms, trunk, and legs on bending the head forward (47). Attacks often awaken the patient from sleep (48). Episodes may be spontaneous, or triggered by a bath or sudden movement. The pathophysiology of itch in MS is poorly understood. It may occur as a result of lesions in the cervical spinal cord or close to it (47,49). The symmetrical, segmental, and paroxysmal nature of these MS phenomena supports their neurological origin (50). Spontaneous axonal discharge generated by a portion of a demyelinated nerve may be responsible for sensory disturbances of MS (51). Sandyk (50) suggested that impaired synaptic conductivity, rather than demyelination, may be responsible for these symptoms. Both pruritus and dysesthesias of MS have responded to carbamazepine.

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VI.

TREATMENTS FOR NEUROPATHIC ITCH

Therapeutic options for neuropathic itch are sparse. There are currently no controlled studies. Successful anecdotal treatments used drugs proven to be eective in neuropathic pain as mentioned above.

VII.

CONCLUSION

It is well established that skin inammation can cause itch, but it is not generally realized that damage to peripheral nerves as well as damage to the brain or spinal cord may be followed by itch. The circumstantial evidence described above that pruritus can result from nervous system pathology, especially as a consequence of vertebral spine disease, is substantial. Patients with itch of neuropathic character may also complain of other paresthetic sensations (tingling; burning; and shooting, lacerating, or deep pain). They should also be evaluated for other sensory abnormalities (e.g., light touch, pinprick, and temperature sensation) that may be present in some cases. Thus, a search for an underlying abnormality in the spine or nervous system may be warranted in certain patients with pruritus when no recognizable primary skin disorder is present, when underlying systemic causes have been excluded, and especially when the itch is localized. Neurological and radiological investigations may be helpful.

REFERENCES
1. 2. Liddell K. Post-herpetic pruritus. Br Med J October 1974:165. Darsow U, Lorenz J, Bromm B, Ring J. Pruritus circumscriptus sine materia: a sequel of postzosteric neuralgia. Evaluation by quantitative psychophysical examination and laser-evoked potentials. Acta Derm-Venereol 1996; 76:4547. Oaklander AL, Cohen SP, Raju SVY. Intractable postherpetic itch and cutaneous deaerentation after facial shingles. Pain 2002; 96:912. Oaklander AL, Bowsher D. Post herpetic itch (PHI), a common neuropathic complication after shingles (herpes zoster). J Pain 2001; 2S1:18. Tennyson H, Levine N. Neurotropic and psychotropic drugs in dermatology. Dermatol Clin 2001; 19:179197. Metze D, Reimann S, Szepfalusi Z, Bohle B, Kraft D, Luger TA. Persistent pruritus after hydroxyethyl starch infusion therapy: a result of long-term storage in cutaneous nerves. Br J Dermatol 1997; 136:553559. Massey EW, Pleet AB. Localized pruritusnotalgia paresthetica. Arch Dermatol 1979; 115:982983.

3. 4. 5. 6.

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Yosipovitch et al. Bernhard JD. Notalgia paresthetica, macular posterior pigmentary incontinence, macular amyloidosis and pruritus. Acta Derm-Venereol 1997; 77:164. Raison-Peyron N, Meunier L, Acevedo M, Meynadier J. Notalgia paresthetica: clinical, physiopathological and therapeutic aspects. A study of 12 cases. J Eur Acad Dermatol Venereol 1999; 12:215221. Savk E, Savk O, Bolukbasi O, Culhaci N, Dikcioglu E, Karaman G, Sendur N. Notalgia paresthetica: a study on pathogenesis. Int J Dermatol 2000; 39:754759. Savk E, Dikcioglu E, Culhaci N, Karaman G, Sendur N. Immunohistochemical ndings in notalgia paresthetica. Dermatology 2002; 204:8893. Eisenberg E, Barmeir E, Bergman R. Notalgia paresthetica associated with nerve root impingement. J Am Acad Dermatol 1997; 37:9981000. Goulden V, Toomey PJ, Highet AS. Successful treatment of notalgia paresthetica with a paravertebral local anesthetic block. J Am Acad Dermatol 1998; 38:114116. Layton AM, Cotterill JA. Notalgia parestheticareport of three cases and their treatment. Clin Exp Dermatol 1991; 16:197198. Wallengren J. Treatment of notalgia paresthetica with topical capsaicin. J Am Acad Dermatol 1991; 24:286288. Wallengren J. Brachioradial pruritus: a recurrent solar dermopathy. J Am Acad Dermatol 1998; 39:803806. Kavak A, Dosoglu M. Can a spinal tumor be a causative factor of brachioradial pruritus? J Am Acad Dermatol 2002; 46:437440. Massey EW, Massey JM. Forearm neuropathy and pruritus. South Med J 1986; 79(10):12591260. Goodkin R, Wingard E, Bernhard J. Brachioradial pruritus: cervical spine disease and neuropathic pruritus. J Am Acad Dermatol 2003; 48:521524. Tait CP, Grigg E, Quirk CJ. Brachioradial pruritus and cervical spine manipulation. Australas J Dermatol 1998; 39:168170. Abbott LG. Neurogenic pruritus [letter]. Australas J Dermatol 1998; 39:198200. Fisher DA. Brachioradial pruritus wanted: a sure cause (and cure) for brachioradial pruritus. Int J Dermatol 1997; 36:817818. Heyl T. Brachioradial pruritus. Arch Dermatol 1983; 119:115116. Bernhard JD. Editors comment. J Am Acad Dermatol 1999; 41:658. Goodless DR, Eaglstein WH. Brachioradial pruritus: treatment with topical capsaicin. J Am Acad Dermatol 1993; 29:783784. Knight TE, Hayashi T. Solar (brachioradial) pruritusresponse to capsaicin cream. Int J Dermatol 1994; 33(3):206209. Bueller HA, Bernhard JB, Dubro LM. Gabapentin treatment for brachioradial pruritus [letter]. J Eur Acad Dermatol Venereol 1999; 13:227230. Rongioletti F. Pruritus as presenting sign of cervical rib. Lancet 1992; 339:55. Johnson RE, Kanigsberg ND, Jimenez CL. Localized pruritus: a presenting symptom of a spinal cord tumor in a child with features of neurobromatosis. J Am Acad Dermatol 2000; 43:958961. Bernhard JD. The itchy scalp and other pruritic curiosities. Semin Dermatol 1995; 14:326329.

10. 11. 12. 13.

14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29.

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31. Bernhard JD. Phantom itch, pseudophantom itch, and senile pruritus. Int J Dermatol 1992; 31(12):856857. 32. King CA, Hu FJ, Jorizzo JL. Unilateral neurogenic pruritus: paroxysmal itching associated with central nervous system lesions. Ann Intern Med 1982; 97 (2):222223. 33. Shapiro PE, Braun CW. Unilateral pruritus after a stroke. Arch Dermatol 1987; 123:15271530. 34. Massey EW. Unilateral neurogenic pruritus following stroke. Stroke 1984; 15:901903. 35. Canavero S, Bonicalzi V, Massa-Micon B. Central neurogenic pruritus: a literature review. Acta Neurol Belg 1997; 97:244247. 36. Summers GC, MacDonald JT. Paroxysmal facial itch: a presenting sign of childhood brainstem glioma. J Child Neurol 1988; 3:189192. 37. Andreev VC, Petkov I. Skin manifestations associated with tumours of the brain. Br J Dermatol 1975; 92:675678. 38. Sullivan MJ, Drake ME. Unilateral pruritus and Nocardia brain abscess. Neurology 1984; 34:828829. 39. Shabtai H, Nispeanu P, Chapman J, Korczyn AD. Pruritus in CreutzfeldtJakob disease. Neurology 1996; 46:940941. 40. Procacci P, Maresca M. Central pruritus. Case report. Pain 1991; 45:307308. 41. Lierman LM. Phantom breast experiences after mastectomy. Oncol Nurs Forum 1988; 15(1):4144. 42. Nail L, Jones LS, Guire M, Jognson JE. Sensations after mastectomy. Am J Nurs 1984; 84(9):11211124. 43. Jacome D. Phantom itching relieved by scratching phantom feet. JAMA 1978; 240(22):2432. 44. Melzack R, Wall PD. Pain mechanisms: a new theory. Science 1965; 150:971 979. 45. Melzack R. Phantom limbs. Sci Am April 1992:120126. 46. Matthews WB, Compston A, Allen IV, Martin CN. McAlpines Multiple Sclerosis. Edinburgh: Churchill Livingstone, 1991:68. 47. Osterman PO. Paroxysmal itching in multiple sclerosis. Br J Dermatol 1976; 95:555558. 48. Yamamoto M, Yabuki S, Hayabara T. Paroxysmal itching in multiple sclerosis: a report of three cases. J Neurol Neurosurg Psychiatry 1981; 44:1922. 49. Osterman PO, Westerberg C-E. Paroxysmal attacks in multiple sclerosis. Brain 1975; 98:189202. 50. Sandyk R. Paroxysmal itching in multiple sclerosis during treatment with external magnetic elds. Int J Neurosci 1994; 75:6571. 51. Yabuki S, Hayabara T. Paroxysmal dysesthesia in multiple sclerosis. Folia Psychiatr Neurol Jpn 1979; 33:97104.

23
Clinical Features of Itch in Atopic Eczema
Ulf Darsow and Johannes Ring
Technical University of Munich, Munich, Germany

I.

INTRODUCTION

Atopic eczema (atopic eczema/dermatitis syndrome, neurodermatitis) is one of the most pruritic skin diseases. In fact, itch is an essential diagnostical feature of atopic eczema (in association with the markedly better characterized criteria: age-related eczematous appearance and localization, history and clinical signs of atopy, and IgE-mediated sensitization) (1). Often, the itch is the rst symptom of eczema relapse of this chronic disorder. In severe cases of atopic dermatitis, patients scratch the involved skin areas until bleeding excoriations result. Nocturnal prolonged scratching is also very frequent and causes sleep loss. The mediators of atopic eczema itch in the skin have not yet been positively identied, although many candidates have been investigated and characterized (24). Histamine, the most important known pruritic mediator, is unlikely to play the major part because the clinical ecacy of nonsedating antihistamines in atopic eczema is very limited. The itch receptors are free endings of thin, unmyelinated, slow-conducting C-bers with the highest density at the dermalepidermal junction level (5,6). In patients with atopic eczema, we found complement and immunoglobulin deposits near the dermalepidermal junction (7). Alloknesis, a phenomenon involving the central
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projection neurons of the itch aerents, plays an important role in the irritability of the atopic skin. A certain area of clinically noninvolved skin surrounding an itching lesion may also be felt as itching after slight mechanical stimulation, such as contact with wool bers (8). A specic chemosensitive subpopulation of C-bers has been described recently (9). To date, these new ndings have not resulted in innovative therapeutic approaches to the excruciating itch of patients with inammatory skin diseases, and this is also due to the lack of methods to evaluate antipruritic eects in a model. Thus, the methods of objective measurement of nociception are far more advanced in pain research than in itch research. The use of laboratory animals for this purpose has been hampered by the dierence between scratch response and itch perception. In contrast to the importance of the symptom, only few specic treatments for itch are available. Like the pain sensation, the subjective perception of itch is a complex emotional experience. It is inuenced by many factors, not only by a stimulus intensity or severity of skin disease.

II.

SCALES FOR CLINICAL ITCH IN PATIENTS

The clinical features of itch in dierent pruritic skin diseases reveal the range of diversity in the perception of this symptom (Table 1). However, in most clinical trials, only a quantication of subjective itch intensity by visual analog scale (VAS) (10) is obtained, or itch is even omitted in symptom scores. In experimental itch in healthy volunteers (11,12), interindividual dierences of itch sensation in response to histamine were high. The use of only VAS may lead to an incomplete registration of the sensation because the inuence of qualitative factors on quantitative scales is already known in pain research.

Table 1 Descriptors of Clinical Itch


. . . . . . . .
n n

Localization: generalized, circumscribed Time: at night, wavelike Trigger factors: stress, animal contact, sun, etc. Intensity: visual analog scale Character: burning, tingling, throbbing, etc. Scratch behavior: scrubbing, kneading, etc. Further prurifensive factors: distraction, cold, etc. Emotional value: disturbing, aecting quality of life Components: qualitative, quantitative, emotional, reactive

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This has led to the development of several questionnaire instruments for pain psychophysiology and for the measurement of quality-of-life outcomes. Atopic eczema in its acute state can be seen as a model disease for clinical pruritus. The severity of atopic eczema can be measured with the SCORAD, an evaluated device (13). It comprises area measurement and several descriptors of eczema intensity and also visual analog scales. In a multicenter trial, 362 patients with atopic eczema were scored with this instrument. We performed correlation analyses of the itch visual analog scale with other eczema parameters and found the highest correlations with sleep loss and the overall intensity of the objective part of the SCORAD (r = 0.4; p<0.001). This correlation was signicant due to the high number of patients investigated; on the other hand, the correlation coecient was not very high. As in studies on experimental itch in healthy volunteers, interindividual variations of itch sensation in response to skin inammation were high. This points to further, usually not monitored, variables such as central nervous inuence on clinical itch (14,15).

III.

THE EPPENDORF ITCH QUESTIONNAIRE IN PATIENTS WITH ATOPIC ECZEMA

The clinical studies led to the development of a new multidimensional questionnaire, the Eppendorf Itch Questionnaire (EIQ) (16,17) (see Chapter 17, Appendix B). The EIQ is designed in analogy to the established McGill Pain Questionnaire (MPQ) (18) in pain research. The MPQ comprises aective (e.g,cruel) as well as pure sensory descriptive (e.g., stinging) items and may on a higher level also give information about quality-of-life parameters. A comparable instrument for the detailed investigation on itch perception was missing. The left side of the rst form of the EIQ consists of descriptors of the itch sensation itself; on the right side descriptors with emotional value are summarized. The second form comprises descriptors of time, pruritofensive behavior, a visual analog scale (VAS), and area distribution. This questionnaire was rst evaluated in a controlled laboratory environment with experimental histamine itch in volunteers. As with the MPQ, it was possible to establish correlations of the questionnaire outcome with VAS of the investigated sensation (12). This questionnaire was used in a large number (n = 108) of patients with acute atopic eczema (17). These patients were also scored with the SCORAD device and lled out the questionnaire. The sensation was perceived as increased warmth, localizable tingling, and burning, and it was associated with many negative aective descriptors. A principal component analysis with varimax rotation of the data was performed to extract main factors of clinical itch. The principal component analysis showed that atopic

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Table 2 Correlation Between Main Components of Subjective Description of Itch (Eppendorf Itch Questionnaire) and Parts of the SCORAD Severity Index in Atopic Eczema (n=108 patients) Correlation coecients Main component 1. Suering 2. Phasic intensity factor 3. Compulsive/active reaction SCORAD 0.59* 0.38* n.s. VAS itch 0.52* n.s. n.s. Area 0.47* n.s. n.s.

Components 13 together explain 58% of the total variance. (From Ref. 17) N=108 patients with atopic eczema. n.s.= not signicant. * =p < 0.05.

itch is a multidimensional sensation with 12 clusters of descriptors, but on a more general level, descriptors could be integrated in three main components (explaining 58% of total variance) that describe the atopic itch in our patients (Table 2). The rst component was the decrease in quality of life, which was caused by the itch sensation. The second component described the quality of the sensation itself as wave-formed and prickling; some further descriptors were chosen here. The third component, a compulsive component describing the loss of control and warm feelings, comprised also positive emotional descriptors chosen by the patients. The striking point on the statistical analysis was that only the rst two main components were signicantly related to the eczema severity. The third component of emotional dimension was statistically independent of the SCORAD. We suggest that this component may be an important factor of the so-called itchscratch cycle in atopic eczema.

IV.

ITCH: A MULTIDIMENSIONAL SYMPTOM NEEDS DIFFERENTIATED THERAPY

The results of these studies show that clinical itch may only partially be quantied by VAS (10). A multidimensional itch questionnaire may be more suitable to fulll the criteria of the complexity of itch perception as compared with the usual visual analog scales used for itch quantication. This is underscored by experimental evidence that within the poorly dened element of itch intensity (described by a visual analog scale), the quantity and quality of the sensations are inuenced by each other (12). There are peripheral and central nervous components that may be modulated independently. Experimental itch can easily be intercepted by tactile stimuli or distraction. The sensation of itch needs an increasing number of descriptors with higher intensities (12).

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These descriptors correlate in a complex manner with objective parameters of skin inammation in atopic eczema (17). We have recently shown an extensive activation of cortex areas in experimental histamine itch perception in the human brain (19) (see also Chapter 7). As a logical consequence, the therapy of clinical pruritus has to consider both sides of origin and perception of itch, namely, the skin and the central nervous system. The ecacy of sedating antihistamines and opioid antagonists (nalmefene) in atopic itch is known (20). Best results are obtained when combined strategies that are dermatologically adequate for the underlying disease are used. For atopic eczema, this means a concept of patient management (21) including rehydrating emollient baseline therapy and appropriate on-demand anti-inammatory treatment with topical steroids, allergological diagnosis (1), and, in selected cases, topical or systemic immunosuppressants, antibiotics, or phototherapy. The therapeutic ecacy of counterstimulation (e.g., cold) is moderate (3,11). One of the most important rules is not to underestimate the impact of pruritus on the quality of life of a patient.

REFERENCES
Ring J. Angewandte Allergologie: 2. Au. Mu nchen: MMV Medizin Verlag, 1995. 2. Darsow U, Scharein E, Bromm B, Ring J. Skin testing of pruritogenic activity of histamine and cytokines at the dermalepidermal junction level. Br J Dermatol 1997; 137:415417. . Studies on pruritogenic and histamine-releasing eects 3. Fjellner B, Ha germark O of some putative peptide neurotransmitters. Acta Derm-Venereol (Stockholm) 1981; 61:245250. 4. Greaves MW, Wall PD. Itch. Lancet 1996; 348:938940. 5. Shelley WB, Arthur RP. The neurohistology and neurophysiology of the itch sensation in man. Arch Dermatol 1957; 76:296323. 6. Tausk F, Christian E, Johansson O, Milgram S. Neurobiology of the skin. In: Fitzpatrick TB, Eisen AZ, Wol K, Freedberg IM, Austen KF, eds. Dermatology in General Medicine. Vol. 1. New York: McGraw-Hill, 1993:396403. 7. Ring J, Senter T, Cornell RC, Arroyave CM, Tan EM. Complement and immunoglobulin deposits in the skin of patients with atopic dermatitis. Br J Dermatol 1978; 99:495501. 8. Heyer G, Ulmer FJ, Schmitz J, Handwerker HO. Histamine-induced itch and alloknesis (itchy skin) in atopic eczema patients and controls. Acta DermVenereol 1995; 75:348352. 9. Schmelz M, Schmidt R, Bickel A, Handwerker HO, Torebjo rk HE. Specic Creceptors for itch in human skin. J Neurosci 1997; 17:80038008. , Wahlgren CF. Some methods for evaluating clinical itch and 10. Ha germark O 1.

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Darsow and Ring their application for studying pathophysiological mechanisms. J Derm Sci 1992; 4:5562. Bromm B, Scharein E, Darsow U, Ring J. Eects of menthol and cold on histamine-induced itch and skin reactions in man. Neurosci Lett 1995; 187:157 160. Darsow U, Ring J, Scharein E, Bromm B. Correlations between histamineinduced wheal, are and itch. Arch Dermatol Res 1996; 288:436441. European Task Force on Atopic Dermatitis. Severity scoring of atopic dermatitis: the SCORAD index. Dermatology 1993; 186:2331. Gil KM, Sampson HA. Psychological and social factors of atopic dermatitis. Allergy 1989; 44:8489. Gupta MA, Gupta AK, Schork NJ. Depression modulates pruritus perception: a study of pruritus in psoriasis, atopic dermatitis, and chronic idiopathic urticaria. Psychosom Med 1994; 56:3640. Darsow U, Mautner V, Scharein E, Bromm B, Ring J. Der Eppendorfer Juckreizfragebogen. Hautarzt 1997; 48:730733. Darsow U, Scharein E, Simon D, Walter G, Bromm B, Ring J. Component analysis of atopic itch using the Eppendorf Itch Questionnaire. Int Arch Allergy Immunol 2001; 124:326331. Melzack R. The McGill Pain Questionnaire: major properties and scoring methods. Pain 1975; 1:277299. Darsow U, Drzezga A, Frisch M, Munz M, Weilke F, Bartenstein P, Schwaiger M, Ring J. Processing of histamine-induced itch in the human cerebral cortex: a correlation analysis with dermal reactions. J Invest Dermatol 2000; 115:1029 1033. Monroe EW. Ecacy and safety of nalmefene in patients with severe pruritus caused by chronic urticaria and atopic dermatitis. J Am Acad Dermatol 1989; 21:135136. Ring J, Brockow K, Abeck D. The therapeutic concept of patient management in atopic eczema. Allergy 1996; 51:206215.

11.

12. 13. 14. 15.

16. 17.

18. 19.

20.

21.

24
Postburn Itch
Robert D. Nelson
Surgery Research Laboratory, Regions Hospital, St. Paul, Minnesota, U.S.A.

Survivors of burn injury often experience itch at wound sites with an intensity and duration sucient to aect their rehabilitation and quality of life postdischarge. Although itch at these sites has been recognized as a signicant problem for several decades, the mechanistic components of this symptom remain to be determined, and a reliable therapy has yet to be found. Antihistamine and moisturizing lotions are currently the therapies of choice for postburn itch, although only a minority of survivors obtain full relief from their use. Here we present brief reviews of the incidence, severity, and duration of postburn itch, and of therapies in use or tested to relieve this symptom. Also included are descriptions of several recent studies that demonstrate the ecacy of a novel antihistamine preparation and provide new information on mechanistic aspects of postburn itch.

I.

INCIDENCE

The rst reports to provide information on this aspect of burn wound healing are represented by the following comments of caregivers that itch is a common problem (1), a major problem with burn scars (2), a problem aecting virtually all patients (3), or a universal problem (4). Later reports cite pruritus as aecting 57% of 35 children (5), 100% of 12 children (6), 25%
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of 60 adults (7), 87% of 35 adults (8), 16% of 38 adults (9), 45% of 236 adults (10), >85% of 151 adults (11), and 83% of 12 children (12). These data establish incidence ranges of 57100% and 2587% for children and adults, respectively. Average incidence values calculated from these data are 61% for 69 children and 60% for 485 adults. It is likely that the lower numerical estimates of postburn itch can be attributed to advances made in patient care that include early wound excision and grafting (13).

II.

SEVERITY

Reports citing severity using a 10-cm visual analog scale (VAS) dene severity as 24.5 (14), 4.6 (11), 5.8 (15), 7.0 (16) 7.6 (8), or 10 (17). Also pertaining to severity are observations that intense itch is associated with hypertrophic scarring (2,18), a prolonged time to wound closure and anatomic area involved (legs>arms>face) (8), the thickness of the wound (partial thickness wounds are itchier than full-thickness wounds) (14), exposure of the wound site to heat (11), and the approach of nighttime (5,19). Additionally, postburn itch can be a greater problem for pediatric patients, related to an inability to ignore the sensation and resist the urge to scratch (20). Uncontrolled scratching can lead to opening of wound sites and graft loss, and prolong the time to discharge.

III.

DURATION

The time at which itch begins postburn has been noted as the time the wound starts to heal (19), when epidermis covers the wound (20), or 1 month postinjury (14). Thereafter, itch has been reported to gradually diminish, but persist for months to 1 or more years (5,14,15,21,22). When itch continues for such time, it becomes easy to accept descriptions of postburn itch as a crippling problem (11), as interfering with activities of daily living, sleep, therapy routines, and concentration (19), or just as de-bilitating as severe, persistent pain (14).

IV.

STANDARD THERAPY

For more than three decades, many burn centers have used an antihistamine and a moisturizing/lubricating product as the standard of care for postburn itch. Antihistamine is used because of its known ability to produce itch

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clinically and experimentally, and moisturizing cream or lotion is used because the glandular products normally available to prevent desiccation are absent in the healed, deeper wound. However, it is a common observation that this therapy does not reliably relieve postburn itch for all subjects. Experimental evidence of the failure of three antihistamine products to control postburn itch is available in the report by Vitale et al. (8), which describes the antipruritic eects of Atarax (hydroxyzine), Benadryl (diphenylhydramine), and Polyhist Forte (a combination of phenylephrine, phenylpropanolamine, pyrilamine, and chlorpheniramine) on discharged adult burn survivors. Thirty-ve patients were started on one of these agents and the agents were changed monthly in a randomized fashion; all subjects were allowed to use surface lubricants as needed. Summary data demonstrated that these agents produced complete relief in 20% of patients, partial relief in 60%, and no relief in 20%, with no dierences in response to the three agents tested. The failure of these rst-generation antihistamines to reliably relieve postburn itch for the majority of survivors has stimulated eorts to discover a more reliably eective therapy for this symptom. In the absence of knowledge of the mechanistic components responsible, the opportunity has been present to test a wide variety of alternative remedies for this itch, including: Preparation H (containing the sympathomimetic agent, phenylephrine) (23), topical capsaicin (24), oral Periactin/cyproheptadine (with antihistaminic and antiserotonic activities) (25), oral Claritin/loratadine (an H1 receptor antagonist) (21), massage with cocoa butter (15,26), bathing products containing liquid paran with or without colloidal oatmeal (27), EMLA cream (eutectic mixture of local anesthetics, lidocaine, and prilocaine) (28), Tagamet/cimetidine (H2 receptor antagonist) and Zyrtec/cetirizine (H1 receptor antagonist) in combination (17), TENS (transcutaneous electrical nerve stimulation) (29), and a topical preparation of Doxepin (16). All of these treatments have produced some benet for the subjects involved, but none has shown ecacy leading to its acceptance as a replacement for the traditional combination of antihistamine and moisturizing cream.

V.

RECENT OBSERVATIONS

One might conclude from this historical perspective that the mechanism of postburn itch must be complex and involve multiple factors that cannot be eectively controlled by a single therapeutic agent or technique. The frequent failure of antihistamine therapy to relieve postburn itch, and the chronic characteristic of this symptom can also lead one to question the constancy of the contribution of histamine. Therefore it may be useful to

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consider three recent abstracts, which may provide new clues to the mechanistic aspects of postburn itch and a better therapy. Demling and De Santi (16) reported on the utility of a topical cream formulation of doxepin for postburn itch. Doxepin is a tricyclic antidepressant with H1 and H2 receptor blocking properties, available in a 5% cream form (16). The study population in this report involved 20 adult burn patients for whom itch negatively aected their quality of life. On baseline day 1, the average itch score was 7 on a 10-point visual analog scale. After the rst study day, and through the 7-day study period, all patients described a decrease in itching represented by an average VAS value of 3. Itch scores returned to the predoxepin level within 2 days after discontinuation of treatment and return of standard care. This result might suggest that topical doxepin oers little advantage over oral anti-histamines, but these authors have since reported results of a follow-up study indicating that extending the use of topical doxepin to 12 weeks reduced the average initial itch score of 5.8 to an average value of 1 (30). These results may demonstrate that histamine is a consistent component of postburn itch, in spite of the observation that other antihistamines produce partial or no relief of this symptom for a majority of subjects over a longer treatment period (8). However, it is also possible to speculate that the ecacy of doxepin reported here may involve its adrenergic, anticholinergic, or antiserotonin eects (31), or its ability to inhibit prostaglandin biosynthesis (32). We have considered a role for prostanoids in postburn itch, based on reports that prostaglandins E1 and E2 cause itch experimentally (33,34), and that prostaglandins PGE1, H2, and E2 can potentiate the itch induced by histamine (35,36). Our initial approach to this issue has involved the application of immunohistochemistry to visualize the expression of the cyclooxygenase isozyme, COX-2, in pruritic burn wound tissue (37). We found COX-2 to be consistently absent in skin biopsy specimens from three healthy volunteers, but consistently present in biopsy and excised wound specimens obtained months after injury from ve burn survivors. Cells expressing COX2 included dermal broblasts and vascular endothelial cells in specimens from four of these survivors, and endothelial cells in the upper dermis in the specimen from the fth survivor. Although no attempt was made to correlate COX-2 expression with the level of itch, this observation implies that a high level of prostaglandin H2 and its metabolites may be available for a prolonged time to inuence itch directly or indirectly at burn wound sites. The nal observation worthy of note is that a topical preparation of dapsone (4,4V-diaminodiphenylsulfone) also appears to have an antipruritic inuence on postburn itch (38). Preliminary evidence of this eect derives from a study involving eight subjects using this product for a period of 2 weeks. At the end of this period, ve subjects reported an 84% reduction

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in their itch symptom, two subjects reported a 33% reduction and one subject reported no change. One can speculate that this eect of dapsone is related to its well-known antiinammatory property and an ability to inhibit signal transduction through G protein-linked receptors that mediate an increase in intracellular free calcium (39). With the information and experience accumulated over decades of attempts to understand and treat chronic postburn itch, it seems that we are not closer to identifying a targetable single agent or cellular event that is central to this symptom. Instead, the information accumulating supports a complex mechanism involving multiple agonists and modifying factors produced by dierent cells, each of which may be subject to control by one or more of the therapies tested to date. Results of clinical tests of available remedies suggest, further, that the mechanism of postburn itch may vary among individuals. Lest this frustrating situation temper ones commitment to solving this puzzle, it is important to remember the statement made by Gordon in 1988 (40) that Burn-related pruritus is a serious problem that often receives little attention, even though it continues to aggravate burn patients during their postburn course of treatment and rehabilitation (40); it still applies!

REFERENCES
1. 2. 3. Munster AM. Burn Care for the House Ocer. Baltimore: Williams and Wilkins, 1980:81. Fowler D. Australian Occupational Therapy: Current Trends and Future Considerations in Burn Rehabilitation. J Burn Care Rehab 1987; 8:415417. Ahrenholz DH, Solem LD. Management of pain after thermal injury. In: Eisenberg MG, Grzesiak RC, eds. Advances in Clinical Rehabilitation. New York: Springer, 1987:225. Head MD. Wound and Skin Care. In: Fisher SV, Helm PA, eds. Comprehensive Rehabilitation of Burns. Baltimore: Williams and Wilkins, 1984:173. Klotki J, Pochon JP. Conservative treatment using compression suits for second and third degree burns in children. Burns 1982; 8:180187. Herndon DN, LeMaster J, Beard S, Bernstein N, Lewis SR, Rutan TC, et al. The quality of life after minor thermal injury in children: an analysis of 12 survivors with >80% total body, 70% third-degree burns. J Trauma 1986; 26:609617. Ward RS, Sae JR, Schnebly A, Hayes-Lundy C, Reddy R. Sensory loss over grafted areas in patients with burns. J Burn Care Rehabil 1989; 10:536538. Vitale M, Fields-Blache C, Luterman A. Severe itching in the patient with burns. J Burn Care Rehabil 1991; 12:330333. Blalock SJ, Bunker BJ, Moore JD, Foreman N, Walsh JF. The impact of burn injury: a preliminary investigation. J Burn Care Rehabil 1992; 13:487492.

4. 5. 6.

7. 8. 9.

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10. Malenfant A, Forget R, Papillon J, Amsel R, Frigon J-Y, Choiniere M. Prevalence and characteristics of chronic sensory problems in burn patients. Pain 1996; 67:493500. 11. Barnden L, Griths T, Littiard K, Sperring B. Burns patients and itching. Aust NZ Burn Assoc Bull 1998; 22:3. 12. Tyack ZF, Ziviani J, Pegg S. The functional outcome of children after a burn injury: a pilot study. J Burn Care Rehabil 1999; 20:367373. 13. Gibran NS, Heimbach MD. Current status of burn wound physiology. Clin Plast Surg 2000; 27:1122. 14. Ahee AM, Smith SJ, Pliska-Matyshak G, Cullen ML. When does itching start and stop post-burn? J Burn Care Rehabil 1999; 20(1 Pt 2):S187. 15. Field T, Peck M, Hernandez-Reif M, Krugman S, Burman I, Ozment-Schenck L. Postburn itching, pain, psychological symptoms are reduced with massage therapy. J Burn Care Rehabil 2000; 21:189193. 16. Demling RH, De Santi L. Topical doxepin cream is eective in relieving severe pruritus caused by burn injury: a preliminary study. Wounds 2001; 13:210215. 17. Baker RAU, Zeller RA, Klein RL, Thornton RJ, Shuber JH, Marshall RE, Leibfarth AG, Latko JA. Burn wound itch control using H1 and H2 antagonists. J Burn Care Rehabil 2001; 22:263268. 18. Lynch JB. Excision of facial scars. In: Feller I, Grabb WC, eds. Reconstruction and Rehabilitation of the Burned Patient. National Institute for Burn Medicine, 1979:202. 19. Bell L, McAdams T, Morgan R, Parshley PF, Pike RC, Riggs P, Carpenter JE. Pruritus in burns: a descriptive study. J Burn Care Rehabil 1988; 9:305308. 20. Smith S. Comments from Brookside Hospital Burn Center, San Pablo, California. J Burn Care Rehabil 1988; 9:309310. 21. Tager K, Jenkins M, Savlors R, Warden GD. The use of Claritin to control itching in thermally injured patients. J Burn Care Rehabil 1998; 19(1 PSt 2): S261. 22. Daltroy LH, Liang MH, Phillips CB, Daugherty MB, Hinson M, Jenkins M, McCauley R, Meyer W III, Munster A, Pidcock F, Reilly D, Tunell W, Warden G, Wood D, Tomkins R. American Burn Association/Shriners Hospitals for Children Burn Outcomes Questionnaire: construction and psychometric properties. J Burn Care Rehabil 2000; 21:2939. 23. Walker S, Dimick AR. Use of Preparation H to heal burn wounds. Abstract, Annual Meeting of the American Burn Association, 1993:230. 24. Choiniere M, Papillon J. Topical capsaicin treatment for post-burn pruritus: a double-blind study. Abstract, 9th Congress of the International Society for Burn Injuries, 2001:3. 25. Hartford CE. Care of out-patient burns. In: Herndon DN, ed. Total Burn Care. Philadelphia: WB Saunders, 1996:7178. 26. Patino O, Novick C, Merlo A, Benaim F. Massage in hypertrophic scars. J Burn Care Rehabil 1998; 19:268271. 27. Matheson JD, Clayton J, Muller MJ. The reduction of itch during burn wound healing. J Burn Care Rehabil 2001; 22:7681.

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28. Kopecky EA, Jacobson S, Hubley P, Palozzi L, Clarke HM, Koren G. Safety and pharmacokinetics of EMLA in the treatment of postburn pruritus in pediatric patients: a pilot study. J Burn Care Rehabil 2001; 22:235242. 29. Whitaker C. The use of TENS for pruritus relief in the burn patient: an individual case report. J Burn Care Rehabil 2001; 22:274276. 30. Demling RH, DeSanti L. Topical doxepin signicantly decreases itching and erythema in the healed burn wound. Wounds 2002; 14:210215. 31. Physicians Desk Reference. 2002:2713. 32. Lee RE. The inuence of psychotropic drugs on prostaglandin biosynthesis. Prostaglandins 1974; 5:6368. 33. Boss M, Burton JL. Lack of eect of the antihistamine drug clemastine on the potentiation of itch by prostaglandin E1. Arch Dermatol 1981; 117:208209. 34. Neisius U, Olsson R, Rukwied R, Lischetzki G, Schmelz M. Prostaglandin E2 induces vasodilation and pruritus, but no protein extravasation in atopic dermatitis and controls. J Am Acad Dermatol 2002; 47:2832. 35. Greaves MW, McDonald-Gibson W. Itch: role of prostaglandins. Brit Med J 1973; 3:608609. 36. Hagermark O, Strandberg K, Hamberg M. Potentiation of itch and are responses in human skin by prostaglandins E2 and H2 and a prostaglandin endoperoxide analog. J Invest Dermatol 1977; 69:527530. 37. Nelson RD, Harmon JM, Ahrenholz DH, Solem LD, Koki AT. COX-2 expression by broblasts and vascular endothelial cells in healed burn wound tissue. J Burn Care Rehabil 2002; 23:S129. 38. Bauling PC, McDermott T, Peterson VM. A pilot study on topical dapsone application to decrease itching in healed burn wounds. J Burn Care Rehabil 2002; 23:S55. 39. Debol SM, Herron MJ, Nelson RD. Anti-inammatory action of dapsone: inhibition of neutrophil adherence is associated with inhibition of chemoattractant-induced signal transduction. J Leukoc Biol 1997; 62:827836. 40. Gordon MD. Pruritus in burns. J Burn Care Rehabil 1988; 9:305.

25
Pruritus in Lichen Simplex Chronicus and Lichen Amyloidosis
Yung-Hian Leow
National Skin Centre, Singapore, Republic of Singapore

Gil Yosipovitch
Wake Forest University School of Medicine, Winston-Salem, North Carolina, U.S.A.

I.

INTRODUCTION

Lichen simplex chronicus (LSC), otherwise known as neurodermatitis, is the prototype chronic eczema. The classical symptom of this condition is pruritus or itch, which is also thought to perpetuate the clinical lesions on patients by invoking scratching. Lichen amyloidosis (LA), a form of primary localized cutaneous amyloidosis, is characterized by the clinical appearance of brown papules that clinically resemble LSC. This condition is associated frequently with severe localized pruritus.

II.

CLINICAL PRESENTATION

LSC can occur in patients with history of atopy, namely, personal history of bronchial asthma and/or allergic rhinitis. There may also be a family history
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of atopy. However, this is not a consistent or pathognomic feature of the condition. It can present clinically as isolated or multiple lichenied thickened plaques that are usually hyperpigmented and excoriated with accentuated skin markings. Patients are often concerned with the intense pruritus and the physical disgurement. Lesions are often found on areas accessible to the patients, namely, the neck, the anogenital areas, and the upper and lower extremities. LA usually presents as idiopathic hyperpigmented papular eruption which occurs symmetrically predominantly on the extensor surfaces of the extremities and back. There are reports of LA appearing at the nipples and vulva, and a generalized form has also been recognized (1,2). Pruritus may be a presenting symptom, although not a pathognomic feature of the condition. There had been some suggestions that itch induces the clinical lesions, and some clinicians consider LA to be a variant of LSC (3). The disorder is seen in all racial groups but seems more common in Asians, especially in Chinese (4).

III.

PATHOPHYSIOLOGY

LSC is classied as one of the prototype examples of chronic endogenous eczema, and patients with history of atopy or endogenous dermatitis may be at increased risk (5). Itch sensation is one of the key symptoms of this condition. Repeated scratching leads to the persistence of clinically apparent plaques, which subsequently perpetuate the itchscratch cycle, which is thought to be one of the most important pathogenetic mechanisms that potentiate the condition. The other suggested factor involved in the itch in LSC is the hypersensitivity of C nerve bers to acetylcholine (6). LA resembles LSC clinically and histopathologically, except for the presence of amyloid deposits in the papillary dermis in the former condition. LA is not a subset of, or related to, systemic amyloidosis, although there had been reports on its association with myelomatosis (7). Amyloid in LA is derived from keratin peptides of necrotic apoptotic keratinocytes. It had been postulated that necrosis of these keratinocytes is induced by pruritus, thus leading to prolonged scratching (3,811). Interestingly, amyloid deposits cannot be found in clinically normal skin of patients with LA. It had also been suggested that perhaps, in view of the similarity in clinical appearance and histopathological ndings, LA is possibly a variant of LSC, with pruritus being the paramount inducing factor that leads to the deposition of amyloid in the papillary dermis in the former condition.

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IV.

PSYCHOGENIC FACTORS AND LICHEN SIMPLEX CHRONICUS AND LICHEN AMYLOIDOSIS

It is dicult to assess the role of psychological factors in these skin disorders. Stress can precipitate or aggravate these disorders such as in other neurodermatitis. In our experience, it seems that LSC appears in high achievers with stressful and competitive lifestyles, who are more introverts and do not express anger and anxiety publicly. V. TREATMENT

LSC can be extraordinarily dicult to manage. The principles in the management of LSC follow those of the treatment of eczema in general. The use of potent topical corticosteroid and sedating antihistamines are the main therapeutic options. Intralesional corticosteroid is useful in the treatment of recalcitrant lesions. However, these lesions tend to reappear and persist for many years despite intensive treatment with high-potency corticosteroids. A recent study has demonstrated that administration of topical aspirin solution was very eective in a double-blind placebo-controlled trial in patients with severe LSC who were resistant to previous treatment with potent corticosteroids (12). Heckman et al. (6) have recently reported that intradermal injection of Botulinum toxin type A in three LSC patients suering from recalcitrant pruritus had a signicant antipruritic eect within 37 days of injection, with no recurrences over a 4-month period. They proposed that the antipruritic mechanism of Botulinum is due to its eect as a potent inhibitor to acetylcholine release from presynaptic vesicles. Acetylcholine has previously been shown to evoke pruritus in patients with atopic dermatitis (13). Going by the principle that pruritus induces the clinical presentation of LA, treatment should be targeted at the alleviation of pruritus. Sedating antihistamines and topical high-potency corticosteroid are partially eective in symptom relief and possibly the control of the condition. Various treatment modalities have been attempted, which include laser ablation, dermabrasion, excision, topical dimethyl sulfoxide (DMSO), topical tretinoin, calcipotriol, and phototherapy (1419), but yielded equivocal results. In most cases, the pigmentation disorder does not clear, although the patients report an improvement of their itch.

REFERENCES
1. Gorodeski IG, Cordoba M, Shapira A, et al. Primary localized cutaneous lichen amyloidosus of the vulva. Int J Dermatol 1988; 27:259.

258 2. 3. 4. 5. 6.

Leow and Yosipovitch Ganor S, Dollberg L. Amyloidosis of the nipple presenting as pruritus. Cutis 1983; 31:318. Weyers W, Weyers I, Bonezkowtiz M, et al. Lichen amyloidosus: a consequence of scratching. J Am Acad Dermatol 1997; 37:923. Yap KB, Siew MG, Goh CL. Pattern of skin diseases in the elderly seen at the National Skin Center. Singap Med J 1994; 35:147150. Singh G. Atopy in lichen simplex (neurodermatitis circumscripta). Br J Dermatol 1973; 89:625. Heckman M, Heyer G, Brunner B, Plewig G. Botulinum toxin type A injection in the treatment of lichen simplex: an open pilot study. J Am Acad Dermatol 2002; 46:617619. Greaves MW, Shuster S. Myelomatosis following lichen amyloidosus. Proc R Soc Med 1963; 56:791. Black MM, Jones EW. Macular amyloidosis. A study of 21 cases with special reference to the role of the epidermis in its histogenesis. Br J Dermatol 1971; 84:199. Leonforte JF. Origin of macular amyloidosis. Apropos of 160 cases. Ann Dermatol Venereol 1987; 114:801. Sumitra S, Yesudian P. Friction amyloidosis: a variant or an etiologic factor in amyloidosis cutis? Int J Dermatol 1993; 32:422. Wong CK, Lin CS. Friction amyloidosis. Int J Dermatol 1988; 27:302. Yosipovitch G, Sugeng MW, Chan YH, et al. The eect of topically applied aspirin on localized circumscribed neurodermatitis. J Am Acad Dermatol 2001; 45:910913. Heyer G, Vogelgsang M, Hornstein OP. Acetylcholine is an inducer of itching in patients with atopic eczema. J Dermatol 1997; 24:621625. Alster TS, Manaloto RM. Nodular Amyloidosis treated with pulseddye laser. Dermatol Surg 1999; 25:133135. Lien MH, Railan D, Nelson BR. The ecacy of dermabrasion in the treatment of nodular amyloidosis. J Am Acad Dermatol 1997; 36:315316. Ozkaya-Bayazit E, Kauak A, Gungor H, Ozarmagan G. Intermitter use of topical dimethyl sulfoxide in macular and popular amyloidosis. Int J Dermatol 1998; 37:949954. Ollague W. Primary cutaneous amyloidosis. Int J Dermatol 1987; 26:135. Khoo BP, Tay YK, Goh CL. Calcipotriol ointment vs. bethanethasone 17valerate ointment in the treatment of lichen amyloidosis. Int J Dermatol 1999; 38:539541. Jin AG, Por A, Wee LK, Kai CK, Leok GC. Comparative study of phototheraphy (UVB) vs. photochemotheraphy (PUUA) vs. topical steroids in the treatment of primary cutaneous lichen amyloidosis. Photoderm Photoimmunol Photomed 2001; 17:4243.

7. 8.

9. 10. 11. 12.

13. 14. 15. 16.

17. 18.

19.

26
Treatment of Pruritus in Internal and Dermatological Diseases with Opioid Receptor Antagonists
nder and Dieter Metze Sonja Sta
nster, Mu nster, Germany University of Mu

Opioid receptor antagonists were originally developed for treatment of heroin dependence and to reverse symptoms of postanesthetic depression, narcotic overdose, and opioid intoxication such as respiratory depression, sedation, and hypotension. Interestingly, in recent years, they were also found to have signicant antipruritic eects (1). In cholestatic pruritus, opioid receptor antagonists are already a well-established therapeutic modality (2). In other diseases like atopic dermatitis, antipruritic eects are variable and further studies will have to examine the long-term ecacy and safety of opioid antagonists. Overall, opioid receptor antagonists seem to be a novel treatment of several pruritic dermatological and internal diseases. In the following chapter, an overview of the pharmacological properties and side eects of dierent opioid receptor antagonists and their application in the treatment of itch will be given.

I. A.

PHARMACOLOGY OF OPIOID RECEPTOR ANTAGONISTS Naloxone

Naloxone, an allyl derivate of noroxymorphone (Fig. 1), was synthesized in 1960 and proved to be more potent and less toxic than previous opioid
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Figure 1

Structural formula of naloxone. (From Ref. 6.)

receptor antagonists such as nalorphine (3). Naloxone has a low oral bioavailability, which necessitates parenteral administration. After subcutaneous or intravenous application, the substance undergoes large rst-pass metabolism in the liver with the production of naloxoneglucuronid and is subsequently excreted by the kidney. Since naloxone has a short duration of action with a plasma half-life of only 1 to 2 hr (3), administration of frequent repeated doses or a continuous infusion is inevitable. Naloxone is rapidly distributed into the brain blocking mainly A-opioid receptors (3) and produces only weak or no agonist eects including analgesia (4). Moreover, naloxone does not lead to physical dependence as seen during the long-term application of morphine (4). Although naloxone showed antipruritic eects, the long-term use is limited due to its pharmacokinetic properties. B. Naltrexone

Naltrexone is an orally active, long-acting, competitive antagonist at A-opioid receptors developed in 1963 (5). The substance is a cyclopropyl derivate of oxymorphone structurally similar to naloxone and nalorphine (Fig. 2). After oral administration, naltrexone results in rapid absorption with peak plasma concentrations of 19 to 44 Ag/l within 1 hr (6,7). In the liver, naltrexone undergoes extensive rst-pass metabolism with rapid reduction to the major metabolite 6-h-naltrexol with subsequent glucuronide conjugation (7,8). Naltrexone and metabolites last for up to 48 hr in the circulation and are excreted by renal clearance (6,8,9). After administration of 50 mg naltrexone, central A-opioid receptors were blocked for at least 72 to 108 hr (10) with negligible agonist eects such as pupillary miosis, dysphoria, and unpleasant sensations. The antagonist potency is at least 1217 times that of nalorphine and twice that of naloxone (5). Naltrexone neither produces physical depen-

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Figure 2 Structural formula of naltrexone. (From Ref. 6.)

dence nor has abuse potential. Due to these pharmacological advantages, naltrexone is a potent antipruritic. C. Nalmefene

Nalmefene (6-desoxy-6-methylene-naltrexone), a chemical analog of naltrexone (Fig. 3), was synthesized in 1975 (11) and is a potent, orally active opioid antagonist at A-, n-, and y-opioid receptors (12,13). Nalmefene shows longer-lasting plasma concentrations and greater oral bioavailability than naltrexone (11,12). By oral, intravenous, intramuscular, or subcutaneous application, nalmefene is rapidly absorbed with therapeutic plasma and brain concentrations after 515 min and metabolized in the liver primarily by glucuronide conjugation (12,14,15). Since nalmefene is mainly excreted by renal clearance, the clearance half-time is elongated in renal disease (16). The

Figure 3 Structural formula of nalmefene. (From Ref. 15.)

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elimination half-time varied from 7 to 15 hr, while brain clearance is about 21 hr slower, reecting the long occupancy of cerebral opioid receptors (15,17). Nalmefene has no agonist activity and binds with equal potency as naltrexone at central A-opioid receptors, but more eectively to y- and nopioid receptors as compared to naloxone or naltrexone (13). Nalmefene does not produce physical dependence nor has abuse potential. In sum, nalmefene has several pharmacological advantages over naltrexone, e.g., prolonged duration of action and increased potency at the opioid receptor level, and, furthermore, proved signicant antipruritic eects. However, nalmefene is available at present only in the United States, but not in Europe, limiting a general application.

II.

CONTRAINDICATIONS FOR OPIOID RECEPTOR ANTAGONIST THERAPY

Naltrexone and nalmefene are contraindicated in patients with acute hepatitis, liver failure, severe liver insuciency, and in patients with marginal evidence of hepatocellular injury. In liver cirrhosis, metabolism of naltrexone into 6h-naltrexol is disturbed, leading to reduced eective circulating concentrations (18). Furthermore, naloxone, naltrexone, and nalmefene must not be used in drug addicts and in patients receiving opioid analgesics and opioidcontaining medicines such as cough, cold, and antidiarrheal preparations. Patients with a history of opioid dependence and preexistent cardiac diseases should be controlled carefully (14). These substances should not be used in pregnant or breast-feeding women and children.

III.

SIDE EFFECTS

In general, naloxone, naltrexone, and nalmefene appear to have a favorable risk-to-benet ratio with comparable occurrence of identical side eects (Table 1). All opioid receptor antagonists are usually well tolerated with dose-dependent side eects generally limited to the rst 2 weeks of treatment (12,14,15,19). The main side eects are nausea, vomiting, fatigue, dizziness and less frequently chills, loss of appetite, heartburn, diarrhea, myalgia, arthralgia, fever, or headache (14,15,1927). Interestingly, females and younger subjects were more likely to report nausea (28). Rarely, opioidwithdrawal reactions occur such as severe lightheadedness, disturbed body image, depersonalization, anxiety, paraesthesia, abdominal pain, tremor, nightmares, hallucinations, and depression (2,1923,25,29,30). These adverse eects were attributed to increased levels of endogenous opiates in some

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Table 1 Side Eects of Opioid Receptor Antagonist Therapy with Naloxone, Naltrexone, and Nalmefene Common side eects Gastrointestinal Cardiovascular Nauseaa, vomitinga, diarrheaa, heartburn, loss of appetite, intermittent abdominal pain Dizzinessa, hypertension, hypotension, pulmonary edema, vasodilatation, cardiovascular instability, ventricular tachycardia, ventricular brillation Fatiguea, headachea, lightheadednessa, anxiety, nightmares, hallucinations, depression, depersonalization, disturbed body image, paraesthesia, tremor, fever, chills Myalgia, arthralgia Urticaria, rhinitis, angioedema, dyspnea

Neurologic

Musculoskeletal Allergic
a

Frequent appearance.

pruritic conditions, e.g., liver diseases. Severe cardiovascular side eects such as pulmonary edema, vasodilatation, cardiovascular instability, hypo- or hypertension, ventricular tachycardia, and ventricular brillation have been mainly reported in connection with treatment of postoperative narcotic overdose and intoxication in patients with opioid dependence, possibly due to abrupt reversal of opioid eects. To diminish side eects, some authors suggest gradual administration of naltrexone or nalmefene with slowly increasing doses (27). Nausea can be easily managed by oral administration of metoclopramid (19). Interestingly, Neuberger and Jones (2) reported on a patient with hallucinations and intense nausea under naltrexone treatment which could be counterbalanced with preceding slow infusion of naloxone (0.002 up to 0.2 Ag/kg/min). However, after long-term application of naloxone, side eects of a subsequent naltrexone therapy may be increased (27). Other endocrinological side eects include signicant increase in serum concentrations of h-endorphin, cortisol, and luteinizing hormone and equivocal changes in prolactin and testosterone as observed after administration of naltrexone (31). Other hormones such as adrenocorticotrophic hormone or follicle-stimulating hormone showed no signicant changes in plasma concentrations (31). In high dosage up to 300 mg, naltrexone has the capacity to produce a transient dose-related hepatocellular injury resulting in the elevation of serum transaminases and to evoke thrombocytopenic purpura (32,33). With regard to antipruritic treatment, neither elevation of liver enzymes nor thrombocytopenic purpura were found (19). In patients with liver diseases, it

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could be demonstrated that the clearance of nalmefene was signicantly reduced in comparison to patients without liver disease (34), but no dosage adjustment is recommended (Baker Norton Pharmaceuticals Inc., U.S.A., datasheet nalmefene). Endogenous opioids inuence immune functions (35), and naloxone was shown to increase T-lymphocyte proliferation, increase Th1 but decrease Th 2 cytokine production, and worsen the development of inammatory responses in animals (36). The role of opioid receptors in the immunoregulatory system in humans has to be determined. Very rarely, allergic hypersensitivity presenting with urticaria, rhinitis, angioedema, and dyspnea has been observed (Table 1).

IV.

TOLERANCE

Tolerance, i.e, loss of ecacy despite unchanged therapy, was infrequently reported under opioid receptor antagonist therapy and occurred with variable latency. One patient receiving naloxone subcutaneously reported on a decline in the benecial eect after several months, which could be resolved by increasing the dose (27). In one study, 5 of 14 patients experienced exacerbation of pruritus after a 4-week oral nalmefene therapy (22). Other studies reported on 6 of 50 patients (19) and 1 of 5 patients (30) with tolerance during naltrexone therapy. The antipruritic eect considerably decreased after 1 to 9 months (19) and 28 weeks (30), respectively. In two patients with chronic prurigo nodularis, it was possible to counterbalance tolerance by increasing dosage of 50 mg naltrexone twice a day (19). Moreover, after an interruption for 2 to 3 weeks, opioid receptor antagonist treatment can be reinitiated with success (19,27,30). Tolerance may possibly result from an up-regulation of receptors in the peripheral and central nervous system following long-term stimulation (37).

V.

CLINICAL APPLICATION

Clinical and experimental observations have shown that pruritus can be evoked or intensied as a side eect of opioid therapy (3842). Accordingly, several studies demonstrated that dierent opioid receptor antagonists may signicantly diminish pruritus (40,4346) (Tables 2,3). Since response of itch to placebo is invariably pronounced, studies that do not control for this should be regarded with suspicion. In experimental studies, pruritus induced by dierent neuropeptides and neurotransmitters such as histamine (44,45), substance P (47), serotonin (48), as well as acetylcholine (70) could be completely suppressed by naloxone and naltrexone. Likewise, upon clinical use,

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Table 2 Antipruritic Therapy of Inammatory Skin Diseases with Opioid Receptor Antagonists Patients (n) 1 20 19 Opiate antagonist, dosage, application Naloxone 6.4 mg i.v., once Nalmefene 20 mg/day, p.o.

Author (Ref. ) Year Smitz (52) Banerjia (53) 1982 1988

Diagnosis Urticaria, angioedema Urticaria Atopic dermatitis

Response Improvement 7/20 patients: complete relief 19/19 patients: no statistical dierence No signicant improvement 35% (20 mg) 60% (10 mg) of patients: signicant improvement Improvement

Burcha (29) Monroea (24)

1988 1989

Psoriasis vulgaris Eczema Urticaria Atopic dermatitis

12 7 21 59

Nalmefene 30 mg/day, p.o. Nalmefene 1020 mg/day, p.o.

Sullivan (27)

1997

Mycosis fungoides

Metze (19)

1999

Atopic dermatitis Psoriasis Prurigo nodularis Lichen simplex Macular amyloidosis Bullous pemphigoid Arthropod assault Xerosis cutis Scabies Lichen sclerosus et atrophicus Skin lymphoma

4 1 17 1 1 1 1 2 1 1 5

Naloxone 0.2 mg s.c. every 34 hr Naltrexone 50 mg Worsening p.o., once Naltrexone 50100 2/4 patients: mg/day, p.o. relief 80% reduction 9/17 complete relief No response Complete relief 70% relief 20% relief 20% and 100% relief No response No response 3/5 relief

i.v.intravenous; s.c.subcutaneously; p.o.orally. a Double-blind, placebo-controlled study.

266

Table 3 Year 1979 1980 Cholestatic pruritus


20

Antipruritic Therapy of Noninammatory Skin and Internal Diseases with Opioid Receptor Antagonists Diagnosis Cholestatic pruritus Naloxone 0.8 mg/day, s.c., 2 days Naloxone 2 mg during 18 hr, i.v., once
1

Author

Patients (n)

Opiate antagonist, dosage, application

Response Complete relief

Bernstein

Summerelda

Bernstein 1982 1984 1988 1992


1 11 1 1

1981

Improvement in placebo nonresponders (7/20 patients) Total prevention Total relief Total relief 9/11 patients: improvement Improvement

Smitz

Naloxone 1.2 mg s.c. prior to butorphanol Naloxone 6.4 mg i.v., once

Andersen Thornton Jones

Butorphanol-induced pruritus Pruritus of unknown origin Renal pruritus Cholestatic pruritus Cholestatic pruritus

Bergasaa 1992 1995 Cholestatic pruritus


29

Cholestatic pruritus

Improvement 4/8 patients: improvement 7/29 patients: improvement

nder and Metze Sta

Bergasaa

Naloxone 0.8 mg i.v., once Nalmefene 60120 mg/day p.o. Naloxone 0.2 Ag/kg/min for 24 hr, i.v., 2 days Nalmefene 80 mg/day, p.o. Naloxone 0.2 Ag/kg/min for 24 hr, i.v., 1 or 2 days Naloxone 0.2 Ag/kg/min for 24 hr, i.v., 2 days

Peera 1996 1996 1997 1998 Naltrexone 50 mg/day, p.o. Naltrexone 50 mg/day, p.o. Naltrexone 50 mg/day, p.o. Nalmefene 60240 mg/day, p.o. Nalmefene 40 mg/day, p.o. Naltrexone 50100 mg/day, p.o. 1998 1999 1999
1 4 5 2 2 1 23 1 1

Renal pruritus Cholestatic pruritus Cholestatic pruritus Renal pruritus Cholestatic pruritus Cholestatic pruritus
14 11 5 8 5

15

Naltrexone 50 mg/day, p.o.

Carson Wolfhagena Ghuraa

Bergasa Bergasaa

Metze

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Pauli-Magnusa Jones Neuberger 2000 2000 2001

Aquagenic pruritus Hydroxyethyl starchpruritus Pruritus of unknown origin Diabetic pruritus Renal pruritus Cholestatic pruritus Renal pruritus Cholestatic pruritus Cholestatic pruritus Naltrexone 50 mg/day, p.o. Naltrexone 25 mg/day p.o. Naloxone 0.0020.2 Ag/kg/min i.v. 2 hr, then naltrexone 12.5150 mg/day, p.o.

15/15 patients: signicant improvement 5/5 patients: 60100% relief 7/8 patients: improvement 3/5 patients: marked improvement 13/14 patients improvement 8/11 patients: 75% improvement Complete relief 2/4 patients: 50%, 100% relief 2/5 patients: 50%, 70% relief 30%, 40% relief 20%, 100% relief 70% relief No signicant improvement Complete relief Complete remission

i.v.intravenous; s.c.subcutaneously; p.o.orally. a Double-blind, placebo-controlled study.

267

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opioid receptor antagonists were shown to have a high capacity to suppress pruritus of diverse etiologies. The initial reports appeared in the early 1980s demonstrating that opioid-induced pruritus, e.g., pruritus occurring after injection of the synthetic analgesic butorphanol (38) or pruritus after epidural or intrathecal analgesia with morphine (1,4951), could be reversed. Many other indications are now known and this eld is ever increasing. For some diseases like cholestatic pruritus, many controlled studies do exist; for others like psoriasis vulgaris and atopic dermatitis, only case reports with variable results are available. Importantly, in one study, patients were divided into two groups according to their reaction upon placebo, namely, placebo responders (pruritus improved upon placebo) and placebo nonresponders. Interestingly, only patients dened as placebo nonresponders experienced itch improvement under naloxone possibly reecting elevated opioid levels contributing to pruritus (46). This would explain the failure in the treatment in a great number of individuals, and further studies should take into account the placebo responder and nonresponder groups. In general, treatment with opioid receptor antagonist is a symptomatic therapy, and accordingly, after discontinuation of the therapy, an abrupt exacerbation of pruritus could be expected (19).

VI. A.

PRURITUS OF INFLAMMATORY SKIN Chronic Urticaria

The rst report of opioid receptor antagonist therapy in chronic urticaria dates back to 1982. Smitz et al. (52) reported of a patient with asthma, chronic urticaria, and angioedema who experienced a signicant improvement of symptoms following a single dose of naloxone (1.6 mg/hr for 4 hr, once). Banerji et al. (53) reported on eective treatment of chronic urticaria with 20 mg oral nalmefene in 20 patients. Peak antipruritic eect occurred after 2 hr and remained signicant for 3 hr. Two double-blind, placebo-controlled studies in 21 patients with urticaria receiving a single dose of 10 and 20 mg nalmefene, respectively, showed a signicant diminution of pruritus (24) (Table 2). B. Atopic Dermatitis

Itch in patients with atopic dermatitis (AD) did not respond to the opioid antagonist nalmefene 20 mg in 19 patients (53). In another study, seven patients with eczema, possibly atopic in etiology, received oral nalmefene (10 mg twice daily) (29,54). Although pruritus decreased by about 50%, dierence to placebo treatment was not signicant (29). In a double-blind, placebo-controlled study, 59 patients with AD received a single oral dose

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of 10 or 20 mg nalmefene and experienced a signicant diminution of pruritus within 1 hr (10 mg nalmefene) to 3 hr (20 mg) (24). Interestingly, although expected to have minor side eects following a single dose, 67% of the patients reported of dizziness or nausea (24). The response of AD to naltrexone (50100 mg/day, 6 weeks12 months) was not convincing. In four patients, only one reported complete relief, another experienced 20% reduction of pruritus, while two patients stated no inuence on pruritus (19). Both immunological and nonimmunological factors contribute to a reduced itch threshold and spontaneous itching in AD, which may account for the poor ecacy of opioid receptor antagonists in many atopic patients (19,55). C. Psoriasis Vulgaris

Anecdotal reports of the antipruritic eect of opiate antagonists have been published. Twelve patients with psoriasis vulgaris with severe pruritus were treated with oral nalmefene (10 mg twice daily, orally) (29). Although a relief of 50% was achieved with the therapy, dierence to placebo treatment was not signicant (29,54). However, a patient treated with naltrexone (50 mg, once daily, orally, for 3 months) experienced a reduction of pruritus of 80% (19). D. Prurigo Nodularis, Lichen Simplex, Macular Amyloidosis

Conditions caused by repeated rubbing and scratching like prurigo simplex and nodularis, lichen simplex, and macular amyloidosis respond variably to naltrexone therapy (19). Naltrexone (50100 mg daily, orally, for 2 weeks14 months) showed a high antipruritic eect in macular amyloidosus (1 patient) and prurigo nodularis (17 patients). In 9 out of 17 patients with prurigo simplex and nodularis, pruritus was signicantly or completely suppressed. A reduction of scratching activity was followed by re-epithelialization of erosions, attening and softening of the nodules, and nal healing of the lesions with some scarring and hyperpigmentation (Fig. 4a and b). In macular amyloidosus, eective antipruritic therapy by naltrexone may also interfere with basic pathophysiological mechanisms, namely, the formation of amyloid K due to chronic friction (19). Only lichen simplex failed to respond to naltrexone as reported in one patient (19). E. Other Inflammatory Diseases Associated with Pruritus

Other patients treated for pruritic symptoms with naltrexone (50100 mg daily, orally, for 5 days4 months) who experienced a signicant relief of

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Figure 4 Patient with prurigo simplex due to chronic scratching before (A) and after (B) 9-month naltrexone therapy. (From Ref. 19.)

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pruritus had bullous pemphigoid (one patient) with 70% reduction of pruritus, papular urticaria (20% reduction of pruritus, one patient), and xerosis cutis (two patients) with 20% and 100% reduction, respectively. No inuence of naltrexone on pruritus was observed in infestation with scabies (one patient) and lichen sclerosus and atrophicus (one patient) (19). F. Pruritus in Cutaneous Lymphoma

Cessation of pruritus associated with cutaneous T-cell lymphoma (mycosis fungoides) was achieved under treatment with naloxone 0.2 mg subcutaneously every 34 hr for 6 weeks. Interestingly, after changing medication to naltrexone (50 mg, orally, once), the patient developed generalized pruritus with subsequent uncontrollable scratching within 30 min (27). In another study, the response to naltrexone of four patients with cutaneous T-cell lymphoma (mycosis fungoides) (50 mg daily, orally, 2 weeks5 months) was variable ranging from 60% to 100% relief of pruritus, while one patient did not respond (19). In cutaneous B-cell lymphoma, one patient failed to improve under naltrexone therapy (50 mg daily, orally, 3 weeks) (19).

VII. A.

PRURITUS ON NONINFLAMMATORY SKIN Aquagenic Pruritus

Naltrexone (50 mg daily, orally, 5 months) was used for aquagenic pruritus. Within 4 weeks, the patient reported complete relief of pruritus. Interestingly, after cessation of therapy, pruritus recurred 8 months later (19) (Table 3). B. Iatrogenic Pruritus

Butorphanol is a synthetic parenteral analgesic related to morphine with narcotic and opioid antagonist properties. In a case report, a patient experienced a severe generalized pruritus after each intramuscular application of butorphanol. Interestingly, this side eect could be totally blocked by previous administration of 1.2 mg naloxone subcutaneously (38). A high incidence of severe, therapy-refractory pruritus has been observed after administration of hydroxyethyl starch (HES), which was given for plasma volume substitution and improvement of microcirculation. Under treatment with naltrexone (50 mg daily, orally, for 5 weeks6 months), four patients with HES-induced pruritus experienced relief of pruritus of 50% (two patients), complete cessation (one patient), or no inuence on pruritus (one patient) (19).

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C.

Pruritus of Unknown Origin

Some patients complain of a generalized pruritus of noninamed skin in which the origin cannot be determined despite thorough clinical and laboratory examination. In one patient with generalized pruritus of unknown origin (PUO) naloxone (single infusion of 1.6 mg/hr for 4 hr) led to complete disappearance of pruritus on the day of infusion (52). Naltrexone (50100 mg daily, orally, for 2 weeks3 months) was given in ve patients with pruritus of unknown origin showing variable ecacy (19). While three patients did not respond to naltrexone, two reported itch reduction up to 50% and 70%, respectively (19). In summary, dierent underlying pathophysiological mechanisms may account for the variable ecacy of opioid receptor antagonists in PUO.

D.

Pruritus in Cholestatic Liver Disease

Dysregulation of the opioid system has been suggested to be an important mechanism in the pathogenesis of cholestatic pruritus in the course of dierent liver diseases including chronic hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, or drug-induced cholestatic liver disease (20,21,56). In some conditions, e.g., primary biliary cirrhosis, plasma levels of enkephalins were detected to be raised (57,58). In a rat animal model of cholestasis, it could be demonstrated that A-opioid receptor density in the central nervous system is signicantly decreased possibly reecting an increased exposure of endogenous opioids (59,60). Although opioid receptor antagonists should be given carefully in liver disease due to depressed drug metabolism, studies showed no deterioration of the underlying liver disease except occasional slight increase in serum bilirubin (61), but a clear eect on cholestatic pruritus (2,23,30,62,63). Nowadays, opioid receptor antagonist therapy is a well-established treatment of cholestatic pruritus. A recent report proposed that a liver transplantation for intractable pruritus is contraindicated unless an adequate trial of opioid antagonist therapy is performed (2). The rst report of eective treatment of cholestatic pruritus with naloxone (0.8 mg daily, s.c., for 2 days) dates back to 1979 (43). Within 30 min after application, pruritus was completely abolished. The ecacy was conrmed in several double-blind, placebo-controlled studies applying naloxone intravenously (21,46,60). Bergasa and Jones (21), for example, gave 0.2 Ag/kg/min of naloxone for 24 hr, for 2 days in 29 patients. Interestingly, naloxone had no inuence on nocturnal scratching as measured by movement meter estimations, suggesting that nocturnal scratching depends on a spinal reex (46). In a case report, two opioid receptor antagonists, namely, naloxone (0.2 Ag/kg/min for 2 days, i.v.) substituted thereafter by nalmefene

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(up to 80 mg daily, orally), were applied successfully in one patient with cholestatic pruritus (64). The eectiveness of nalmefene was conrmed in a following report. Nine patients with primary biliary cirrhosis experienced an improvement of pruritus receiving nalmefene 2040 mg thrice daily orally for 6 months (58). An open-label long-term trial of oral nalmefene (30120 mg twice daily, up to 24 months, orally) showed amelioration of pruritus in 13 of 14 patients (22). The antipruritic eect was further evaluated in a placebocontrolled study applying nalmefene (up to 40 mg daily, for 2 months, orally) in 11 patients (61). Nalmefene was reported to be better tolerated than naltrexone in cholestatic patients (61) due to a higher potential hepatotoxic eect of naltrexone (33). A pilot study was performed in 1996 using naltrexone 50 mg/day (for 1 week, orally) in ve patients with cholestatic pruritus (30). All reported signicant improvement of pruritus. One double-blind, placebo-controlled study with eight patients receiving naltrexone 50 mg/day (for 4 weeks, orally) and eight patients receiving placebo revealed signicant improvement of pruritus upon naltrexone therapy (63). Other case reports conrmed signicant relief of cholestatic pruritus with naltrexone in a dosage of 25, 50, and 150 mg/day, for 12, 9, and 3 months, respectively (2,19,23). Overall, only few patients reported on tolerance, which could be managed with increasing the dose (22,30,62). The main side eects of the oral opioid receptor antagonists in the treatment of cholestatic pruritus were nausea, vomiting, lightheadedness, and dizziness (20,21,30,6163); these symptoms were transient and not severe. E. Pruritus in Renal Disease

Renal itch is dened as a localized or generalized pruritus in patients with chronic renal failure. Elevation of endogenous opioids has been postulated as a contributory factor (6567). Based on these ndings, several studies applying opioid receptor antagonists were employed. Andersen et al. (68) reported on successful treatment of renal pruritus with intravenous naloxone (single infusion of 0.8 mg). Five minutes after the infusion, pruritus was totally relieved, lasting for 2 hr. A randomized double-blind, placebocontrolled, crossover trial with naltrexone in 15 hemodialysis patients with severe therapy-resistant pruritus demonstrated signicant reduction of pruritus (26). Naltrexone 50 mg daily was given orally for 1 week and was associated with few side eects. This result was conrmed in two patients (50 mg/day, orally, for 3 weeks) in an uncontrolled study (19) as well as in ve patients (50 mg/day, orally, for 1 week) in a double-blind, placebo-controlled, crossover study receiving naltrexone (69). In another double-blind, placebocontrolled study in 23 patients, no signicant dierence between placebo and naltrexone was observed. Of all the patients, 29% reported on the improve-

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ment of pruritus under oral naltrexone 50 mg/day (for 4 weeks), while 17% of the patients improved under placebo (25). This discrepancy of eectiveness was discussed to be related to intensity of pruritus, suggesting that only very severe forms of renal pruritus may respond to opioid receptor antagonists (25).

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52. Smitz S, Legros JJ, LeMaire M. Naloxone, itch, asthma, urticaria and angioedema. Ann Intern Med 1982; 97:788. 53. Banerji D, Fox R, Seleznick M, et al. Controlled antipruritic trial of nalmefene in chronic urticaria and atopic dermatitis [abstr]. J Allergy Clin Immunol 1988; 81:252. 54. Harrison PV. Nalmefene and pruritus. J. Am Acad Dermatol 1990; 23:530. 55. Sta nder S, Steinho M. Pathophysiology of pruritus in atopic dermatitisan overview. Exp Dermatol 2002; 11:12. 56. Jones EA, Bergasa NV. The pruritus of cholestasis: from bile acids to opiate agonists. Hepatology 1990; 11:884. 57. Thornton JR, Losowsky MS. Plasma methionine enkephalin concentration and prognosis in primary biliary cirrhosis. Br Med J 1988; 297:1241. 58. Thornton JR, Losowsky MS. Opioid peptides and primary biliary cirrhosis. Br Med J 1988; 297:1501. 59. Bergasa NV, Rothman RB, Vergalla J, et al. Central mu-opioid receptors are down-regulated in a rat model of cholestasis. J Hepatol 1992; 15:220. 60. Bergasa NV, Talbot TL, Alling DW, et al. A controlled trial of naloxone infusions for the pruritus of chronic cholestasis. Gastroenterology 1992; 102:544. 61. Bergasa NV, Alling DW, Talbot TL, et al. Oral nalmefene therapy reduces scratching activity due to the pruritus of cholestasis: a controlled study. J Am Acad Dermatol 1999; 41:431. 62. Terra SG, Tsunoda SM. Opioid antagonists in the treatment of pruritus from cholestatic liver disease. Ann Pharmacother 1998; 32:1228. 63. Wolfhagen FH, Sternieri E, Hop WC, et al. Oral naltrexone treatment for cholestatic pruritus: a double-blind, placebo-controlled study. Gastroenterology 1997; 113:1264. 64. Jones EA, Bergasa NV. The pruritus of cholestasis and the opioid system. JAMA 1992; 268:3359. 65. Aronin N, Krieger DT. Plasma immuno-reactive (h-endorphin is elevated in uremia. Clin Endocrinol 1983; 18:459. 66. Murphy M, Carmichael AJ. Renal itch. Clin Exp Dermatol 2000; 25:103. 67. Trelewicz P, Grzeszczak W, Drabczyk R. Serum beta-endorphin in nondialysed and haemodialysed patients with chronic renal failure. Int Urol Nephrol 1994; 26:117. 68. Andersen LW, Friedberg M, Lokkegaard N. Naloxone in the treatment of uremic pruritus: a case history. Clin Nephrol 1984; 21:355. 69. Ghura HS, Patterson AD, Carmichael AJ. Naltrexone in the treatment of renal itch. Br J Dermatol 1998; 139(suppl 51):64.

27
Prospects for a Novel n-Opioid Receptor Agonist, TRK-820, in Uremic Pruritus
Hiroo Kumagai and Takao Saruta
Keio University School of Medicine, Tokyo, Japan

Shigeaki Matsukawa
Inagi Municipal Hospital, Tokyo, Japan

Jun Utsumi
Toray Industries, Inc., Tokyo, Japan

I.

INTRODUCTION

Uremic pruritus is a common and frustrating symptom experienced by hemodialysis patients that provokes vigorous scratching, extensive excoriation, and sleep disturbance (1,2). A large-scale study of 2500 hemodialysis patients revealed that uremic pruritus is systemically induced with the total incidence reaching 73% (3). Forty percent of these patients had a moderate to severe itching, while 13% of the patients suered from sleep disturbance. The pathogenesis of uremic pruritus remains unclear. Several studies showed that morphine and A-opioid agonists induced itching or pruritus (4,5), and that naltrexone (A-opioid antagonist) was effective for severe uremic pruritus in hemodialysis patients (6). However, a randomized double-blind clinical study failed to conrm the ecacy of
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naltrexone for uremic pruritus (7). Recently, we have found that a nopioid agonist suppresses scratching in the mouse pruritus model (8). These reports suggest that A- and n-opioid systems are involved in the itching mechanism. We now describe our studies on the relationship between endogenous opioid peptides and itching, and evaluate n-opioid agonist TRK-820 as a novel antipruritic drug for the treatment of uremic pruritus.

II. A.

MATERIALS AND METHODS Subjects

Forty healthy volunteers (26 males and 14 females, mean age 55.4 F 13.3 yr) and 37 hemodialysis patients (20 males and 17 females, mean age: 60.7 F 13.1 years) were screened for this study. Hemodialysis patients were divided into three groups comprised of those with no itching, moderate itching, or severe itching because of uremic pruritus. Six patients (4 males and 2 females, mean age: 56.2 F 6.2 yr) complaining of severe uremic pruritus were enrolled for the preliminary open-labeled clinical pharmacological study of TRK-820. Itching intensity was determined by each individual patient. B. Determination of Serum Factors and Opioid Peptides

Blood samples were collected from each subject and separated into serum and cell precipitate. Sera were subjected to the determination of serum factors and endogenous opioid peptides. Serum factors measured included histamine, serotonin, intact parathyroid hormone (PTH), and eosinophil cationic protein (ECP), which have been previously suggested to be involved in the pathogenesis of itching. Endogenous opioid peptides h-endorphin and dynorphin A were also measured. All serum factors and opioid peptides were tested at BML Inc. (Tokyo, Japan), a professional clinical laboratory. C. Drug

A novel n-opioid agonist TRK-820 (()-17-(cyclopropylmethyl)-3,14 h-dihydroxy-4,5 a-epoxy-6-[N-methyl-trans-3-(3-furyl) acrylamidol morphinan hydrochloride, Toray Industries, Inc., Tokyo, Japan) (see also Chapter 11) was given orally to all six patients at a single dose of 10 Ag in the form of a soft capsule. The patients were prohibited from eating for 3 hr after administration.

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D.

Clinical Evaluation of the Drug

Pharmacokinetics, safety, and antipruritic ecacy of TRK-820 were evaluated as follows: For pharmacokinetics, blood samples were collected and the plasma concentration of TRK-820 was determined. Pharmacokinetic parameters, Tmax (the time it took to reach Cmax of plasma) and t1/2 (half-life), were calculated. For assessing safety and toxicity, the physical ndings, vital signs, and laboratory parameters (hematology, blood biochemistry, endocrine test, and urinalysis) were determined for 48 hr after administration of the drug. For evaluation of antipruritic ecacy, the visual analog scale (VAS) and itching intensity, categorized according to ve grades (none, slight, mild, moderate, and severe) were used. VAS is a linear scale of 100 mm that ranged from 0, or No itching, to 100, or Intolerable itching. VAS score was assessed by the patient. The physician assessed patient itching and categorized the intensity according to ve grades of intensity.

III. A.

RESULTS Serum Factors and Opioid Peptides

Figure 1 shows that serum levels of known mediators involved in itching, such as histamine, serotonin, intact PTH, and ECP, did not dier between healthy volunteers and hemodialysis patients. However, the serum level of intact PTH was higher in patients than in 40 healthy volunteers, although there was no signicant correlation between intact PTH and itching intensity. As shown in Figure 1, none of the measured serum factors correlated with the itching intensity in hemodialysis patients. Serum levels of h-endorphin and dynorphin A in healthy volunteers and hemodialysis patients are illustrated in Figure 2. There was an apparent increase of h-endorphin level proportionate to the increase in itching intensity in hemodialysis patients (Fig. 2a). We assumed that the balance of the A- and n-opioid systems may be a key factor controlling itching sensation. The ratio of concentrations of h-endorphin to dynorphin A in individuals was calculated. An arbitrary index between h-endorphin and dynorphin A, the [hendorphin/dynorphin A] ratio (E/D ratio), is shown in Fig. 2b. The E/D ratios were 2.17 F 0.38, 2.48 F 1.08, 2.83 F 1.74, and 3.59 F 1.36 for healthy volunteers, patients with no itching, moderately itchy patients, and severely itchy patients, respectively. These results imply that serum levels of opioid peptides dier among individuals, and the balance of endogenous A- and nopioid systems is relevant to understanding the itch status.

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Figure 1 Serum factors, histamine, serotonin, intact PTH, and ECP. The number in parentheses represents the number of patients. Bar denoted as the mean F SD.

Figure 2 Serum concentration of endogenous opioid peptides in each group of healthy volunteers and hemodialysis patients with pruritus; (a) concentration of hendorphin and dynorphin A in the sera; (b) balance of endogenous A- and n-opioid peptides. [h-endorphin/dynorphin A] ratio calculated from the data of serum concentrations. Bar denoted as the mean F SD.

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B.

Clinical Evaluation of a Novel K-Opioid Agonist TRK-820

The pharmacokinetics of TRK-820 were analyzed in only ve patients. As shown in Figure 3, Tmax was 4.00 F 4.47 hr, Cmax was 14.3 F 1.3 pg/mL, and t1/2 was 16.8 F 10.2 hr, suggesting a long-acting drug. Concerning assessment of safety, the adverse drug reactions of somnolence (one case) and asthenia (one case) were mild, and both cases recovered without any additional treatment. Mild laboratory abnormalities were observed in two patientsa plasma testosterone decrease and a leukocytosis, respectively. No serious clinical adverse drug reactions were observed. Thus, all adverse drug reactions observed in this study were mild in intensity and transient. A remarkable antipruritic eect of TRK-820 was observed. Mean VAS score before administration was 54.2 F 3.8 mm, and the scores decreased in all patients after administration of TRK-820, as shown in Figure 4. The mean VAS scores 4 and 12 hr after administration were 12.2 F 2.4 and 1.8 F 0.6 mm, respectively, and this score showed an increase, with the exclusion of one patient, 24 hr after administration. The categorical assessment of itching intensity also signicantly changed as shown in Figure 5. The initial itching intensity was considered as moderate itching in 3 patients, mild itching in 2 patients, and slight itching in 1 patient. The severity ameliorated to mild itching or less in all

Figure 3 Pharmacokinetics prole of TRK-820 after oral administration in hemodialysis patients (n = 5).

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Figure 4 VAS score proles after oral administration of TRK-820 in uremic pruritus patients (n = 6).

Figure 5 Itching intensity proles after oral administration of TRK-820 in uremic pruritus patients (n = 6).

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patients from 2 hr after administration. Twelve hours after administration, 3 patients described themselves as slightly itching and another 3 patients as not itching. These results suggest that oral administration of TRK-820 in hemodialysis patients is a promising treatment for uremic pruritus. IV. DISCUSSION

The underlying mechanism of uremic pruritus is still not clear. Opioids have been proposed as a possible pathogenic factor for pruritus, but to date only A-opioid agonists are known to be pruritogenic. It is well known to clinicians that A-opioids induce itching in postoperative pain management and A opioid agonists induce itching through central A-opioid receptors in mice (9). In earlier studies, h-endorphin, an endogenous A-opioid peptide, was elevated in severe atopic dermatitis patients (10,11), but no relationship to uremic pruritus could be found (12). Concerning met-enkephalin, another Aopioid peptide, conicting ndings have been reported (13,14). We initially focused on the endogenous n-opioid peptide dynorphin and found that the balance of A- and n-opioid peptides could potentially be related to the pathogenesis of uremic pruritus. Thus, our data suggests that the major contributors to uremic pruritus are not the serum factors previously suggested, such as histamine and serotonin, but rather the A- and n-opioid ratio. Our ndings also support the idea that the A-opioid system is itch-inducible, while the n-opioid system is itch-suppressive (Fig. 6). In support of this hypothesis, a recently published review article showed that activation of the n-receptor antagonized various A-receptor-mediated actions (15). This implies that the n-opioid system may perform actions opposing A-opioid system. We have demonstrated a remarkable antipruritic ecacy of a novel n-opioid agonist TRK-820 for uremic patients in a small uncontrolled study.

Figure 6 Our hypothesis of pruritus/itching control by the opioid system. This hypothesis implies that the A-opioid system induces itching while the n-opioid system suppresses itching.

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Although the present clinical pharmacological study was open-labeled and small in scale, rendering it necessary to further investigate and conrm the ecacy of TRK-820, the results suggest that oral administration of TRK820 in hemodialysis patients may be of value in the treatment of uremic pruritus.

REFERENCES
1. 2. 3. Szepietowski JC, Schwartz RA. Uremic pruritus. Int J Dermatol 1998; 37:247 253. Schwartz IF, Iaina A. Uraemic pruritus. Nephrol Dial Transplant 1999; 14:34 839. Omori K, Aioke I, Aoyanagi H, et al. Risk factors for uremic pruritus in long term hemodialysis patients. J Jpn Soc Dial Ther 2001; 34:14691477 (in Japanese). Duy BL. Itching as a side-eect of epidural morphine. Anesthesia 1981; 36:67. Ballantyne JC, Loach AB, Carr DB. Itching after epidural and spinal opiates. Pain 1988; 33:149160. Peer G, Kivity S, Aqami O, Fireman E, Silverberg D, Blum M, Iaina A. Randomised crossover trial of naltrexone in uraemic pruritus. Lancet 1996; 348: 15521554. Pauli-Magnus C, Mikus G, Alscher DM, et al. Naltrexone does not relieve uremic pruritus: results of a randomized, double-blind, placebo-controlled crossover study. J Am Soc Nephrol 2000; 11:514519. Togashi Y, Umeuchi H, Okano K, et al. Antipruritic activity of the kappaopioid receptor agonist, TRK-820. Eur J Pharmacol 2002; 435:259264. Kuraishi Y, Yamaguchi T, Miyamoto T. Itchscratch responses induced by opioids through central mu opioid receptors in mice. J Biomed Sci 2000; 7:248 252. Glinski W, Brodecka H, Glinska-Ferenz M, Kowalski D. Increased concentration of beta endorphin in the sera of patients with severe atopic dermatitis. Acta Derm Venereol 1995; 75:911. Georgala S, Schulpis KH, Papaconstantinou ED, Stratigos J. Raised betaendorphin serum levels in children with atopic dermatitis and pruritus. J Dermatol Sci 1994; 8:125128. Mettang T, Fischer FP, Dollenbacher U, Kuhlman U. Uraemic pruritus is not related to beta-endorphin serum levels in haemodialysis patients. Nephrol Dial Transplant 1998; 13:231232. Danno K, Nishiura K, Tanaka M. Increased met-enkephalin plasma levels in hemodialysis patients with or without pruritus. J Dermatol Sci 1995; 10:238240. Odou P, Azar R, Luyckx M, Brunet C, Dine T. A hypothesis for endogenous opioid peptides in uraemic pruritus: role of enkephalin. Nephrol Dial Transplant 2001; 16:19531954. Pan ZZ. mu-Opposing actions of the kappa-opioid receptor. Trends Pharmacol Sci 1998; 19:9499.

4. 5. 6.

7.

8. 9.

10.

11.

12.

13. 14.

15.

28
Treatment of Pruritic Skin Diseases with Topical Capsaicin
nder and Dieter Metze Sonja Sta
nster, Mu nster, Germany University of Mu

Abbreviations CGRP DRG NKA PGP 9.5 SIC SP VIP VR1 VRL-1 VRL-2 VR.5Vsv calcitonin gene-related peptide dorsal root ganglion neurokinin A protein gene product 9.5 mechanosensitive stretch-inhibitable cation channel substance P vasoactive intestinal polypeptide vanilloid (capsaicin) receptor 1 vanilloid receptor-like protein 1 vanilloid receptor-like protein 2 vanilloid receptor 5V splice variant

I.

CAPSAICIN AND THE VANILLOID RECEPTOR

Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide)(Fig. 1) is a naturally occurring lipophile alkaloid derived from plants of the nightshade family and is the major pungent of hot chili peppers (1). Capsaicin is an exogenous, but not an endogenous expressed, ligand at a capsaicin-specic receptor, i.e.,
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Figure 1

Structural formula of capsaicin. (From Ref. 1.)

the vanilloid receptor 1 (VR1) (2,3). Vanilloid receptor 1 is also activated by the endogenous cannabinoid anandamide (46), increase in temperature (above 42jC), and protons (pH below 5.9) (28). Recently, other members of the vanilloid receptor family were identied (914). These include vanilloid receptor-like protein 1 (VRL-1), vanilloid receptor-like protein 2 (VRL-2), vanilloid receptor 5V splice variant (VR.5Vsv), and a mechanosensitive stretchinhibitable cation channel (SIC) with dierent distributions in the tissues together with corresponding ligands and biological functions. However, capsaicin has been, up to now, known only to exert its functions via the VR1. In animal studies, VR1 could be demonstrated in small myelinated Aytype and C-type sensory nerve bers of the spinal cord and dorsal root ganglion (DRG) (3,15) as well as in central nervous system, sciatic nerve, and small nerve bers in the skin and cornea of rat (2,8,12,1618). Interestingly, VRL-2 was found in animal cutaneous sympathetic and parasympathetic nerve bers, kidney, trachea, and salivary gland (9). In humans, VR1 is expressed in the dorsal horn of the human spinal cord (12), dorsal root ganglia (19), and central nervous system (17). In human skin, VR1 could recently be shown on cultured (20) and in vivo epidermal keratinocytes (21). Receptor binding of capsaicin opens nonselective cation channels with high permeability to calcium (13). Receptor activation on nerve bers and subsequent calcium currents into the axon result in depolarization of the nerve bers and release of secretory granules containing neuropeptides such as substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP), and neurokinin A (NKA) (1,10,12,14,22,23). In animal studies it could be demonstrated that systemic application of capsaicin at high concentrations is associated with neurotoxic eects. Moreover, systemic application of capsaicin in neonatal mice induces permanent degeneration of primary sensory neurons (11,22,2426). Likewise, in sensory neurons of cultured rat dorsal root ganglion, capsaicin irreversibly damages C-type nerves via activation of intracytoplasmic calcium-sensitive proteases (11,2729). In morphological studies in man, it was demonstrated that epidermal protein

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gene product (PGP) 9.5-positive nerve ber density is decreased upon intradermal injection and topical application of capsaicin but nearly normalized within 46 weeks after capsaicin therapy (30,31), while dermal nerve bers remain unaected (32,33). However, repeated topical application of capsaicin in low concentrations (0.0250.3%) does not lead to any degeneration or inammation of epidermal and dermal nerve bers (33). Furthermore, capsaicin inuences other skin cells upon external application. Human cultured keratinocytes and broblasts showed a reduced cell growth under capsaicin concentrations of 0.0250.2% (34). Repeated application of capsaicin results in suppression of pain and itch sensations which are mediated by unmyelinated C-bers, while tactile sensations remain unaected (28,29,35,36). After 35 days of continuous treatment, capsaicin-sensitive nerve bers are desensitized and reaccumulation of neuropeptides is inhibited (37). Furthermore, the axoplasmic transport of neuropeptides to the periphery is suppressed (28,38). In morphological studies the specic eect of capsaicin could be conrmed in skin biopsies obtained before and during capsaicin treatment by means of confocal laser scanning microscopy (32,33) and immunouorescence microscopy (39). Therefore, capsaicin treatment could be shown to be associated with a complete attenuation of SP expression in dermal papillary nerve bers. The antipruritic potency of capsaicin has been conrmed in experimental studies suppressing histamineinduced itch (40). Interestingly, capsaicin was not able to reduce serotonininduced pruritus (41).

II. A.

TOPICAL APPLICATION OF CAPSAICIN FOR THERAPEUTIC PURPOSES Capsaicin Preparations and Concentrations

For the topical application, a liquid capsaicin extract consisting of dierent capsaicinoids with 8090% capsaicin and dihydrocapsaicin has proved to be ecacious and safe (32,33). However, the extraction of pure capsaicin, a white powder, from chili plants is very dicult and expensive, and only a few capsaicin ointments are commercially available; these include DolenonR (0.05% capsaicinoids) and ZostrixR (0.025% and 0.075% capsaicin). However, the oily 1% capsaicin extract (Extractum Capsici aetherea 1%; Caesar and Loretz GmbH, Hilden, Germany) could be added easily to various emollients or ointments and selectively applied to the skin lesions (32,33,42). As the capsaicin extract is dark red, the capsaicin ointments of 0.0250.5% concentration are orange-red, occasionally staining the clothing. Capsaicin should be utilized regularly four to six times daily to prevent reaccumulation of neuropeptides and, thus, recurrence of itch and pain. In order to enhance the

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penetration rate through the markedly hyperkeratotic lesions of, e.g., prurigo nodularis, capsaicin can be administrated twice daily under occlusion bandages for the initial three days. Before starting capsaicin therapy, erosive lesions should be pretreated with a topical antiseptic or corticosteroidal ointment to avoid burning sensations on erosive skin (33). Because of poor compliance due to the initial side eects of neurogenic inammation, the necessity of frequent daily application and occasional staining of the orange ointment on clothes, and in order to improve the evaluation of the therapeutic eect, it is recommended to hospitalize the patients for a short time. Generally, the practicability of capsaicin therapy is largely limited by the high application frequency as long as capsaicin analogues with prolonged tissue persistence are not available. When starting, capsaicin cream should be used in low concentrations of 0.025% (e.g., Extractum capsici 1% 2.5 g in ointment ad 100.0 g) or 0.05%. After the cessation of the primary symptoms of neurogenic inammation, capsaicin concentration can be individually raised in steps of 0.025% every 35 days until a total relief of pruritus is achieved. The concentration applied regularly should not exceed 0.1%; in rare cases, capsaicin concentration can be raised carefully to 0.3% or 0.5% (32,33,42). After the discontinuation of the capsaicin therapy, pruritus and pain recur immediately within 18 days due to restoration of neuropeptide deposits in sensory nerve bers.

B.

Side Effects

The side eects of the capsaicin treatment can be attributed to the primary release of neuropeptides and as such are limited. The transient symptoms are those of neurogenic inammation, i.e., stinging, pricking, and burning sensations, erythema, as well as increase of pain or itch caused by the action of the neuropeptides on mast cells and blood vessels (33,4244). The symptoms of neurogenic inammation start within 2030 min after application and last for no longer than 3060 min (33,45). Interestingly, pretreatment with a topical anesthetic (EMLAR) signicantly reduced the burning sensations from capsaicin (46). Topical application of capsaicin has never been reported to lead to systemic eects. The latter fact is of crucial importance because upon systemic administration and in cultured sensory neurons, capsaicin potentially damages C-type nerves in an irreversible fashion due to activation of intracytoplasmic calcium-sensitive proteases (see above). However, ultra-structural investigations showed that cutaneous nerve bers appeared to be regular and revealed no degenerative changes during or after capsaicin treatment (33). Despite long-term therapy and application of high concentrations of capsaicin, loss of skin sensibility has never been reported. Furthermore, contact

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dermatitis did not occur upon treatment with capsaicin; interestingly, anecdotal cases of the Hunan hand syndrome, a contact dermatitis resulting from direct handling of chili peppers containing capsaicin for preparation of Chinese or Mexican meals, have been reported (4749). Capsaicin therapy can be combined with other topical and systemic therapies without any additional side eects. However, warm temperatures as developed during UV irradiation (UVA, UVB, PUVA) will result in increased neurogenic inammation. This is due to a lowered temperature threshold for the VR1 activation caused directly by capsaicin pretreatment (3). Likewise, in warm summer months, many patients complain of enhanced burning of the skin due to the same mechanism. Accordingly, during the summer, capsaicin therapy should be restricted to lower concentrations (33). C. Tolerance

Tolerance, i.e., decreased ecacy of capsaicin therapy despite regular application, may result either from rapid raising of capsaicin concentrations or from an irregular application regimen (50,51). Animal studies have conrmed a dose-dependent loss of vanilloid receptors as induced by the capsaicin analogue RTX (12). Accordingly, in our experience, only a few patients complained of recurrence of itch under capsaicin therapy following the appropriate therapeutical protocol (33,42). Interestingly, the ecacy of capsaicin could be reestablished after a relatively short interruption of the therapy.

III.

THERAPEUTIC EFFICACY OF CAPSAICIN IN THE TREATMENT OF PRURITIC SKIN DISEASES

Capsaicin was rst isolated by Thresh (52) and used for pain research. However, topical capsaicin therapy was not introduced as a treatment until the latter end of the 20th century. Among the rst authors reporting on topical capsaicin treatment were Bernstein et al. in 1986 and 1987 (43,53) and Cappugi et al. in 1989 (54). Up to now, topical administration of capsaicin has been reported to be eective in many inammatory and noninammatory pruritic and painful skin diseases. The majority of the papers report on open-label use of capsaicin because blinding of the studies, and control treatment seemed to be hampered by the regular appearance of the initial capsaicin-associated side eects of neurogenic inammation. In general, capsaicin treatment represents mainly a symptomatic antipruritic and analgesic therapy, and, accordingly, after discontinuation of capsaicin an immediate exacerbation of symptoms can be expected. In the following, an overview of the ecacy of capsaicin therapy in generalized pruritus and in pruritus of inammatory skin diseases is given.

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A. 1.

Pruritus of Noninflammatory Skin Diseases Hemodialysis-Related Pruritus

In 1992, Breneman et al. reported on eective capsaicin therapy of hemodialysis-related pruritus (44) (Table 1). Patients were treated open-labeled uncontrolled (n = 21) and double-blind, vehicle-controlled (n = 7), respectively, with 0.025% capsaicin ointment (ZostrixR, four times daily, 6 weeks). Ten of the 21 patients and 3 of the 7 treated patients, respectively, reported of marked decrease to complete relief of pruritus. 2. Pruritus Associated with Lymphoproliferative Disease

Pruritus due to lymphoproliferative disease such as Hodgkins disease responds to topical capsaicin therapy (0.05%, ve times daily, 2 months) with a clear relief of the otherwise intractable itch (42). Cutaneous T-cell lymphoma is frequently associated with pruritus and was found to respond to capsaicin therapy with a complete relief of itch (0.3%, ve times daily, 4 weeks) (42). 3. Hydroxyethyl Starch-Induced Pruritus

Hydroxyethyl starch (HES)-induced pruritus due to storage of the colloid plasma expander HES in cutaneous nerve bers was reported to respond to topical administration of capsaicin. Although capsaicin was applied twice daily only, one patient experienced improvement of pruritus after 3 days of 0.05% capsaicin (55). Interestingly, after the discontinuation of the capsaicin therapy, pruritus recurred after the third week. Another three patients showed total relief of pruritus with low concentrations of capsaicin (0.025 0.5%, four to six times daily) treated for 5 weeks up to 6 months. After the cessation of the treatment, pruritus recurred immediately (42). 4. Brachioradial Pruritus

Brachioradial pruritus (solar pruritus), a rare pruritic dermatosis with distinct localization at the elbows and forearms supercial to the proximal region of the brachioradialis muscle, was reported to be diminished after 0.025% and 0.075% capsaicin therapy (ZostrixR, Zostrix HPR, four to ve times daily, 26 weeks) in two patients (56). In both patients, pruritus was relieved completely after 2 weeks of treatment. In a larger group of 15 patients with brachioradial pruritus treated with capsaicin (0.025%, four times daily, 3 weeks) (57), 10 of the patients found signicant relief of pruritus within the rst days of therapy. As expected, after the discontinuation of the therapy pruritus recurred within 112 weeks.

Table 1
Author (Ref.)

Treatment of Noninammatory Pruritic Skin Diseases with Topical Capsaicin


Year

Diagnosis

Patients (n=) 4

Capsaicin therapy

Response of pruritus

1989 Pruritus of unknown origin Wallengren (77) 1991 Notalgia paresthetica

Cappugi (54)

10

0.025%, No inuence three times per day, 10 days 0.025%, 8/10 Patients: three to ve complete relief times per day, 3 week9 months 0.025%, four times per day, 6 weeks 7/21 Patients: improvement 3/7: Partial to complete relief 2/2 Patients: complete relief

Brenemana (44) 1992 Hemodialysisrelated pruritus

21

7a Goodless (56) 1993 Brachioradial pruritus 2 0.025%, 0.075%, four to ve times per day, 26 weeks 0.025%, 4 times per day, 3 weeks 0.0251.0%, three times per day, 4 weeks 0.0250.1%, three times per day, 4 weeks 0.05%, two times per day, 6 weeks 0.025%, three to ve times per day, 4 weeks 0.025%, four times per day, 6 days 0.0250.5%, 5 weeks6 months 0.250.5%, 2 months 0.05%, 2 months 0.3%, 4 weeks

Knight (57)

1994 Brachioradial pruritus 1994 Aquagenic pruritus 1994 Aquagenic pruritus

15

Lotti (39)

10/15 Patients: partial to total relief 5/5 Patients: complete relief 7/7 Patients: complete relief Improvement

Hautmann (58)

Szeimies (55)

1994 Hydroxyethyl starch-induced pruritus Wallengren (74) 1995 Notalgia paresthetica Kirby (73) 1997 PUVA-induced itch

10

8/10 Patients: total relief 5/6 Patients: complete relief 3/3 Patients: complete relief Complete relief Complete relief Complete relief

Reimann (42)

2000 Hydroxyethyl starch-induced pruritus Notalgia paresthetica Pruritus in Hodgkins lymphoma Pruritus in T-cell lymphoma Aquagenic pruritus

2 1 1 1

0.025%, Complete relief 3 weeks all four to six times per day

Double-blind, vehicle-controlled study.

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5.

Aquagenic Pruritus

Aquagenic pruritus characterized by intense itching after contact with water was rst described to respond to topical capsaicin by Lotti et al. in 1994 (39). Five patients were treated with 0.025%, 0.05%, and 1.0% capsaicin (three times daily, 4 weeks). After 3 weeks, three of the ve patients no longer experienced pruritus; after 4 weeks complete relief from pruritus was experienced by all patients, independent of capsaicin concentration. Hautmann et al. reported in 1994 on eective therapy with capsaicin 0.0250.1% (three times daily, 4 weeks) in seven patients with aquagenic pruritus all experiencing complete remission of symptoms during the fourth week (58). After the cessation of the therapy, itch recurred within 1018 days. This clear effect was also conrmed in one patient treated with 0.025% capsaicin (four times daily, 3 weeks). After 3 days, pruritus did not occur during contact with water (42).

B.

Pruritus of Inflammatory Skin Diseases

Inammatory skin diseases were reported to show a signicant improvement of pruritus upon capsaicin treatment (Table 2). Cappugi et al. reported in 1989 in an abstract on signicant antipruritic eect in a range of skin diseases including lichen planus (seven patients), atopic dermatitis (ve patients), aquagenic urticaria (three patients), and contact dermatitis (eight patients) treated with 0.025% capsaicin (three times daily, 10 days), while four patients with pruritus of unknown origin (Table 1) failed to respond to capsaicin (54). In addition, nummular (two patients) and asteatotic eczema (one patient) were described to respond to capsaicin therapy of higher concentration, 0.05 0.1% (four to six times daily, for 4 weeks to 9 months) (42). 1. Psoriasis Vulgaris

Recently, an experimental study showed that capsaicin treatment leads to a signicant decrease of blood perfusion in lesional psoriatic skin (59). This suggests that, in addition to a symptomatic antipruritic eect, capsaicin may have a direct inuence on the pathophysiology of psoriasis. Accordingly, psoriasis vulgaris treated with 0.025% capsaicin (ZostrixR, four to six times daily, 6 weeks) in 44 patients was reported to result in marked reduction of scaling and erythema (43). Another group showed signicant reduced pruritus in 15 patients with psoriasis vulgaris treated with 0.025% capsaicin (three times daily, 10 days) (54). Both results were conrmed in a large double-blind study of 197 patients (98 patients treated with 0.025% capsaicin, four times daily for 6 weeks, 99 patients with vehicle) (60). A signicant reduction of both pruritus as well as psoriasis severity score was demonstra-

Treatment of Pruritic Skin Diseases Table 2


Author Bernsteina (43)

295

Treatment of Inammatory Pruritic Skin Diseases with Topical Capsaicin


Year 1986 Diagnosis Psoriasis vulgaris Patients (n=) 44 Capsaicin concentration Response of pruritus

Psoriasis vulgaris Eczema

2 3

Cappugi (54)

1989

Tupker (62)

1992

Ellis a (60)

1993

Lichen planus Atopic dermatitis Aquagenic urticaria Contact dermatitis Psoriasis vulgaris Prurigo nodularis Chronic prurigo Neurodermatitis circum. Psoriasis vulgaris

7 5 3 8 15 3 2 2 98

67% Patients: 0.025%, four to six times less scaling and erythema per day, 6 weeks 0.0250.1%, 2/2 Complete relief 4 weeks, 10 months 3/3 Complete relief 0.050.1%, 4 weeks, 9 months all four to six times per day 0.025%, All patients: relief three times of pruritus per day, 10 days 0.025%, ve times per day, 2 weeks to 2 months 0.025%, four times per day, 6 weeks 0.1%, ve times per day, 5 weeks 0.1%, ve times per day, 6 months 0.075%, four times per day, 6 weeks 0.025% or 0.075%, three times per day, 2 weeks 5/7 Patients: relief of pruritus and skin lesions Signicant relief of pruritus (57% of patients) and psoriasis Complete relief

Reimann (32)

1995

Lichen simplex

Prurigo nodularis

Complete relief

Kantor a (63)

1996

Lichen simplex

Munn a (64)

1997

Prurigo nodularis

14

Neess (61)

2000

Pityriasis rubra pilaris

Reimann (42)

2000

Prurigo nodularis Lichen simplex

21 3

0.03%, once daily, 8 weeks 0.0250.3%, 21/21 Relief 2 weeks33 months 0.0250.1%, 3/3 Complete relief 48 weeks (continued on next page)

No signicant dierence to vehicle 36% Patients: complete relief of pruritus and skin lesions Relief

296 Table 2
Author Sta nder (33)

nder and Metze Sta Continued


Year 2001 Diagnosis Prurigo nodularis Patients (n=) 33 Capsaicin concentration 0.0250.3%, four to six times per day, 2 weeks33 months Response of pruritus 24/33 Relief of pruritus, attening of skin lesions; 9/33 complete relief of pruritus and skin lesions

Double-blind, vehicle-controlled study.

ted. Moreover, higher capsaicin concentrations of 0.1% (four to six times daily, 4 weeks, 10 months) revealed a signicant eect on psoriasis vulgaris and psoriasis inversa in two patients (42). 2. Pityriasis Rubra Pilaris

In pityriasis rubra pilaris, a pruritic dermatosis, a signicant relief of pruritus was noted during capsaicin therapy (0.03% capsaicin solution, once daily, 8 weeks). Interestingly, previous medications given such as antihistamines, retinoids, topical steroids, and PUVA, all described to be helpful in pruritus of dierent causation, had no antipruritic eect on this patient (61). 3. Prurigo Nodularis and Lichen Simplex

Prurigo nodularis and lichen simplex are distressing conditions characterized by intensely pruritic, lichenied or excoriated papules and nodules. They are widely assumed to represent a cutaneous reaction pattern to repeated rubbing or scratching caused by pruritus of dierent origins. In 1992, Tupker et al. rst reported on the successful therapy of prurigo nodularis and lichen simplex with capsaicin (62). Three patients with prurigo nodularis, two with chronic prurigo and two with neurodermatitis circumscripta, were treated with 0.025% capsaicin (ve times daily) and reported that the lesions attened (n = 3) or disappeared (n = 2) within 2 weeks to 2 months. A double-blind study with seven patients could not conrm the ecacy of capsaicin (0.075%, four times daily, 6 weeks) on lichen simplex chronicus (63). Although the patients reported an improvement of itching with capsaicin in comparison with vehicle in the rst 2 weeks, after 6 weeks no dierence between capsaicin and placebo was evident. In 1997, Munn et al. performed a double-blind study comparing two concentrations of capsaicin (0.025% ZostrixR and 0.075%

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AxsainR, three times daily, 2 weeks) in prurigo nodularis (64). In 36% of the patients a complete relief of pruritus and attening of the skin lesions was obtained. No dierence could be found between the two capsaicin concentrations used. Other reports conrmed the ecacy of 0.0250.3% capsaicin (four to six times daily, for 2 weeks to 33 months) in prurigo nodularis and lichen simplex (32,42). In a larger uncontrolled study, 33 patients with prurigo nodularis all experienced a complete remission of itching within 12 days upon capsaicin therapy (four to six times daily, for 2 weeks to 33 months) (33). The applied capsaicin concentrations varied between 0.025% and 0.3%; on average, concentrations of 0.05%, 0.075%, and 0.1% were eective. As expected, relief of pruritus was accompanied by a reduced scratching rate which allowed for attening, softening (24 patients), and nally complete regression (9 patients) of the nodular lesions (33) (Figs. 2 and 3). In summary, capsaicin at higher concentrations is an eective antipruritic treatment in prurigo nodularis and lichen simplex. In addition to the symptomatic antipruritic eect, it can be assumed that capsaicin contributes directly to the regression of the nodules. Histological, immunohistochemical, and ultrastructural investigations showed prominent S-100 positive dermal nerve bundles as well as neural hyperplasia with an increased content of SP,

Figure 2 Eective treatment of prurigo nodularis with capsaicin. Pruritic nodules before starting capsaicin treatment (a). Flattening of the nodules after a 9-month 0.01% capsaicin therapy (b).

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Figure 3 Eective treatment of severe pruritus in prurigo simplex with capsaicin. Linear erosions and crusts due to scratching on the back before therapy (a). After 4-month 0.025% capsaicin therapy, a complete regression of skin lesions was achieved (b). After discontinuation of capsaicin, itch did not recur.

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VIP, and CGRP in prurigo nodularis (6569). In view of the fact that sensory neuropeptides have been recognized to stimulate the proliferation of keratinocytes and broblasts (70,71), downregulation of these trophic factors may well reduce epidermal hyperplasia and dermal brosis. Furthermore, since SP is capable of inducing the production of proinammatory cytokines such as IL-1a, IL-1h, and IL-8, and can participate in leukocyte recruitment by upregulation of adhesion molecules (72), long-term application of capsaicin may decrease inammatory inltrate in the pruritic nodules. 4. PUVA-Induced Nociception

Pain and itch related to PUVA therapy occur in up to 20% of patients, and the underlying mechanism is as yet, not fully understood. Substance P, which is released from terminal nerve endings upon UV irradiation, may mediate PUVA-induced nociception (73). Five of six patients complaining of PUVAinduced itch were treated eectively with 0.025% capsaicin (AxsainR, four times daily, 6 days) with total relief of pruritus (73) (Table 1). 5. Notalgia Paresthetica

Notalgia paresthetica, characterized by itch and pain conned to the interscapular area, was rst reported to respond to topical capsaicin by Wallengren (74). Ten patients were treated with 0.025% capsaicin (ZostrixR, three to ve times daily, 3 weeks to 9 months) and improvement of symptoms was evident within 4 weeks in all of them. In a subsequent double-blind study with 20 patients (10 patients receiving 0.025% capsaicin three to ve times daily for 4 weeks, 10 patients the vehicle) (75), these results were conrmed when 8 of 10 the patients receiving capsaicin experienced relief of itch. However, in another report, even higher concentrations such as 0.5% (four to six times daily, 2 months) were not able to achieve a total relief of pain and itch (42) (Table 1). 6. Postherpetic Neuralgia

Capsaicin of high concentration proved to have a signicant antinociceptive eect in postherpetic neuralgia. Although postherpetic neuralgia is mainly associated with pain, it has also been associated with itch (see Chap. 22) (7678). REFERENCES
1. Surh YJ, Lee SS. Capsaicin, a double-edged sword: toxicity, metabolism, and chemopreventive potential. Life Sci 1995; 56:1845.

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nder and Metze Sta Caterina MJ, Schumacher MA, Tominaga M, et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997; 389:816. Caterina MJ, Julius D. The vanilloid receptor: a molecular gateway to the pain pathway. Annu Rev Neurosci 2001; 24:487. Smart D, Gunthorpe MJ, Jerman JC, et al. The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1). Br J Pharmacol 2000; 129:227. nyi J. Are cannabionoids endogenous ligands for the VR1 capsaicin reSzolcsa ceptor? Trends Pharmacol Sci 2000; 21:41. Zygmunt PM, Petersson J, Andersson DA, et al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 1999; 400:452. Sasamura T, Kuraishi Y. Peripheral and central actions of capsaicin and VR1 receptor. Jpn J Pharmacol 1999; 80:275. Tominaga M, Caterina MJ, Malberg AB, et al. The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 1998; 21:531. Delany NS, Hurle M, Facer P, Alnadaf T, Plum P, Kinghom I, et al. Identication and characterization of a novel human vanilloid receptor-like protein, VRL-2. Physiol Genomics 2001;4:165. Griths CD, Eldershaw TPD, Geraghty DP, et al. Capsaicin-induced biphasic oxygen uptake in rat muscle: antagonism by capsazepine and ruthenium red provides further evidence for peripheral vanilloid receptor subtypes (VN1/VN2). Life Sci 1996;58:105. Holzer P. Capsaicin: cellular targets, mechanism of action and selectivity for thin sensory neurons. Pharmacol Rev 1991;43:143. Szallasi A. Autoradiographic visualization and pharmacological characterization of vanilloid (capsaicin) receptors in several species, including man. Acta Physiol Scand Suppl 1995;629:1. Szallasi A. Vanilloid (capsaicin) receptors in health and disease. Am J Clin Pathol 2002;118:110. Walpole CSJ, Bevan S, Bovermann G, et al. The discovery of capsazepine, the rst competitive antagonist of the sensory neuronexcitants capsaicin and resiniferatoxin. J Med Chem 1994;37:1942. Ma QP. Vanilloid receptor homologue, VRL1, is expressed by both A- and Cber sensory neurons. NeuroReport 2001;12:3693. Guo A, Vulchanova L, Wang J, et al. Immunocytochemical localization of the vanilloid receptor 1 (VR1): relationship to neuropeptides, the P2X3 pruinoceptor and IB4 binding sites. Eur J Neurosci 1999;11:946. th Z, Cortright DN, et al. Distribution of mRNA for vanilloid Mezey E, To receptor subtype 1 (VR1), and VR1-like immunoreactivity, in the central nervous system of the rat and human. Proc Natl Acad Sci USA 2000;97:3655. Szallasi A, Nilsson S, Farkas-Szallasi T, Caterina MJ, Hokfelt , Lundbeng JW, et al. Vanilloid (capsaicin) receptors in the rat: distribution in the brain, regional dierences in the spinal cord, axonal transport to the periphery, and depletion by systemic vanilloid treatment. Brain Res 1995;703:175. Cortright DN, Crandall M, Sanchez JF, et al. The tissue distribution and

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functional characterization of human VR1. Biochem Biophys Res Commun 2001;281:1183. Inoue K, Koizumi S, Fuziwara S, et al. Functional vanilloid receptors in cultured normal human epidermal keratinocytes. Biochem Biophys Res Commun 2002;291:124. Denda M, Fuziwara S, Inoue K, et al. Immunoreactivity of VR 1 on epidermal keratinocyte of human skin. Biochem Biophys Res Commun 2001;285:1250. nyi J. Sensory neuron-specic actions of capsaicin: mechaBevan S, Szolcsa nisms and applications. Trends Neurosci 1990;11:330. Docherty RJ, Robertson B, Bevan S. Capsaicin causes prolonged inhibition of voltage-activated calcium currents in adult rat dorsal root ganglion neurons in culture. Neuroscience 1991;40:513. Carobi C. A quantitiative investigation of the eects of neonatal capsaicin treatment on vagal aerent neurons in the rat. Cell Tissue Res 1996; 283:305 311. Chung K, Klein CM, Coggeshall RE. The receptive part of the primary aerent axon is most vulnerable to systemic capsaicin in adult rats. Brain Res 1990; 511:222. Hiura A, Sakamoto Y. Quantitative estimation of the eects of capsaicin on the mouse primary sensory neurons. Neurosci Lett 1987; 76:101. Chard PS, Bleakman D, Savidge JR, et al. Capsaicin-induced neurotoxicity in cultured dorsal root ganglion neurons: involvement of calcium-activated proteases. Neuroscience 1995;65:1099. Fox AJ. Mechanisms and modulation of capsaicin activity on airway aerent nerves. Pulm Pharmacol 1995;8:207. Jancso N, Jancso-Gabor A, Szolcsanyi J. Direct evidence for neurogenic inammation and its prevention by denervation and by pretreatment with capsaicin. Br J Pharmacol 1967;31:138. Nolano M, Simone DA, Wendelschafter-Crabb G, et al. Topical capsaicin in humans: parallel loss of epidermal nerve bers and pain sensations. Pain 1999;81:135. Simone DA, Nolano M, Johnson T, et al. Intradermal injection of capsaicin in humans produces degeneration and subsequent reinnervation of epidermal nerve bers: correlation with sensory function. J Neurosci 1998;18:8947. Reimann S, Metze D. Topische Capsaicin-Therapie bei Lichen simplex und Prurigo nodularis. Z Hautkr 1995;70:586. Sta nder S, Luger T, Metze D. Eective treatment of prurigo nodularis with topical capsaicin. J Am Acad Dermatol 2001;44:471. Ko L, Diaz M, Smith P, et al. Toxic eect of capsaicin on keratinocytes and broblasts. J Burn Care Rehabil 1998;19:409. Buck SH, Burks TF. The neuropharmacology of capsaicin: review of some recent observations. Pharmacol Rev 1986;38:143. Cappugi P, Tsampau D, Lotti T. Substance P provokes cutaneous erythema and edema through a histamine-independent pathway. Int J Dermatol 1992;31:206.

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37. Green BG, Shaer GS. The sensory response to capsaicin during repeated topical exposures: dierential eects on sensations of itching and pungency. Pain 1993;53:323. 38. Fitzgerald M, Woolf CJ. Axon transport and sensory C-bre function. In: Chahl LA, Szolcsanyi J, Lambeck F, eds. Antidromic Vasodilatation and Neurogenic Inammation. Akademiai Kiado: Budapest, 1984:119. 39. Lotti T, Teofoli P, Tsampau D. Treatment of aquagenic pruritus with topical capsaicin cream. J Am Acad Dermatol 1994; 30:232. 40. Weisshaar E, Heyer G, Forster C, et al. Eect of topical capsaicin on the cutaneous reactions and itching to histamine in atopic eczema patients compared to healthy skin. Arch Dermatol Res 1998; 290:306. 41. Weisshaar E, Ziethen B, Gollnick H. Lack of ecacy of topical capsaicin in serotonin-induced itch. Skin Pharmacol Appl Skin Physiol 2000; 13:1. 42. Reimann S, Luger T, Metze D. Topische Anwendung von Capsaicin in der Dermatologie zur Therapie von Juckreiz und Schmerz. Hautarzt 2000;51: 164. 43. Bernstein JE, Parish LC, Rapaport M, Robenbaum , Roenigk MA, et al. Eects of topically applied capsaicin on moderate and severe psoriasis vulgaris. J Am Acad Dermatol 1986;15:504. 44. Breneman DL, Cardone JS, Blumsack RF, Lather RM, Seaule , and Pollock UE, et al. Topical capsaicin for treatment of hemodialysis-related pruritus. J Am Acad Dermatol 1992;26:91. 45. Magnusson BM, Koskinen LOD. In vitro percutaneous penetration of topically applied capsaicin in relation to in vivo sensation responses. Int J Pharm 2000;195:55. 46. Yosipovitch G, Maibach HI, Rowbotham MC. Eect of EMLA pre-treatment on capsaicin-induced burning and hyperalgesia. Acta Derm Venereol (Stockholm) 1999;79:118. 47. Burnett JW. Capsicum pepper dermatitis. Cutis 1989; 43:534. 48. Weinberg RB. Hunan hand. N Engl J Med 1981; 305:1020. 49. Williams SR, Clark RF, Dunford JV. Contact dermatitis associated with capsaicin. Ann Emerg Med 1995; 25:713715. 50. Bernstein JE, Swift RM, Soltani K, et al. Inhibition of axon reex vasodilatation by topical applied capsaicin. J Invest Dermatol 1981; 76:394. 51. Liu L, Simon SA. Capsaicin-induced currents with distinct desensitization and Ca2+ dependence in rat trigeminal ganglion cells. J Neurophysiol 1996; 75:1503. 52. Thresh LT. Isolation of capsaicin. Pharm J 1876; 6:941949. 53. Bernstein JE, Bickers DR, Dahl MV, et al. Treatment of chronic postherpetic neuralgia with topical capsaicin. A preliminary study. J Am Acad Dermatol 1987; 17:93. 54. Cappugi P, Lotti T, Tsampau D, et al. Capsaicin treatment of dierent dermatological aection with itching [abstr]. Skin Pharmacol 1989; 2:230. 55. Szeimies RM, Stolz W, Wlotzke U, et al. Successful treatment of hydroxyethyl starch-induced pruritus with topical capsaicin. Br J Dermatol 1994; 131: 380.

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56. Goodless DR, Eaglstein WH. Brachioradial pruritus: treatment with topical capsaicin. J Am Acad Dermatol 1993; 29:783. 57. Knight TE, Hayashi T. Solar (brachioradial) pruritusresponse to capsaicin cream. Int J Dermatol 1994; 33:206. 58. Hautmann G, Teofoli P, Lotti T. Aquagenic pruritus, PUVA and capsaicin treatments. Br J Dermatol 1994; 131:920. 59. Krogstad AL, Lo nnroth P, Larson G, et al. Capsaicin treatment induces histamine release and perfusion changes in psoriatic skin. Br J Dermatol 1999; 141:87. 60. Ellis CN, Berberian B, Sulica VI, et al. A double-blind evaluation of topical capsaicin in pruritic psoriasis. J Am Acad Dermatol 1993; 29:438. 61. Neess CM, Dissemond J, Herrmann G, et al. Treatment of pruritus by capsaicin in a patient with pityriasis rubra pilaris receiving RE-PUVA therapy. Clin Exp Dermatol 2000; 25:209. 62. Tupker RA, Coenraads PJ, van der Meer JB. Treatment of prurigo nodularis, chronic prurigo and neurodermatitis circumscripta with topical capsaicin. Acta Derm Venereol 1992; 72:463. 63. Kantor GR, Resnik KS. Treatment of lichen simplex with topical capsaicin cream. Acta Derm-Venereol 1996; 76:161. 64. Munn SE, Burrows NP, Abadia-Molina F, et al. The eect of topical capsaicin on substance P immunoreactivity: a clinical trial and immuno-histochemical analysis. Acta Derm Venereol 1997; 77:158. 65. Abadia Molina F, Burrows NP, Russel Jones R, et al. Increased sensory neuropeptides in nodular prurigo: a quantitative immunohistochemical analysis. Br J Dermatol 1992; 127:344. 66. AlAbadie MSK, Senior HJ, Bleehen SS, et al. Neuronal marker and neuropeptide studies in nodular prurigo. Eur J Dermatol 1994; 4:154. 67. Doyle JA, Connolly SM, Hunziker N, et al. Prurigo nodularis: a reappraisal of the clinical and histological features. J Cutan Pathol 1979; 6:392. 68. Harris B, Harris K, Penneys NS. Demonstration by S-100 protein staining of increased numbers of nerves in the papillary dermis of patients with prurigo nodularis. J Am Acad Dermatol 1992; 26:56. 69. Sandbank M. Cutaneous nerve lesions in prurigo nodularis. J Cutan Pathol 1976; 3:125. 70. Nilsson J, von Euler AM, Dasgaard C-J. Stimulation of connective tissue cell growth by substance P and substance K. Nature 1985; 315:61. 71. Tanaka T, Danno K, Ikai K, et al. Eect of substance P and substance K on the growth of cultured keratinocytes. J Invest Dermatol 1988; 90:399. 72. Scholzen T, Armstrong CA, Bunnett NW, et al. Neuropeptides in the skin: interactions between the neuroendocrine and the skin immune system. Exp Dermatol 1998; 7:81. 73. Kirby B, Rogers S. Treatment of PUVA itch with capsaicin. Br J Dermatol 1997; 137:152. 74. Wallengren J. Treatment of notalgia paresthetica with topical capsaicin. J Am Acad Dermatol 1991; 24:286.

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75. Wallengren J, Klinker M. Successful treatment of notalgia paresthetica with topical capsaicin: vehicle-controlled, double-blind, crossover study. J Am Acad Dermatol 1995; 32:287. 76. Watson CP, Tyler KL, Bickers DR, et al. A randomized vehicle-controlled trial of topical capsaicin in the treatment of postherpetic neuralgia. Clin Ther 1993; 15:510. 77. Bernstein JE, Korman NJ, Bickers DR, Dahl MU, Millikan E, et al. Topical capsaicin treatment of chronic postherpetic neuralgia. J Am Acad Dermatol 1989; 21:265. 78. Hautkappe M, Roizen MF, Toledano A, et al. Review of the eectiveness of capsaicin for painful cutaneous disorders and neural disfunction. Clin J Pain 1998; 14:97.

29
Mechanistic and Clinical Assessment of Zangradoo, an Extract of the Amazonian Ethnomedicine Sangre de Grado, for the Treatment of Itch
R

Mark J. S. Miller and Brian K. Reuter


Albany Medical College, Albany, New York, U.S.A.

John L. Wallace and Keith A. Sharkey


University of Calgary, Calgary, Alberta, Canada

Paul Bobrowski
Rainforest Pharmaceuticals, LLC, Scottsdale, Arizona, U.S.A.

I.

INTRODUCTION

Itch and pain are responses to breakdowns in the barrier function of the skin, with the peripheral nervous system signaling for awareness of these breaches. Mediated by the sensory aerent nerves, they are accompanied by a local tissue response called neurogenic inammation. Treatment remains problematical, particularly for itch, where attention has been focused on reducing the activation of these nerves by individual mediators (e.g., histamine), which may be released following the initiating insult. However, this approach does not address the wide variety of insults or diseases that
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may evoke an itch response. Hence, there is substantial need for new therapeutic approaches that have a broad therapeutic potential. Given that the activation of sensory aerent nerves is the nal pathway in eliciting an itch, any agent that suppresses sensory aerent nerve activation would fulll the criteria of this search. In zangrado k , a botanical extract derived from an Amazonian ethnomedicine, we believe that there is the potential for such a therapeutic innovation. Zangrado is an extract of sangre de grado or sangre de drago, a latex obtained from various Croton species from the jungles of the upper Amazon, primarily Peru and Ecuador. Zangrado has reduced proanthocyandin content, which allows it to be topically useful because the inherent ethnomedicine has a rich burgundy color that accounts for its reference to blood in its ethnic name. The ethnomedical uses for sangre de grado are diverse but include wound healing, anti-itch, and analgesia. In addition, taken orally, it alleviates nausea and diarrhea and promotes the healing of gastrointestinal ulcers (1). We have been researching the scientic basis for these ethnomedical reports, and have noted that a suppression of sensory aerent nerves appears to underlie all of these actions (2,3). Sangre de grado is collected ethnomedically by slashing the tree and applying the sap or resin (Fig. 1), as required, to the aicted area. Relief is very rapid, usually within seconds. Thus, historically, this would not impair the native hunters from pursuing their activities. Commercially, the tree is not suitable for tapping (as maple or rubber is) because repeated slashing of the tree results in opportunistic fungal infections and compromised productivity. Additionally, the sap is quite viscous and ows slowly. Hence, harvesting usually involves cutting down the tree and making incisions every 9 in.from these cuts the sap is collected. One of the key applications of sangre de grado in the Amazon is topical administration to relieve the symptoms of insect bites, stings, and plant reactions. These are numerous and extensive problems. In order to assess the ecacy of sangre de grado for these disorders under more controlled conditions, we set about to compare a balm with sangre de grado vs. a placebo in pest management workers. These individuals are prone to these types of complications as a work hazard. Specically, the study was conducted in New Orleans, LA, in the spring when re ants are a major pest. Fire ants (Solenopsis invicta) are derived from South America and inict a painful but intensely pruritic response. The itch persists for a week and scratching can lead to secondary complications of infection. Current therapies for re ant stings are noneective and largely conned to nonprescription pharmaceuticals. Interestingly, heat exacerbates the itch further, highlighting the interactive components of thermal hyperalgesia and itch for this condition. Fire ants represent a major problem of

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Figure 1 The resin of Amazonian Croton lechleri is collected by cutting the bark and the red bloodlike sap (sangre de grado or sangre de drago) can then be applied topically, or collected for oral administration.

epidemic proportions in the southern United States. One third of all residents and 50% of all children in the southern United States are stung each year and an estimated 27 million people are stung annually. Fire ants (Solenopsis spp.) are exceptional among the arthropods in producing venoms that are rich in alkaloids and unusually low in proteins (4,5). The venoms are stored in the poison sac and delivered through the stinger in microgram quantities. In humans, injection of venom leads to pronounced necrosis of the epidermis with the formation of pruritic pustules. Coma and death have even been reported in a few cases involving multiple stings coupled with anaphylactic shock (6). The incidence of allergic/anaphylactic reactions is approximately 0.5% for those suering repeat bites. As the pustules develop, the rst uid is clear, and then necrotic polymorphonuclear cells and lymphocytes abound, and by 72 hr, the most common cells are necrotic plasma cells. The pustule oor disintegrates as the lesion begins to heal, and the uid spreads into connective tissues (7). Non-

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allergic victims have suered thousands of stings with no lasting adverse consequences other than the pustules and associated annoying symptoms, although repeated scratching can establish infected, slow-to-heal wound sites (8). There are virtually no studies that have addressed the types and amounts of inammatory mediators released in response to re ant stings, let alone therapies that negate these events. The venoms are composed mainly of 2-alkyl or alkenyl-6-methyl piperidines, alkaloids also known as the solenopsins (9). As only the alkyl or alkenyl group diers among the various piperidines, it is used to identify the alkaloids readily (10). For example, C11 : 0 denotes an alkaloid with an 11-carbon chain and no double bond, and C13 : 1 denotes an alkaloid with a 13-carbon chain and one double bond. Both cis and trans isomers of the solenopsins are usually present, but their relative proportions are speciesspecic. For instance, cis forms predominate in S. xyloni and S. geminata, whereas trans forms predominate in S. richteri and S. invicta (11). Considering the extent of the problem that re ants pose and the need for new therapeutic approaches, the pest management worker study was designed to address this potential application among pest management workers. Another dicult-to-manage pruritic condition is itch associated with opioid analgesia. Opioid narcotics are commonly associated with the induction of nausea and vomiting, as well as itch. The current understanding suggests that this complication results from a spinal disinhibition. Specically, the sensory aerent nerves responsible for mediating itch are activated subsequent to removal of the inhibitory inuence of pain pathways. In contrast, the same scenario is thought to be responsible for the ability of capsaicin creams to block itch, thereby promoting a pain-induced inhibition of itch pathways at the spinal level. Currently, therapy is focused on reversing the opioid eects with receptor antagonism, but there is little research directed at the potential benets of agents that directly suppress the trac of itch signals, largely because of the lack of available pharmacological tools. Zangrado was tested as a potential therapy in an appropriate animal model, morphine-induced itch, and emesis in ferrets. Ferrets are particularly responsive to opioids in this regard (12).

II. A.

METHODS Clinical TrialInsect Bites and Stings

We designed a double-blind placebo-controlled trial with Zangrado in pest management workers. These individuals routinely suer from insect bites and stings as part of their occupation and were asked to apply either placebo or zangrado balms (coded) to the skin following events and to document the

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symptoms and time taken to achieve relief. Ten participants were also asked to describe their preference using the two test balms. The trial was performed in New Orleans, LA, in the spring when the primary hazard is re ants.

B.

Inhibition of Sensory Afferent Nerve Pathways

To assess directly the eects of zangrado on sensory aerent nerves and their activation, we evaluated the capsaicin-induced increases in gastric blood ow in anesthesized rats using a laser Doppler ow probe. Previously, we have reported that zangrado negates the capsaicin-induced secretory responses in intestinal epithelia in a manner that was independent of neurokinin receptors, as well hyperalgesia responses to protease-activated 2 receptors and prostaglandin E2 (3).

C.

Inhibition of Opioid-Induced Itch

We evaluated whether zangrado could alleviate opioid-induced licking in ferrets. Morphine-6-glucuronide (15 mg/kg, i.p.) was administered to ferrets, with either zangrado (3 mg/kg, i.p.) or vehicle administered 15 min before the opioid. Ferrets were videotaped for behavioral analysis and the number of grooming or licking episodes was counted over the course of 1 hr as an index of itch response. With the knowledge that opioid-induced emetic responses are attenuated by cannabinoids, we also examined whether this opioidinduced licking/itch response could be reversed by the cannabinoid receptor 1 antagonist (AM 251).

III.

RESULTS

In the pest management workers evaluated over the course of 3 months, re ants were the most common event, with all 10 participants suering from at least one episode. The remaining events were in order of incidence: wasps = other ants (six), cuts, bee = mosquito = plant reactions = abrasions (all one). For all applications, the participants preferred the zangrado balm to the placebo. Relief was reported for all symptoms, including itch and pain, on average, in less than 2 min. Given the current diculties in treating the itching response to re ants, this result was regarded as being remarkable, consistent with the ethnomedical experience from the Amazon. Of interest to note is that the active balm only needed to be reapplied once or twice, suggesting that, in addition to rapidly ameliorating the pruritic condition,

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zangrado curtailed the duration of this response to re ant stings. One individual reported an itch response to a plant reaction, and this was also eectively blocked by zangrado. Opioid administration to ferrets resulted in a signicant licking/grooming response, which was virtually abolished by zangrado (Fig. 2). Coadministration of the cannabinoid receptor 1 antagonist, AM 251, failed to reverse the actions of zangrado. Additionally, zangrado did not produce any sedation or hypothermia characteristic of cannabinoids. Collectively, these results suggest that the antipruritic action of zangrado is pharmacologically distinct from cannabinoids. In anesthetized rats, topical capsaicin evoked a dramatical increase in gastric blood ow (Fig. 3). This response was abolished by topical pretreat-

Figure 2 Induction of itch in ferrets is prevented by zangrado but not reversed by cannabinoid antagonists. Morphine-6-glucuronide (15 mg/kg, i.p.) resulted in a substantial induction in licking and grooming in ferrets, indicative of itch. Zangrado given as a 15-min pretreatment (3 mg/kg, i.p.) prevented this response ( p < 0.01). This action of zangrado was not mediated by cannabinoid receptors because the cannabinoid antagonist, AM 251, was without eect.

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Figure 3 Zangrado blocks the hyperemia response to topical capsaicin. Blood ow, measured by a laser Doppler ow meter, was increased by topical capsaicin as a means of activating sensory aerent nerves. Zangrado completely prevented this response ( p < 0.01), indicating its ability to suppress sensory aerent nerve activation.

ment with zangrado, consistent with its analgesic actions and its actions on capsaicin-induced intestinal epithelial secretion (2,3).

IV.

DISCUSSION

From these results and our previous studies (2,3), we have determined that zangrado has a profound ability to suppress the activation of sensory afferent nerves. As a result, zangrado provides relief for itch, pain, and neurogenic inammation. The topical application of a zangrado balm for re ant bites highlights the signicant anti-itch actions. Indeed, participants reported that only one to three applications in total were required to almost immediately relieve itching, which otherwise would persist for a week. It appears that zangrado promoted rapid healing of re ant stings, and negated an otherwise persistent response. This suggests that the actions of

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zangrado may extend beyond immediate relief but to a termination of a positive feedback cycle that may maintain these conditions. Given this therapeutic ecacy, it is critical to determine how these actions are achieved as it will provide important information as to the basic mechanisms of itch and pain. Currently, zangrado dees denition. Therapeutic approaches such as antihistamines and 5-HT3 receptor active agents cannot explain zangrados analgesic actions or its reported eects on protease-mediated neurogenic inammation. We have previously documented that sangre de grado is a very eective inhibitor of the thermal hyperalgesia and edema associated with intradermal application of peptide agonists for proteinase-activated 2 receptors (PAR-2). PAR-2 receptors are located directly on sensory aerent nerves (13) and mediate the itch and pain response following mast cell release of tryptase. Apart from peptide ligands that function as receptor antagonists, there is no other therapy known to block the actions of PAR-2 activation. This highlights the unique functional prole of zangrado. The prevention of morphine-induced itch could indicate that zangrado is an opioid antagonist, but that is not compatible with zangrados analgesic actions. With inhibition of capsaicin-induced hyperemia responses, zangrado could be acting as a vanilloid receptor 1 (VR1) antagonist. However, that is not consistent with the ability of zangrado to prevent protease-activated 2 receptor responses on sensory aerent nerves; furthermore, capsaicin, a VR1 agonist, is often used to block itch largely by evoking concurrent pain responses and short-circuiting the itch sensation. Thus, this pathway is also unlikely. Cannabinoids have been found to negate the skin responses of capsaicin (14,15), as well as attenuate the emetic responses of opioids (8,16). The itch response induced by morphine, which was blocked by zangrado, was not reversed by cannabinoid receptor antagonists, indicating that zangrado is not working through cannabinoid-dependent mechanisms. These comparisons are detailed in Table 1. Collectively, although it is clear that zangrado is eective in blocking itch and pain in response to a variety of stimuli, these eects are not consistent with known pharmacological approaches. Indeed, the best way of describing these actions is the activation of a yet-to-be-identied receptor that evokes a generalized inhibitory action on sensory aerent nerves. Possible candidates for action are sodium channels or tetrodotoxin-resistant voltage channels, but this remains to be explored. There is a possibility that because it is a natural product with multiple chemical constituents, the bioactivity reects diverse mechanisms mediating by distinct components. For example, zangrado has some similarities to vanilloid receptor antagonists in terms of signal transduction mechanisms, and because zangrado

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Table 1 Comparison of the Bioactivity Proles of Common Therapeutic Approaches to Itch and Pain Agent Antihistamine 5-HT3 compounds Capsaicin Opioids Cannabinoids Zangrado Itch # Mild # # z # # Pain p! p! # z # # # Capsaicin responses p! p! p! # # PAR2 responses p! p! ? p! ? # Central complications z z p! z z p! Opioid responses Mild # p! ? # #

This panel highlights the unique prole of bioactivity of zangrado among known agents that either relieve or induce itch and pain.

attenuates capsaicin responses, it may block vanilloid (capsaicin) receptors. There are a substantial number of papers that suggest that numerous vanilloid receptors exist, or at least that the current receptor classication does not explain the plethora of observations (17,18). Given that endogenous chemicals that interact with cannabinoid and vanilloid receptors have been found to exist (19,20), zangrado may also provide insight into potential endogenous anti-itch chemicals. However, until that time, zangrado deserves further exploration as a therapeutically useful tool for a variety of pruritic conditions.

REFERENCES
1. 2. Duke J, Vasquez R. Amazonian Ethnobotanical Dictionary. Boca Raton, FL: CRC Press Inc., 1994. Miller MJS, MacNaughton WK, Zhang X-J, Thompson JH, Charbonnet RM, Bobrowski P, Lao J, Trentacosti AM, Sandoval M. Treatment of gastric ulcers and diarrhea with the Amazonian medicinal, sangre de grado. Am J Physiol 2000; 279:G192G200. Miller MJS, Vergnolle N, McKnight W, Musah RA, Davison CA, Trentacosti AM, Thompson JH, Sandoval M, Wallace JL. Inhibition of neurogenic inammation by the amazonian herbal medicine, sangre de grado. J Invest Dermatol 2001; 117:725730. Baer H, Liu TY, Anderson MC, Blum M, Schmid WH, James FJ. Protein components of re ant venom (Solenopsis invicta). Toxicon 1979; 17:397405. Attygalle AB, Morgan ED. Chemicals from the glands of ants. Chem Soc Rev 1984; 13:245278.

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Miller et al. Rhoades RB. Medical Aspects of the Imported Fire Ant. Florida: The University Presses of Florida, 1977. Homan DR. Fire ant venom allergy. Allergy 1995; 50:53445355. Diaz JD, Lockey RF, Stablein JJ, Mines HK. Multiple stings by imported re ants (Solenopsis invicta) without systemic eects. South Med J 1989; 82:775777. MacConnell JG, Blum MS, Fales HM. The chemistry of re ant venom. Tetrahedron 1971; 26:11291139. MacConnell JG, Blum MS, Buren WF, Williams RN, Fales HM. Fire ant venoms: chemotaxonomic correlations with alkaloidal compositions. Toxicon 1976; 14:6978. Brand JM, Blum MS, Fales HM, MacConnell JC. Fire ant venoms: comparative analyses of alkaloidal components. Toxicon 1972; 11:325331. Van Sickle MD, Oland LD, Ho W, Hillard CJ, Mackie K, Davison JS, Sharkey KA. Cannabinoids inhibit emesis through CB1 receptors in the brainstem of the ferret. Gastroenterology 2001; 121:767774. Steinho M, Vergnolle N, Young SH, Tognetto M, Ennes HS, Trevisani M, Hollenberg MD, Wallace JL, Caughey GH, Mitchell SE, Williams LM, Geppetti P, Mayer EA, Bunnett NW. Agonists of proteinase-activated receptor-2 induce inammation by a neurogenic mechanism. Nat Med 2000; 6:151158. Ko M-C, Woods JH. Local administration of D9-tetracannabinol attenuates capsaicin-induced thermal nociception in rhesus monkeys: a peripheral cannabinoid action. Psychopharmacology 1999; 143:322326. Li J, Daughters RS, Bullis C, Benjamin R, Stucky MW, Brennan J, Simone DA. The cannabinoid receptor agonist WIN 55,212-2 mesylate blocks the development of hyperalgesia by capsaicin in rats. Pain 1999; 81:2533. Simoneau II, Hamza MS, Mata HP, Siegel EM, Vanderah TW, Porreca F, Makriyannis A, Malan TP. The cannabinoid agonist WIN 55,212-2 suppresses opioid-induced emesis in ferrets. Anesthesiology 2001; 94:882887. Di Marzo V, Bisogno T, Melck D, Ross R, Brockie H, Stevenson L, Pertwee R, De Petrocellis L. Interactions between synthetic vanilloids and the endogenous cannabinoid system. FEBS Lett 1998; 436:449454. Schumacher MA, Mo I, Sudanagunta SP, Levine JD. Molecular cloning of an N-terminal splice variant of the capsaicin receptor. Loss of N-terminal domain suggests functional divergence among capsaicin receptor subtypes. J Biol Chem 2000; 275:27562762. Hwang SW, Cho H, Kwak J, Lee S-Y, Kang C-J, Jung J, Cho S, Min KH, Kim D, Oh U. Direct activation of capsaicin receptors by products of lipoxygenases: endogenous capsaicin substances. Proc Natl Acad Sci USA 2000; 9:61556160. Maccarone M, Lorenzon T, Bari M, Melino G, Finazzi-Agro A. Anandamide induces apoptosis in human cells via vanilloid receptors. J Biol Chem 2000; 275:3193831945.

11. 12.

13.

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16.

17.

18.

19.

20.

30
Reduction in Itch Severity with Topical Immunomodulators: A New Approach for Patients with Inflammatory Disease
Alan B. Fleischer, Jr.
Wake Forest University School of Medicine, Winston-Salem, North Carolina, U.S.A.

I.

INTRODUCTION

The most common pruritic disorders are caused by inammatory skin diseases. Atopic dermatitis is a chronic, relapsing form of eczema characterized by scaling, itchy, inamed skin that can be triggered by an interplay of genetic, immunological, and environmental factors. Along with asthma and allergic rhinitis, atopic dermatitis is part of a larger family of allergic diseases (1). Immune dysregulation appears to play an important role in the etiology of atopic dermatitis (2,3). Bone marrow-derived cells may play a primary role because sensitivity to antigens has been transferred to recipients of bone marrow cells from patients with atopic dermatitis (4). Altered T-cell function appears to be the primary immunological abnormality present in atopic dermatitis and patients have elevated levels of IgE. Agents that decrease the inammation may indirectly improve the sensation of itch. Topical corticosteroid agents have been the mainstay of therapy for atopic dermatitis due to their broad immunomodulatory eects. Topical
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corticosteroid agents are not ideal agents because when used over the long term, they may cause cutaneous atrophy (57). Not infrequently, patients display disease refractory to short-term topical corticosteroid agents. Indeed, the majority of patients with atopic dermatitis fail to clear their skin by the end of the approved durations of treatment. Clinicians and patients must then decide whether the benets of ongoing topical therapy outweigh its associated ever-increasing risks. Clinicians have been searching for corticosteroid-sparing agents that can be used when long-term topical therapies are required, yet lack the expense, inconvenience, and monitoring required of phototherapy and systemic immunosuppressive therapy. The recent development of topical tacrolimus may ll this role. Tacrolimus is a 23-member macrolide of molecular mass 822 Dalton (Fig. 1) produced by Streptomyces tsukabaensis, a fungus found in the soil of Mount Tsukuba, Japan (8). The drugs name is derived as follows: tMount Tsukuba, acrolmacrolide, imusimmunosuppressant. It is frequently also

Figure 1

Chemical structure of tacrolimus.

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referred to as FK506, its research compound designation. There are a series of complex immunodysregulatory activities within patients with atopic dermatitis and other chronic inammatory dermatoses. T lymphocytes are activated, release cytokines, and interact with a broad range of other cell types in the dermis and epidermis. Tacrolimus acts directly on the T lymphocytes, especially CD4+ cells, by binding to immunophilins (FK-binding protein) (9). This tacrolimusimmunophilin complex then binds to and competitively inhibits calcineurin, a phosphatase that is active only when bound to calcium and calmodulin. This binding phenomenon inhibits the ability of calcineurin to activate the promoter region of the gene for IL-2, IL-3, IL-4, IL-5, GMCSF, and TNF-a, all of which participate in the early immune response and are postulated to play a role in atopic dermatitis pathogenesis (1012). Tacrolimus may also bind to cell surface steroid receptors, inhibit the release of mast cell preformed mediators, downregulate IL-8 receptor expression, decrease ICAM-1 and E-selectin lesional blood vessel expression, and downregulate Fc RI on Langerhans cells (13). This broad range of inammatory inhibition mechanisms may decrease antigen recognition and downregulate the entire inammatory cascade leading to clinical disease and itch. Once itch occurs, scratching likely perpetuates the inammatory condition. It should be noted that topical tacrolimus does not have the potential to aect collagen synthesis. Reitamo et al. (14) conducted a randomized, double-blind, placebo-controlled trial to assess the atrophogenicity of tacrolimus ointment. In a combined group of atopic dermatitis patients (n =14) and healthy volunteers (n =12), 0.3% tacrolimus, 0.1% tacrolimus, betamethasone valerate, and a vehicle control were applied in a randomized order to nonsymptomatic 4 4-cm regions of abdominal skin. After 7 days of treatment under occlusion, the carboxy-terminal and amino-terminal propeptides of procollagen I (PICP, PINP) and the amino-terminal propeptide of procollagen III (PIIINP) were measured from suction blister uid with specic radioimmunoassays, and ultrasound measurements of skin thickness were taken. Betamethasone-treated areas showed median PICP, PINP, and PIIINP concentrations of 17.0%, 17.6%, and 39.5% of the vehicle control at the end of the treatment period, respectively, whereas the 0.1% and 0.3% tacrolimus-treated areas showed median concentrations of approximately 100% of the vehicle control. Betamethasone was also the only treatment to signicantly decrease skin thickness; the median decrease in skin thickness was 7.4% relative to 0.1% tacrolimus, 7.1% relative to 0.3% tacrolimus, and 8.8% relative to the vehicle control. Results for atopic dermatitis patients and healthy volunteers were similar. These ndings suggest that tacrolimus does not cause skin atrophy that a medium potency corticosteroid agent can produce in 1 week of therapy. These results are supported by longterm trials conducted with up to 4 years of continuous treatment without demonstrated atrophy (15,16).

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Although there is a vast amount of information about topical tacrolimus, and tacrolimus improves atopic dermatitis severity (1719), the relationship between the use of topical tacrolimus and itch has not been fully described to date. Moreover, the relationship between the change in quality of life (QOL) and the change in itch severity needs further exploration as well.

II.

METHODS

We reviewed data from the Phase III clinical trials of topical tacrolimus used for the treatment of atopic dermatitis in the United States. These studies included 233 evaluable pediatric patients (from Fujisawa trial 97-0-037) and 412 evaluable adult patients (from Fujisawa trials 97-0-035 and 97-0-036) enrolled in 12-week double-blind, parallel group, vehicle-controlled clinical trials. In the study designs of the controlled trials, at baseline, subjects were randomized to receive tacrolimus 0.03% ointment BID, tacrolimus 0.1% ointment BID, or vehicle. For purposes of this analysis, treatment groups were grouped together and compared at week 12 with baseline values. The safety and ecacy results of these trials have previously been reported (1517). The severity of disease was assessed using the eczema area severity index. The itch score was evaluated by patients, using a visual analog scale. The quality of life scores diered by the age of the subjects, and were grouped into Toddlers, Children, and Adults. Surveys used to assess QOL include the Toddler QOL Survey (age 24 years), Childrens DLQI (CDLQI) (515 years), and the Dermatology Life Quality Index (DLQI) (16 years and older). Statistical treatment consisted of correlation and regression of the change in the EASI score with the change in the itch score. Correlation analysis and regression analysis were performed to explore the relationship between itch and the EASI score, and between the itch score and the change in the QOL score. Analyses were performed based on the data from patients in two tacrolimus concentration groups (0.03% and 0.1%) in three Phase III studies. For the analysis of pediatric and adult studies, results were not pooled across populations. For QOL, analyses were also performed by three age groups because dierent QOL instruments were used for each age group.

III. A.

RESULTS Effect of Topical Tacrolimus on Itch Severity

Topical tacrolimus treatment clearly reduced itch severity. Statistically signicant correlations were seen between reduction in itch score and reduction in EASI score. We found that correlation coecients and regression

Reduction in Itch Severity with Topical Immunomodulators Table 1 Correlation Between Itch and EASI Score

319

n Overall Children (215 years) Adults (16 years or older) 645 233 412

Correlation coecient r = 0.412 ( p < 0.001) r = 0.424 ( p < 0.001) r = 0.404 ( p < 0.001)

Regression equation ( Y=reduction in EASI score; X=reduction in itch score) Y = 8.40 + 1.54X Y = 9.44 + 1.47X Y = 7.86 + 1.56X

equations are similar between children and adults (Table 1). Because of this homogeneity, it appears valid to present the overall results (Fig. 2). B. Effect of Topical Tacrolimus on Quality of Life

Topical tacrolimus treatment also clearly improved QOL. A statistically signicant correlation was seen between reduction in itch score and reduc-

Figure 2 The relationship between the change in the itch score and the change in the eczema area severity index (EASI) is presented, with linear regression (solid line) and 95% condence interval (dashed lines).

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Figure 3

Total quality of life score change from baseline to the end of treatment.

tion in total QOL score (Fig. 4). Analyses were also performed by three age groups because dierent QOL instruments were used for each age group. Subjects using tacrolimus signicantly improved their QOL scores (Fig. 3). Correlation coecients and regression equations are somewhat dierent among age groups. Therefore, it may be better to present the result by each age group (Table 2). There is a highly statistically signicant relationship between the change in itch and the change in QOL.

IV.

DISCUSSION

The cardinal symptom of atopic dermatitis, as with many inammatory skin diseases, is itch. This chapter describes the relationship between improveTable 2 Reduction in EASI and QOL Scores with Topical Tacrolimus Regression equation ( Y=reduction in EASI score; X=reduction in total QOL score) Y = 14.03 Y = 16.63 Y = 19.00 Y = 11.60 + + + + 3.01X 3.72X 1.40X 3.32X

Correlation coecient Overall Toddler (24 years) Children (515 years) Adults (z16 years) 608 96 126 386 r = 0.472 r = 0.532 r = 0.258 r = 0.511 ( p < 0.001) ( p < 0.001) ( p = 0.004) ( p < 0.001)

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Figure 4 Correlation between itch and QOL. The relationship between the change in the itch score and the change in the QOL score is presented, with linear regression (solid line) and 95% condence interval (dashed lines).

ment in disease severity and improvement in QOL with improvement in itch. Topical tacrolimus clearly has demonstrated its ability to decrease the severity of itching in a large cohort of study subjects with moderate to severe atopic dermatitis. This reduction in itch severity is closely related to improvement in the signs of atopic dermatitis, as measured by the EASI, and with improvement in QOL, as measured by the three study instruments. Thus, tacrolimus is a safe, long-term, anti-inammatory and antipruritic treatment for atopic dermatitis. Unlike corticosteroid agents, tacrolimus appears to have no potential to cause cutaneous atrophy, yet is a highly eective therapy for improving the itch and lessening the severity of atopic dermatitis. The agent may be of particular benet to children, among whom an alternative to the chronic use of corticosteroids, either topically or systemically, is highly desirable. Whether this agent will be used primarily as an independent therapy, or as part of a combination therapeutic regimen with corticosteroid agents is unknown. It is certain, however, that topical tacrolimus will nd a unique place in the treatment of atopic dermatitis and other inammatory dermatoses.

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REFERENCES
1. 2. 3. 4. 5. 6. Umeki S. Allergic cycle: relationships between asthma, allergic rhinitis, and atopic dermatitis. J Asthma 1994; 31:1926. Sampson HA. Atopic dermatitis. Ann Allergy 1992; 69:469481. Hanin JM. Assembling the puzzle pieces in atopic inammation. Arch Dermatol 1996; 132:12301232. Rudiko D, Lebwohl M. Atopic dermatitis. Lancet 1998; 351:17151721. Smith EW. Four decades of topical corticosteroid assessment. Curr Probl Dermatol 1995; 22:124131. Lubach D, Rath J, Kietzmann M. Skin atrophy induced by initial continuous topical application of clobetasol followed by intermittent application. Dermatology 1995; 190:5155. Pierard GE, Pierard-Franchimont C, Ben Mosbah T, Arrese Estrada J. Adverse eects of topical corticosteroids. Acta Dermato-Venereol 1989; 151 (suppl):26 30. Spencer CM, Goa KL, Gillis JC. Tacrolimus. An update of its pharmacology and clinical ecacy in the management of organ transplantation. Drugs 1997; 54:925975. Kelly PA, Burckart GL, Venkataramana R. Tacrolimus: a new immunosuppressive agent. Am J Heath Syst Pharm 1995; 52:15211535. Mori A, Suko M, Nishizaki Y, Kaminuma O, Matsuzaki G, Ito K, et al. Regulation of interleukin-5 production by peripheral blood mononuclear cells from atopic patients with FK506, cyclosporin A and glucocorticoid. Int Arch Allergy Immunol 1994; 104(suppl 1):3235. De Paulis A, Stellato C, Cirillo R, Ciccarelli A, Oriente A, Marone G. Antiinammatory eect of FK-506 on human skin mast cells. J Invest Dermatol 1992; 99:723728. Eberlein-Konig B, Michel G, Ruzicka T, Przybilla B. Modulation of histamine release in vitro by FK506 and interleukin-3 is determined by sequence of incubation. Arch Dermatol Res 1997; 289:606608. Lawrence ID. Tacrolimus (FK506): experience in dermatology. Dermatol Ther 1998; 5:7484. Reitamo S, Rissanen J, Remitz A, Granlund H, Erkko P, Elg P, et al. Tacrolimus ointment does not aect collagen synthesis: results of a single-center randomized trial. J Invest Dermatol 1998; 111:396398. Paller A, Caro I, Weinstein G, Rico MJ, and the Tacrolimus Ointment Study Group. Long-term safety and ecacy of tacrolimus ointment monotherapy in atopic dermatitis patients: open-label study results (poster). Presented at the 20th World Congress of Dermatology, Paris, July 2002. Koo JYM, Prose N, Fleischer A, Rico MJ, and the Tacrolimus Ointment Study Group. Safety and ecacy of tacrolimus ointment monotherapy in over 7,900 atopic dermatitis patients: results of an open label study (poster). Presented at the 20th World Congress of Dermatology, Paris, July 2002. Paller A, Eicheneld LF, Leung DYM, Stewart D, Appell M, the Tacrolimus

7.

8.

9. 10.

11.

12.

13. 14.

15.

16.

17.

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Ointment Study Group. A 12-week study of tacrolimus ointment for the treatment of atopic dermatitis in pediatric patients. J Am Acad Dermatol 2001; 44(suppl):S47S57. 18. Hanin JM, Ling MR, Langley R, Breneman D, Rafal E. Tacrolimus ointment for the treatment of atopic dermatitis in adult patients: Part I. Ecacy. J Am Acad Dermatol 2001; 44(suppl):S28S38. 19. Soter N, Fleischer AB, Webster GF, Monroe E, Lawrence I. Tacrolimus ointment for the treatment of atopic dermatitis in adult patients: Part II. Safety. J Am Acad Dermatol 2001; 44(suppl):S39S46.

31
5-HT3 Receptor Antagonists as Antipruritics
Elke Weisshaar
University of Heidelberg, Heidelberg, Germany

I.

SEROTONIN AND ITCH

Serotonin (5-hydroxytryptamine or 5-HT) is a biogenic amine found in platelets and serum. It is stored in the platelets in an inactive form and released when platelets aggregate. Mast cells of mice and rats contain serotonin, but not those of humans. It has been known for many years that 5-HT can excite nociceptive C-bers (1). Serotonin produces algesic or analgesic eects, depending on where in the nervous system it is released. Peripherally, it depolarizes aerent bers and causes pain, as well as potentiates the algesic action of other substances (2). When serotonin is injected intradermally or induced by iontophoresis, it induces itch but is less potent than histamine (35). Serotonin is also vasoactive, contributing to the pathophysiology of diseases such as carcinoid syndrome, hypertension, atherosclerosis, and ischemic heart disease. Because serotonin is synthesized in the proximal tubular cells of the kidney, it may play a role in the pathogenesis of various kidney diseases. Raised levels of serotonin have been detected in patients with renal impairment, especially those on hemodialysis (HD) but also on continuous ambulatory peritoneal dialysis (CAPD) (69). There was no positive correlation of serotonin levels with pruritus (6,7). In a recent study investigating platelet325

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poor plasma of patients on HD, serotonin levels ranged within normal limits (10). Most likely, elevated serotonin levels in previous studies (Balakas et al., 1998; (7)) were obtained by measuring the total blood pool of serotonin including the intraplatelet component (7).

II.

5-HT3 RECEPTORS AND THEIR ANTAGONISTS

Serotonin receptors are widely distributed throughout the body and there are at least seven dierent types as well as 14 serotonin receptor subtypes. They are present exclusively on peripheral and central neurons. The 5-HT3 receptor is a ligand-gated cation channel belonging to the nicotine/GABA receptor superfamily (11). 5-HT3 receptors are mainly found in the substantia gelatinosa of the spinal cord, in multiple nucleoli of the brainstem, in the area postrema, and in the enteric nervous system. They are linked to several serotonin-mediated processes including vasomotor reexes, pain, cardiovascular regulation, behavior and limbiccortical functioning, and the enteric nervous system (12). 5-HT3 receptor antagonists (serotonin type 3 receptor antagonists) were developed for relief of chemotherapy-induced nausea and vomiting. Further established indications are radiotherapy-induced and postoperative emesis (11). There are several 5-HT3 receptor antagonists such as ondansetron, tropisetron, granisetron, dolasetron, azasetron, and ramosetron. In vitro studies demonstrated dierences in receptor binding: tropisetron has a high anity for the 5-HT3 receptor and a weak anity for the 5-HT4 receptor. Ondansetron has low anity for the 5-HT1b, 5-HT1c, adrenergic, and opioid receptors. Thus, pharmacokinetic dierences among these drugs are unlikely to contribute signicantly to clinical dierences in activity (13,14). 5-HT3 receptor antagonists are rapidly absorbed and penetrate the bloodbrain area easily. They are metabolized by diverse subtypes of the cytochrome P450 system and the metabolites are excreted mainly in urine (11). Ondansetron is rapidly and completely absorbed from the gastrointestinal tract after oral administration. Due to a signicant rst-pass metabolism, only 60% is bioavailable. Maximum plasma concentrations occur after 12 hr. There is no evidence of accumulation after repeated oral administration (12). Ondansetron is mainly metabolized by the liver to inactive glucuronide and sulfate conjugates that are excreted in the urine and feces. As a result, a reduced dosage schedule should be employed when prescribing ondansetron to patients with hepatic impairement. However, no such adjustment is necessary in renal failure. The standard oral dose is 8 mg twice daily. Tropisetron is almost completely absorbed from the gastrointestinal tract and undergoes dose-dependent rst-pass metabolism. The peak plasma

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concentration occurs approximately 1 hr postdose (15). The bioavailability of oral tropisetron exhibits a wide range at therapeutic doses (16). The mean half-life period is 710 hr. It is metabolized to inactive metabolites by the hydroxylation of the indole moiety and further conjugation to glucuronides and sulfates. Approximately 80% of a dose is excreted via the kidneys, mainly as metabolites. Clearance is decreased in patients with impaired hepatic or renal function, but dose adjustment is not required. The recommended dose is 5 mg/day (15). Adverse eects of 5-HT3 receptor antagonists include headache, dizziness, sedation, abnormalities of liver biochemistry, and, rarely, anaphylaxis (12). When prescribing 5-HT3 receptor antagonists, the physician should be aware of the serotonin syndrome that has been reported when they were given in combination with other drugs such as mirtazapine and fentanyl (17). The serotonin syndrome is characterized by a triad of clinical manifestations: altered mental status, autonomic dysfunction, and neuromuscular abnormalities such as cogwheel rigidity, hyperreexia, and myoclonus. 5-HT3 receptor antagonists may pose a potential risk when used in severely ill patients with multidrug therapy, especially with central acting substances. Perhaps, blocking one type of serotonin receptor and functionally increasing systemic and central nervous system levels of serotonin simultaneously (hence presenting excessive serotonin to other receptors) increase the risk of serotonin syndrome.

III.

ANTIPRURITIC POTENCY OF 5-HT3 RECEPTOR ANTAGONISTS

The widespread distribution of 5-HT3 receptors in the peripheral and central nervous systems indicates that this receptor type may have a role in various disease states. This has resulted in the investigation of 5-HT3 receptor antagonists in the treatment of pruritus. Relief of itch by ondansetron was rst reported by Schwo rer and Ramadori (18,19) in a patient suering from cholestatic pruritus. Several reports and clinical trials followed and demonstrated benet from the use of 5-HT3 receptor antagonists in various types of pruritus (Fig. 1). In cholestatic pruritus, opioid levels are raised and facilitate itch (20). Greater central opioid tone can cause increased serotonergic tone, perhaps accounting for the anecdotal reports of benecial eects of ondansetron in cholestatic pruritus (21,22). Equivocal results have been obtained in controlled studies investigating cholestatic pruritus. Intravenous ondansetron reduced or abolished pruritus in 10 patients within 3060 min after injection, with a more prolonged eect when the dose of 8 mg was compared to 4 mg (23).

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Figure 1 Evidence of benet from the use of 5-HT3 receptor antagonists in the treatment of nonrenal pruritus.

Ondansetron tablet 8 mg t.d.s. also had a small but signicant eect on cholestatic pruritus in 18 patients. However, patients did not prefer ondansetron over placebo when asked to make a blind choice (24). In a further study with 19 patients, the rst dose of 8 mg of ondansetron was administered intravenously, followed by 8 mg of ondansetron twice daily over 5 days, and showed no benet compared to placebo (25). There are a number of uncontrolled (26) and controlled (27) studies reporting successful treatments of opioid-induced pruritus with ondansetron. However, the most recent systematic review of the pharmacological control of opioid-induced pruritus failed to nd good evidence of a role for 5-HT3 receptor antagonist in opioid itch (28).

IV.

ONDANSETRON IN RENAL ITCH

Schwo rer and Ramadori (19) published the rst report of a patient with renal itch who responded to ondansetron 8 mg i.v. Andrews et al. (29) reported a reduction of pruritus in a patient with renal itch who received 8 mg of oral ondansetron twice daily. It was apparent that there was a need for trials to objectively assess the role of 5-HT3 antagonists in renal itch. Balaskas et al. (6) treated 11 pruritic

5-HT3 Receptor Antagonists as Antipruritics 329

Figure 2 Overview of studies on 5-HT3 receptor antagonists in continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD)-associated renal itch.

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CAPD patients with 4 mg of oral ondansetron twice daily for a mean period of 3 months (range 15 months). All patients responded to the treatment. From commencement of treatment, a signicant reduction of the severity of pruritus was seen. At the end of the rst week, pruritus disappeared in 7/11 and was abolished in all patients at the end of the second week. This response was maintained throughout the study (Fig. 2). However, Ashmore et al. (30) randomly assigned 16 HD patients with persistent pruritus to treatment with 8 mg of ondansetron three times daily for 2 weeks. No signicant antipruritic eect was detected; the median daily use of escape medication (antihistamines) decreased with both ondansetron and placebo. The most recent double-blind, randomized, placebo-controlled crossover trial to assess the eectiveness of oral ondansetron in renal itch was performed by Murphy et al. (31). Twenty-four HD patients suering from pruritus were enrolled in the study. Baseline values for itch were obtained for 7 days prior to the treatment period and there was a 7-day washout between the treatment periods. Patients received either 8 mg of ondansetron three times a day or a placebo tablet three times a day for 3 weeks. Patients were asked to record the severity of their pruritus on a visual analogue scale (VAS) twice a day (the morning score representing the itch during the night and the evening score representing the itch during the day). The VAS consisted of a 10-cm horizontal line marked 0 (no itch) to 10 (maximum itch). At the end of the study, patients were asked blindly which treatment they had preferred. Seventeen of 24 patients completed the trial. Pruritus decreased by 16.3% during active treatment and by 24.9% during treatment with placebo. The changes in the VAS scores during treatment with ondansetron and placebo were both signicant. The eect of ondansetron was not as marked as that of placebo, although this did not achieve signicance. The time period and sequence of the administration of the drug were not found to have an eect. Eleven patients expressed a preference: seven for placebo and four for ondansetron. In summary, the results show that ondansetron is no better than placebo in controlling renal itch.

V.

TROPISETRON IN RENAL ITCH

There is only one report of the successful use of intravenous tropisetron in paraneoplastic itch (32). Experimental work has shown that the antipruritic eects of tropisetron may be mediated through mast cell activity in the skin (4,5). However, in a trial of 5-HT3 receptor antagonists in renal itch, plasma serotonin and histamine levels were normal before and after treatment.

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Neither 5 mg of tropisetron nor 8 mg of ondansetron achieved an antipruritic eect (10). A role for serotonin receptor antagonists in renal itch appears unlikely, but not denitively excluded, because: Whole blood serotonin levels are elevated in chronic renal failure, especially in those on CAPD, whereas the levels of free plasma serotonin are not. There is a wide variation in the bioavailability of 5-HT3 receptor antagonists through variable absorption between individuals, route of administration, and dose prescribed. Wide variation in study designs restricts the potential for metaanalysis.

ACKNOWLEDGMENT I thank Andrew J. Carmichael (Department of Dermatology, James Cook University Hospital, Middlesborough, UK) for reviewing the manuscript.

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Beck PW, Handwerker HO. Bradykinin and serotonin eects on various types of cutaneous nerve bres. Pfugers Arch 1974; 347:209. 2. Richardson BP. Serotonin and nociception. Ann NY Acad Sci 1990; 600:511. . Peripheral and central mediators of itch. Skin Pharmacol 1992; 3. Ha germark O 5:1. 4. Weisshaar E, Ziethen B, Gollnick H. Can a serotonin type 3 (5-HT3) receptor antagonist reduce experimentally-induced itch? Inamm Res 1997; 46:412. 5. Weisshaar E, Ziethen B, Gollnick H. The antipruritic eect of a 5-HT3 receptor antagonist (tropisetron) is dependent on mast cell depletionan experimental study. Exp Dermatol 1999; 8:254. 6. Balaskas EV, Bamihas GI, Karamouzis M, Voyiatizis G, Tourkantonis A. Histamine and serotonin in uremic pruritus: eect of ondansetron in CAPD-pruritic patients. Nephron 1998; 78:395. 7. Kerr PG, Argiles A, Mion C. Whole blood serotonin levels are markedly elevated in patients on dialytic therapy. Am J Nephrol 1992; 12:14. 8. Parbtani A, Frampton G, Cameron JS. Platelet and plasma serotonin concentrations in glomerulonephritis II. Clin Nephrol 1980; 13:112. K, Raucinova M, Dzu 9. Sebekova rik R. Serotonin metabolism in patients with decreased renal function. Nephrology 1989; 53:229. 10. Weisshaar E, Dunker N, Domro se U, Neumann KH, Gollnick H. Plasma 1.

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Weisshaar serotonin and histamine levels in haemodialysis-related pruritus are not signicantly inuenced by 5-HT3 receptor blocker and antihistaminic therapy. Clin Nephrol 2003; 59:124. Wolf H. Preclinical and clinical pharmacology of the 5-HT3 receptor antagonists. Scand J Rheumatol 2000; 113:37. Wilde MI, Markham A. Ondansetron. A review of its pharmacology and preliminary clinical ndings in novel applications. Drugs 1996; 52:773. Gregory RE, Ettinger DS. 5-HT3 receptor antagonists for the prevention of chemotherapy-induced nausea and vomiting. A comparison of their pharmacology and clinical ecacy. Drugs 1998; 55:173. Roila F, Ballatori E, Tonato M, Del Favero A. 5-HT3 receptor antagonists: dierences and similarities. Eur J Cancer 1997; 33:1364. Rhoda Lee C, Plosker GL, McTavish D. Tropisetrona review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential as an antiemetic. Drugs 1993; 46:925. Kees F, Fa rber L, Bucher M, Mair G, Mo rike K, Grobecker H. Pharmacokinetics of therapeutic doses of tropisetron in healthy volunteers. Br J Clin Pharmacol 2001; 52:705. Turkel SB, Nadala JGB, Wincor MZ. Possible serotonin syndrome in association with 5-HT3 receptor agent. Pyschosomatics 2001; 42:258260. Schwo rer H, Ramadori R. Improvement of cholestatic pruritus by ondansetron. Lancet 1993; 341:1277. Schwo rer H, Ramadori G. Treatment of pruritus: a new indication for serotonin type 3 receptor antagonists. Clin Invest 1993; 71:659. Bergasa NV, Jones EA. The pruritus of cholestasis: potential pathogenetic and therapeutic implications of opioids. Gastroenterology 1995; 108:1582. Raderer M, Mu ller C, Scheithauer W. Ondansetron for pruritus due to cholestasis. N Engl J Med 1994; 330:1540. Jones EA. Relief from profound fatigue associated with chronic liver disease by long-term ondansetron therapy. Lancet 1999; 354:397. Schwo rer H, Hartmann H, Ramadori R. Relief of cholestatic pruritus by a novel class of drugs: 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists: eectiveness of ondansetron. Pain 1995; 61:33. Mu ller C, Pongratz S, Pidlich J, Penner E, Kaider A, Schemper M, Raderer M, Scheithauer W, Ferenci P. Treatment of pruritus in chronic liver disease with the 5-hydroxytryptamine receptor type 3 antagonist ondansetron: a randomized, placebo-controlled, double-blind cross-over trial. Eur J Gastroenterol Hepatol 1998; 10:865. ODonohue JW, Haigh C, Williams R. Ondansetron in the treatment of cholestasis: a randomised controlled trial. Gastroenterology 1997; 112:A1349. Larijani GE, Goldberg ME, Rogers KH. Treatment of opioid-induced pruritus with ondansetron: report of four patients. Pharmacotherapy 1996; 16:598. Borgeat A, Stirnemann HR. Ondansetron is eective to treat spinal or epidural morphine-induced pruritus. Anesthesiology 1999; 90:432. Kjellberg F, Tramer MR. Pharmacological control of opioid-induced pruritus:

11. 12. 13.

14. 15.

16.

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24.

25. 26. 27. 28.

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29. 30. 31.

32. 33. 34.

a quantitative systematic review of randomized trials. Eur J Anaesthesiol 2001; 18:346. Andrews PA, Quan V, Ogg CS. Ondansetron for symptomatic relief in terminal uraemia. Nephrol Dial Transplant 1995; 10:140. Ashmore SD, Jones CH, Newstead CG, Daly MJ, Chrystin H. Ondansetron therapy for uremic patients in hemodialysis. Am J Kidney Dis 2000; 35:827. Murphy M, Reaich D, Pai P, Finns P, Carmichael AJ. A randomised placebocontrolled, double-blind trial of ondansetron in renal itch. Br J Dermatol 2003; 148:314. Zylicz Z, Krajnik M. Pruritus in cancer: uncommon, but sometimes worse than pain. Ned Tijdschr Geneeskd 1999; 25:408. ` res Clin Bergasa NV. Pruritus and fatigue in primary biliary cirrhosis. Baillie Gastroenterol 2000; 14:643. Downs AM, Kennedy CT. Successful treatment of intractable palmoplantar pruritus with ondansetron. Arch Dermatol 1998; 134:925.

32
Cutaneous Nerve Stimulation in the Treatment of Localized Itch
Joanna Wallengren
University Hospital, Lund, Sweden

Rubbing, massage, vibration, cupping, or even painful stimulation of the skin as dierent means of relieving pain and scratching to relieve itch have stood the test of time. Electrotherapy for relieving pain was introduced during the 19th century. Studies of the eects of electrical stimulation on nerve bers have contributed to advances in neurophysiology and to our present view of pain and itch. Pain sensation is mediated by unmyelinated Ay- and polymodal Cbers located in the epidermis and the upper dermis (1). Impulses propagated by the Ay-bers enter the dorsal horn of the spinal cord, cross over to the contralateral side, and pass through the neospinothalamic tract and the thalamus to arrive nally in the somatosensory cortex area I and convey the rst pain. Impulses owing through the C-bers pass through the spinal cord in much the same way and then follow a phylogenetically old track, the paleospinothalamic tract (1). This system, which is much slower in reaching the brain, transmits information regarding the state of the organism, although information regarding location is more diuse. The sensation of itch is mediated by a subset of epidermal C-bers that is insensitive to mechanical stimuli but is sensitive to thermal stimuli and comprises about 5% of the C-bers (2).
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In 1965 Melzack and Wall suggested a new theory of pain. This theory, since then modied, postulates that the stimulation of large nerve bers impairs nociceptive transmission by activating the inhibitory cells of the spinal ganglia. On the basis of Melzack and Walls (3) ndings, transcutaneous electrical nerve stimulation (TENS) was developed for the activation of large myelinated nerve bers (4,5). The TENS device consists of a pair of at rubber electrode-plates (4 6 cm or 8 13 cm) and a stimulator that generates an alternating current. With an increase in the intensity of the current, TENS induces pressure and vibration that produce paresthesia (Ah-bers), contractions of the muscles (motor Aa-bers), and pain (Ay-and C-bers). Two types of TENS are employed in the treatment of pain. The conventional type utilizes highfrequency stimulation that induces paresthesia in the painful area during treatment (Ah-bers). Whenever conventional TENS does not give satisfactory pain relief, low-frequency TENS producing visible muscle contractions during treatment (motor Aa- bers) is recommended (6,7). Several clinical studies on the treatment of generalized itch with high-frequency TENS have been carried out. Fjellner and Ha germark (8) employed TENS that induced biphasic asymmetric pulses with an amplitude of 4060 V, a duration of 0.120.2 msec, and a frequency of 6080 Hz, the plates being fastened on each side of the spinal column at the level of the scapula. Transcutaneous nerve stimulation was applied for 530 min at a time, inducing relief of itch after 5 min of treatment, without any local eects on the skin. The relief continued for 24 hr after the discontinuation of TENS. Of nine patients with generalized pruritus (mycosis fungoides, atopic dermatitis, and prurigo nodularis) who used TENS daily for 27 weeks, ve reported a local partial eect and three a general eect at the end of the treatment. However, only one patient wanted to continue the TENS therapy. More positive eects with the use of high-frequency TENS have been reported for a few patients with generalized pruritus (9,10). The mechanism at the basis of TENS is the central inhibition of the nerve conduction in the spinal cord. The inhibition occurs in the segments of the spinal cord involved, because it can be elicited in a spinal cord that has been transected (11). Thus, alleviating generalized itch by local or segmental nerve stimulation is probably no more likely to succeed than opening all doors in a house by simply unlocking the front door. In two studies of experimental itch induced by intradermal histamine, one of the TENS electrodes (cathode) was placed on the area of the skin to be tested. Low-frequency TENS (2 Hz) was found to induce a signicant reduction in itch, whereas neither high-frequency TENS (100 Hz) nor vibration (100 Hz) had any signicant eect (12,13). Low-frequency TENS activates Ay- and C-bers with increasing amplitude, which may be painful (14).

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When stimulation of the C-bers occurs, part of the impulses are conducted in retrograde direction through an axon reex, resulting in are and neurogenic inammation. Sensory nerves release neuropeptides, such as substance P (SP) and calcitonin gene-related peptide (CGRP), preferentially in response to low-frequency (5 Hz) rather than high-frequency (15 Hz) antidromic electrical stimulation (15). Many of these transmitters act as inammatory mediators. High concentrations of SP, CGRP, vasoactive intestinal peptide (VIP), neuropeptide Y, and somatostatin have been found in spontaneous blisters occurring in a variety of pathogenetically diering itchy inammatory skin diseases (16). A new technique, cutaneous eld stimulation (CFS), which activates unmyelinated C-bers electrically, has been developed by Nilsson et al. for treating localized itch (13). The CFS device employed consists of a cathode, a exible rubber electrode-plate (8 8 cm or 8 16 cm), an anode, a at reference electrode (5 5 cm) placed close to the treated area, and a stimulator (a 9-V battery) (13) (Fig. 1). The CFS electrode plate is covered by 16 needle-like electrodes (0.3 mm in diameter) surrounded by a stopdevice protruding out 2 mm from the plate. The plate is pressed gently onto the area of the skin to be treated, the electrode tips being positioned in the epidermis and in the supercial layer of the dermis. A constant current having monophasic square pulses, a duration of 1 msec, and a frequency of 4 Hz is delivered to each electrode (13). The pulse amplitude can be adjusted so that the intensity of the stimulus is either increased or decreased. Cutaneous eld stimulation is used for 2030 min at a time. Initially, it induces a prickling and a slightly burning pain sensation. These sensations indicate the activation of nociceptive Ay- and C-bers, respectively (17). After a single treatment with CFS there is a are reaction around each electrode, indicating axon reex and a release of neuropeptides. If histamine is applied by iontophoresis to skin treated with CFS, itch is abolished (13). The inhibition of itch is complete for up to 2 hr after treatment, then declining successively. Eight hours after treatment the itch is perceived in the normal way, indicating a recovery of the C-bers. After treatment by CFS, the thresholds for the detection of warming and cooling of the skin show an increase (18), indicating that the C-bers that respond to CFS treatment are thermosensitive, which is in agreement with the nding that some of the heat-responsive C-bers mediate itch (2). The experiments just described indicate that the mechanism behind CFS is mainly peripheral. Suppression of the itch sensation probably reects the fact that the nerve bers that are depleted of their transmitters become refractory. Repeated treatment by CFS depletes the nerve transmitters, interrupting itch and abolishing the vascular eects around the electrodes. Central mechanisms may also operate in CFS. Low-frequency electrical

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Figure 1 A cutaneous eld stimulation device consisting of a exible electrode rubber plate (8 8 cm) to be fastened on the itchy area or the area to be tested, a at reference electrode (5 5 cm) to be placed on the same part of the body, and a stimulator (a 9-V battery). The pulse amplitude is adjustable from 0 to 10 A for controlling the intensity of the stimulus.

stimulation of Ay-bers can produce a lasting depression of nociceptive Cber transmission in vivo (6,7). What clinical eects does CFS have? The eects of a single CFS treatment for 25 min were registered in 27 patients with chronic itch, peak inhibitory eect being noted between 1 and 5 hr postconditioning (19). In a more recent study, 16 patients with localized itch (notalgia paresthetica or brachioradial pruritus) and 3 patients with generalized itch were treated by CFS once daily 30 min at a time for 5 weeks (20). In order to visualize the cutaneous innervation, skin biopsy specimens were collected before and after treatment and were immunostained for the general nerve protein marker PGP 9.5. Localized itch was reduced in mean values (from 78% before treatment to 42% by the end of the fth week) on a visual analog scale. By the end of treatment, the number of protein gene product 9.5-immunoreactive

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nerve bers in the epidermis was reduced by 40% as compared with baseline values (20). Several patients reported a relapse, but none of the patients complained of any worsening of symptoms. Topical treatment by capsaicin, the pungent agent of hot pepper, reduces pain. Such eect has been reported to be paralleled by a loss of epidermal nerve bers (21). After several weeks the nerve function recovers, as measured by axon reex are (22). Thus there are similarities in the pharmacological action of capsaicin and the physical action of CFS, both of them depleting the sensory nerve bers of their mediators (23). However, capsaicin aects immunological reactions in the skin as well. Administered systemically to guinea pigs or mice, it enhances allergic reactions of a delayed type (24,25). Topical administration of capsaicin for 3 days also enhances contact dermatitis in human subjects (26). Of interest here is the question of whether CFS has any eect on inammation of the skin. In a recent study, experimental allergic contact dermatitis, tuberculin reactions, and irritative contact dermatitis remained unchanged when treated by CFS (27). Cutaneous eld stimulation has its eect where sensory nerve bers are located and mainly aects SP and CGRP within the epidermis and at the dermalepidermal junction. There is evidence that SP enhances delayed immunologic reactions whereas CGRP inhibits such reactions (28,29). A possible explanation for this could be that the eects of the two neuropeptides tend to balance out. Capsaicin in an ethanol solution that can diuse and penetrate deeply into the dermal layer inuences not only the sensory nerve bers but also the autonomic nerve bers around the blood vessels. Neuropeptides such as VIP and somatostatin, which are known to inhibit immunologic reactions (30), will be released and eventually depleted. In conclusion, high-frequency TENS, operating at the segmental level in the spinal cord, has no signicant eect on generalized itch. Local treatment by low-frequency TENS, which activates the C-bers, inhibits experimental itch. Cutaneous eld stimulation has mainly peripheral eects on the C-bers and is useful in treating neuropathic itch. Preliminary data indicate that it has no adverse eects on experimental inammation, which suggests that it can be used in treating localized dermatopathic itch as well.

REFERENCES
1. Bonica JJ. Anatomic and physiologic basis of pain. In: Bonica JJ, Loeser JD, Chapman CR, Fordyce WE, eds. The Management of Pain, 2d. Philadelphia, London: Lea & Febiger, 1990:28.

340 2. 3.

Wallengren Schmelz M, Schmid R, Bickel A, et al. Specic C receptors for itch in human skin. J Neurosci 1997; 17:8003. Melzack R, Wall PD. Pain mechanisms: a new theory. A gate control system modulates sensory input from the skin before it evokes pain perception and response. Science 1965; 150:971. Wall PD, Sweet WH. Temporary abolition of pain in man. Science 1967; 155: 108. Long DM. Fifteen years of transcutaneous electrical stimulation for pain control. Strereotact Funct Neurosurg 1991; 56:2. Sjo lund BH. Peripheral nerve stimulation suppression of C-ber-evoked exion reex in rats: Part 1. Parameters of continuous stimulation. J Neurosurg 1985; 63:612. Sjo lund BH. Peripheral nerve stimulation suppression of C-ber-evoked exion reex in rats: Part 1. Parameters of low-rate train stimulation of skin and muscle aerent nerves. J Neurosurg 1988; 68:279. . Transcutaneous nerve stimulation and itching. Acta Fjellner B, Ha gemark O Derm Venereol (Stockholm) 1978; 58:131. Monk BE. Transcutaneous electronic nerve stimulation in the treatment of generalized pruritus. Clin Exp Dermatol 1993; 18:67. Bjorna H, Kaada B. Successful treatment of itching and atopic eczema by transcutaneous nerve stimulation. Acupunct Electrother Res 1987; 12:101. Willis WD. Modulation of primate spinothalamic tract discharges. In: Kruger L, Libeskind JC, eds. Advances in Pain Research and Therapy. Vol 6. New York: Raven Press, 1984:217. Ekblom A, Hansson P, Fjellner B. The inuence of extrasegmental mechanical vibratory stimulation and transcutaneous electrical nerve stimulation on histamine-induced itch. Acta Physiol Scand 1985; 125:541. Nilsson HJ, Levinsson A, Schouenborg J. Cutaneous eld stimulation (CFS) a new powerful method to combat itch. Pain 1997; 71:49. Westerman RA, Widdop RE, Hogan C, Zimmet P. Non-invasive tests of neurovascular function: reduced responses in diabetes mellitus. Neurosci Lett 1987; 81:177. Khalil Z, Merhi M, Livett BG. Dierential involvement of conotoxin-sensitive mechanisms in neurogenic vasodilatation responses. Eects of age. J Gerontol A Biol Sci Med Sci 2001; 56:356. Wallengren J, Ekman R, Mo ller H. Substance P and vasoactive intestinal peptide in bullous and inammatory skin disease. Acta Derm Venereol (Stockholm) 1986; 66:23. Bromm B, Treede RD. Human cerebral potentials evoked by CO2 laser stimuli causing pain. Exp Brain Res 1987; 67:10013. Nilsson HJ, Schouenborg J. Dierential inhibitory eect on human nociceptive skin senses induced by local stimulation of thin cutaneous bers. Pain 1999; 80:103. Nilsson HJ. Itch and pain inhibitory mechanisms in humans. Evidence for a dierential control of nociceptive senses. Thesis, Lund University, 1999.

4. 5. 6.

7.

8. 9. 10. 11.

12.

13. 14.

15.

16.

17. 18.

19.

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20. Wallengren J, Sundler F. Cutaneous eld stimulation (CFS) in treatment of severe localized itch. Arch Dermatol 2001; 137:1323. 21. Nolano M, Simone DA, Wendelschafer-Crabb G, Johnson T, Hazen E, Kennedy WR. Topical capsaicin in humans: parallel loss of epidermal nerve bers and pain sensation. Pain 1999; 81:135. kanson R. Eects of capsaicin, bradykinin and prostaglandins 22. Wallengren J, Ha in the human skin. Br J Derm 1992; 126:111. 23. Fitzgerald M. Capsaicin and sensory neurons: a review. Pain 1983; 15:109. 24. Girolomoni G, Tigelaar RE. Capsaicin-sensitive primary sensory neurons are potent modulators of murine delayed-type hypersensitivity reaction. J Immunol 1990; 145:1105. 25. Wallengren J, Ekman R, Mo ller H. Capsaicin enhances allergic contact dermatitis in guinea pig. Contact Dermatitis 1991; 24:30. 26. Wallengren J, Mo ller H. The eect of capsaicin on some experimental inammations in human skin. Acta Derm Venereol (Stockholm) 1986; 66:375. 27. Wallengren J. Cutaneous eld stimulation of sensory nerve bers reduces itch without aecting delayed cutaneous reactions. Allergy 2002; 57(12):11951199. 28. Wallengren J. Substance P antagonist inhibits immediate and delayed type cutaneous hypersensitivity reactions. Br J Dermatol 1991; 124:324. 29. Torii H, Hosoi J, Asahina A, Granstein RD. Calcitonin gene-related peptide and Langerhans cell function. J Invest Dermatol Symp Proc 1997; 1:82. 30. Lundeberg L, Mutt V, Nordlind K. Inhibitory eect of vasoactive intestinal peptide on the challenge phase of allergic contact dermatitis in humans. Acta Derm Venereol (Stockholm) 1999; 79:178.

33
Psychosomatic Aspects of Pruritus
rg Kupfer Uwe Gieler, Volker Niemeier, and Jo
Justus-Liebig University, Giessen, Germany

Burkhard Brosig
University Hospital of Giessen, Giessen, Germany

Psychogenic and psychosocial factors play an important role in the etiology of pruritus. In 1967 Musaph postulated the term psychogenic pruritus and described 10 patients in psychological treatment. He hypothesized that psychogenic itch is related to emotional conicts, and inability to manage aggressive tendencies, especially anxiety, exaggerated cleanliness and fear of disorder (1). Although this hypothesis has not been proved, the psychogenic etiology of pruritus was described in case studies in which life-events correlated with the onset of itching (2), and has been useful in psychotherapy of patients with psychogenic itch.

I.

PSYCHOLOGICAL STUDIES

Psychological correlations with itching have rarely been investigated. Only a few studies have discussed the possibility of mental induction of itching. A purely mental induction of itching was suggested by Rechenberger (3). Robinson et al. (4) reported a psychogenic epidemic disease with itching
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and skin rash associated with stress at a primary school. Sim and Echt (5) described the eruption of itching skin lesions in a group of workers, whereby it could not be excluded in this case report that pruritus was caused in some of the workers by contact with brous glass bers. In addition, a telepathic puritus was described (6). We have recently performed a study, with the cooperation of a public television company which prepared a scientic program on itching, on the psychologic aspects of itch (7). Interested volunteers were invited to participate in a public lecture entitled Itching whats behind it?. The aim of the lecturers was to initially present an itchinducing lecture to the still uninformed audience, followed by a neutral verbal and visual stimulation to induce relaxation. Accordingly, the rst part included slides that induce itching (mites, eas, scratch marks on the skin, allergic reactions, etc.), while the second part showed slides that induce relaxation and a sense of well-being. At the same time the listeners tactile reactions were recorded by television cameras which were placed all over the lecture hall, to allow rating of the scratch impulses. The results showed that itching measured by self-rating scales (n=24) was induced by the itchinducing verbal and visual intervention. The frequency of scratching recorded by the television cameras was evaluated independently by two raters. The t-

Figure 1

The psychosomatic network of pruritus.

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test conrmed a signicant mean dierence between the two states. The results of the study conrmed the previous assumption that itching can be induced by psychic factors. In an experimental study using a histamine prick test, Hermans and Scholz (8) investigated the inuence of cognitive evaluation patterns on the intensity of itching and wheal reaction. Volunteers who had been instructed to think in relative terms reacted less intensely to the prick test than those directed toward a dramatizing cognition. In the study of Sheehan-Dare et al. (9), 34 patients with idiopathic generalized pruritus were investigated in comparison with unselected general dermatological outpatients. More patients with generalized pruritusnearly one thirdhad signicantly depressive symptoms. For further discussion and new studies on psychologic factors and itch, see Chapter 34. The possible psychosomatic network in pruritus is shown in Figure 1.

II.

PRURITUS AS A SOMATOFORM DISORDER

Somatoform disorders in dermatologic patients represent a common and manifold group of disorders mentioned in the DSM IV, which have not drawn signicant attention in research. A classication of somatoform disorders and important dierential diagnoses are necessary in dealing with patients of socalled pruritus sine materia. This is a somatoform itch which cannot be explained by physical disease. A study from Stangier and Gieler (10) in a university outpatient department showed that 6.5% of the dermatological outpatients had somatoform pruritus. The therapeutic concepts of somatoform disorders will probably help to manage patients with psychogenic pruritus. A psychosomatic basic diagnosis should be made in every case of chronic pruritus. The comorbidity of generalized pruritus with special regard to depression and anxiety disorders has to be recognized and treated (9).

III.

LOCALIZED FORMS OF PSYCHOGENIC ITCH

There are several localized forms of itch without somatic ndings such as the itchy scalp (11), pruritus ani, and pruritus vulvae et scroti. Pruritus ani was investigated psychologically by Laurent et al. (12) who pointed out that depression is a comorbid factor in patients with this localized pruritus. Pruritus vulvae and scroti were also described as psychosomatic and have been associated with sexual frustration and may arise from neurotic sources (13).

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IV.

PSYCHOTHERAPY OF PRURITUS

There are a few studies on psychotherapy for treatment of itch and scratching in dermatological patients. Insight-oriented psychotherapy or psychoanalysis is eective in patients with generalized or localized pruritus, or obsessive compulsive syndromes, if the criteria for these modalities are otherwise met. Younger patients, those for whom the quality of life is signicantly impaired, or those who do not respond readily to dermatological treatment should therefore be oered to under go such treatment (13). Behavioral therapy strategys aim was to feed back the scratching behavior to the patients. This technique could use a vibration-transducer attached to the bed (14). New cognitive behavior therapy to prevent recurrent itching and scratching cycles has been successful in atopic eczema patients (15). Bo ddecker and Bo ddecker worked out a behavioral-therapeutic approach in itching (16). In a presentation of the dynamics of the scratch reaction, they revealed the unconscious aspect of this process. Diuse distress and not the visual perception of a scratch site precedes the scratching reaction typical of atopic eczema. At the start of the scratching phase, the need to scratch increases, only to decrease rapidly again when pain and bleeding have begun. The curve of circadian scratching rate recorded on a large patient group is a mirror image of the daily activity curve. This makes it apparent that wakefulness and nonwakefulness exert a control function and are one criterion of scratching. The vicious cycle of scratching begins when a frustrating, fear-eliciting stimulus (S) meets an organism (O) with a characteristic behavioral decit (decit in recognition, permissiveness, and in dealing with its own emotions). These patients tend to reject a psychological interpretation of the scratching symptoms. The authors attribute this attitude to the fact that the organ skin in our culture is the one which most readily permits expression of emotional distress, without being unmasked by the patient or his environment (16). The tension reduction (C1) appears more spontaneously under reaction (R) in the form of scratching when S meets O than the negative consequences (C2) such as pain and exacerbation of the skin condition. The therapy concept of Bo ddecker and Bo ddecker is based on positive reinforcement of not scratching, punishment preceding reward (tension reduction), for example, by documenting before scratching and scratching with withdrawal of reinforcement (e.g., wristwatches with alarm devices). For the alteration of the itching perception there are several approaches. Schubert (17) transformed some suggestion techniques of hypnosis studies into an imagination training, and Luthe and Schultz (18) used imagination

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techniques (imagination of coolness), which were also used by Gray and Lawlis (19) and Horne et al. (20). A therapeutic approach which involves prolonged hypnosis for the treatment of itch which included the analysts suggestive inuence has been reported to be eective in reducing the course of itch (2124). Moreover, Hajek et al. (25) reported long-lasting positive eects in raising the itching sensory threshold. The results suggest that the imaginative methods can be eective therapy elements because of the relationship between perceptions, (auto-) suggestive reaction expectations, and physiological skin functions in skin diseases. Bar and Kuypers (26) report their work with children whose scratching behavior in atopic eczema was simply ignored, while abstaining from scratching was rewarded. The reduction of itchingscratching was maintained during the 18 months of follow-up. The technique based on a better perception of an automated procedure and the learning of alternative behavior incompatible with scratching (pinching, muscle tension) has proved a success (27,28). In a single case study, Rucklidge and Saunders (29) reported that hypnosis leads to a remarkably reduced itching from pre- to post-treatment and after the 4-month follow-up. A systemic family approach in a severe case of pruritus was described by Lantz (30). Psychobiologic treatments have been reported to be an eective treatment in several case reports (31,32). Koblenzer (13) summarized the possibilities for a psychobiological way of treatment. The new SSRIs seem to have a signicant role in the treatment of pruritus related to depression, anxiety, and obsessivecompulsive disorders; however, currently there are no published studies evaluating the eect of these new treatments.

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