Академический Документы
Профессиональный Документы
Культура Документы
Effective pain management presents a significant challenge for physicians, other healthcare
professionals and their patients. Pain is one of the most common reasons for patients to seek
medical attention and one of the most prevalent medical complaints in the US; 1,2 9 out of 10
Americans aged 18 or older suffer pain at least once a month, and 42% experience it every day.3
In America, more than 116 million Americans are burdened with chronic pain alone.4
Consequently, physicians and other practitioners need education to assist in developing the skills
needed to evaluate and manage patients with pain.
Educational Objectives
Compare and contrast pharmacologic and nonpharmacologic options for the management
of pain.
Review recommended approaches for risk stratification and appropriate monitoring of
patients who might receive opioid analgesics.
Recognize and manage the side effects of nonopioid and opioid analgesics.
Utilize a rational approach to the selection, administration, and titration of analgesics used
in pain management.
Copyright 2013 American Medical Association. All rights
reserved. The contents of this CME program may not be
reproduced in any form without written permission from the AMA.
This CME program does not define a standard of care, nor is it
intended to dictate an exclusive course of management.
Standards of medical care are determined on the basis of all the
facts and circumstances involved in an individual case and are
subject to change as scientific knowledge and technology advance
and patterns evolve.
The products appearing in this continuing medical education
program are given for information purposes only. Their inclusion
does not imply AMA endorsement, nor does omission of any
product indicate AMA disapproval.
The American Medical Association designates this enduring
material for a maximum of 2 AMA PRA Category 1 Credit.
Physicians should claim only the credit commensurate with the
extent of their participation in the activity.
The American Medical Association is accredited by the
Accreditation Council for Continuing Medical Education to
provide continuing medical education for physicians.
claim credit.
experiencing pain.
submit button
5. The CME certificate will then appear and can be printed
Financial Support
Disclosure Policy
In order to assure the highest quality of certified CME programming, and to comply with the
ACCME Standards for Commercial Support, the AMA requires that all faculty, planning committee
and AMA CME Program Committee members disclose relevant financial relationships with any
commercial or proprietary entity producing health care goods or services relevant to the content
being planned or presented. The following disclosures are provided:
CME Advisory Board
Dr. Argoff:
Dr. Berek:
Dr. Ferrell:
Dr. Gordin:
Dr. Grabois:
Dr. Knox :
Dr. McCarberg
Dr. Lambing:
Dr. Lipman:
Dr. Portenoy:
Dr. Savage:
Dr. Thompson:
Consultant, Speakers Bureau, Grant support: Endo, Forest, Lilly, Neurogenex, Pfizer,
Consultant: Insys Pharmaceuticals, Gruenthal Pharmaceuticals, King, Sanofi-Aventis,
Nuvo Research, Jazz, Shinogi, Iroko, Zogeniz,
Consultant, Speakers Bureau: Ameritox, Covidien, Depomed, Millenium, Quest
Diagnostics
Speakers Bureau: Horizon
Nothing relevant to disclose
Nothing relevant to disclose
Nothing relevant to disclose
Consultant: Pfizer
Nothing relevant to disclose
Consultant: Endo, Insys Pharmaceuticals, Neurogenex, Pfizer, Purdue Pharma, QRx
Pharma, Salix, Sucampo, Teva
Nothing relevant to disclose
Nothing relevant to disclose
Grant support: Boston Scientific, Covidien Mallinckrodt, Endo, Medtronic, ProStrakan,
Purdue Pharma, Salix, St. Jude
Speakers Bureau: Grupo Ferrer
Nothing relevant to disclose
Nothing relevant to disclose
AMA Staff
Dr. Dickinson: Nothing relevant to disclose
Ms. LePard:
Nothing relevant to disclose
Ms. Williams:
Nothing relevant to disclose
AMA CME Program Committee members have no relevant relationships to disclose
Introduction
The goals of pain management vary from patient to patient. When pain is acute, the overriding
goal is to reduce pain intensity as quickly as possible, often in association with amelioration of its
underlying cause. In those with persistent pain related to a serious medical illness, such as
cancer, the goal of comfort may become linked to other concerns, such as the relief of other
symptoms and management of diverse problems undermining physical, psychosocial and
spiritual well being. In common types of persistent musculoskeletal pain, the goal of functional
restoration may be given equal importance to the goal of pain management.
Although the importance of concurrent goalsidentifying and potentially treating the underlying
cause of the pain, and providing therapies to address related and comorbid problemsis clear,
these imperatives should not distract attention from the importance of pain control. The
effectiveness of any strategy usually is enhanced if undertaken when pain is at a tolerable level.
Analgesics Strategies
Effective pain management, particularly in the context of persistent pain, requires the skillful
application of one or more specific therapies, implemented safely and adjusted based on
repeated outcome assessment over time. In some cases, a single modality, such as an analgesic
drug or an injection is appropriate. In other cases, particularly those characterized by persistent
pain associated with a high level of disability or a poor response to analgesic trials in the past, the
best approach is a multimodality strategy (see Module 7). A subset of patients who are good
candidates for a multimodality strategy presumably would be optimally managed through referral
to a interdisciplinary team of pain specialists.
Analgesic treatments can be broadly grouped into seven categories. Clinicians should carefully
consider the broad range of options in these categories when developing the plan of care for a
patient with pain. (Table: Categories of Analgesic Strategies)
Rehabilitative
Psychological
Neurostimulation
Interventional
Surgical
Complementary and
Alternative
Examples
Nonopioid drugs
Opioid drugs
Adjuvant analgesics
Physical and occupational therapy
Modalities (heat, cold, ultrasound, electrical stimulation)
Cognitive-behavioral therapy
Specific treatments (e.g., biofeedback)
Other types of psychotherapy
Trancutaneous electrical nerve stimulation, peripheral
nerve stimulation, spinal cord stimulation, transcranial
direct current or magnetic stimulation
Injection therapy (e.g., spinal injections, or trigger point or
joint injections)
Neural blockade (e.g., stellate ganglion block and other
regional anesthesia techniques, neurolytic procedures)
Implant therapies (spinal cord stimulator, peripheral nerve
stimulation, neuraxial analgesia via pump)
Neurectomy, nerve decompression, cordotomy
Acupuncture, massage, chiropractic, nutraceuticals/
botanicals, energy therapies, non-Western systems
(traditional Chinese medicine)
Nonpharmacologic Strategies
Although systemic pharmacotherapy is the mainstay approach in the treatment of acute and
many types of persistent pain, optimal pain management includes diverse nonpharmacologic
therapies. These include an array of non-invasive strategies and a number of invasive
approaches. Many patients also appear to benefit from complementary and alternative medicine
(CAM) approaches, and some of the latter therapies, such as acupuncture and massage, have
sufficient evidence of safety and potential effectiveness to be recommended by clinicians.
Interventional Approaches
The invasive analgesic therapies are known generically as interventional approaches. 1,2 These
include varied injection therapies, many types of neural blockade, and implant therapies. Patients
suffering from focal or regional pain that is likely to be relieved with injection and patients failing to
achieve adequate analgesia without intolerable adverse effects from acceptable non-invasive
therapies represent the major indications for referral for interventional therapies.
Injection Therapies
The injection therapies comprise a diverse array of approaches that differ in technical complexity
and objectives. The simplest approachestrigger point injections into tender muscles or their
connections and joint injectionsusually are within the purview of the primary care physician.
Other injections target specific structures, such as the spinal epidural space, the small joints that
connect vertebral bodies or scars that may entrap neuromas. In some cases, the technical skills
required to inject these sites is relatively minor and the primary care physician can provide the
treatment. In other cases, referral to an interventionally-trained pain specialist is necessary. For
further discussion on interventional approaches see Module 12.
Cognitive-Behavioral Therapy and Other Psychological Approaches
Psychological traits or experiences, environmental factors, and varied types of psychopathology
affect an individuals response to pain and suffering. Psychological approaches almost always
should be considered when developing a plan of care for chronic pain. Many types of
psychoeducational and psychotherapeutic strategies may be used to provide support, enhance
coping and adaptation, reduce catastrophization, encourage the appropriate use of health care,
and help to ameliorate pain and sustain functioning. The most common types used in practice are
subsumed under the broad framework of cognitive-behavioral therapy (CBT). CBT employs a
combination of cognitive therapy (composed primarily of education) in conjunction with behavioral
therapy. The integration of these two approaches is aimed at reducing or extinguishing the
influence of the factors that reinforce or maintain patients maladaptive behaviors, beliefs, and
patterns of thought. Included are strategies that can be taught to the patient and may lessen pain
intensity, improve coping, increase function and reduce overall disability. These strategies include
education about pain and its impact; cognitive strategies to reduce catastrophization and
helplessness; training in cognitive therapies such as biofeedback, relaxation and imagery; and
specific behavioral interventions such as graduated exercise, pacing and time management and
sleep hygiene training.
A CBT strategy at its most comprehensive requires a multidisciplinary approach performed by
experts.3 Certain aspects of the strategy, such as training in biofeedback, can be obtained
separately by referral to specific practitioners. Others, like education about pain and disability and
use of an activity diary to encourage exercise, can be performed by the individual physician.4
CBT is most appropriate for patients who have pain-associated disability or distress, and express
a willingness to work on psychological components of care. Studies demonstrate that the addition
of CBT can reduce pain and disability for certain chronic pain conditions, especially low back pain
and fibromyalgia.5-8 These approaches appear to be less effective in patients suffering from
persistent neuropathic pain.9
6
Other types of specific psychological modalities should be similarly considered when patients
have pain associated with a premorbid or comorbid psychiatric disorder. This is particularly
important if the pain has been persistent, or may be transitioning from an acute phase to a
chronic phase. Among the most important premorbid disorders to recognize are personality
disorders, an affective disorder such as generalized anxiety or recurrent depression, or a
substance use disorder including significant drug abuse or the possibility of alcoholism or another
addiction. A comprehensive evaluation of the patient that identifies these problems may allow
early referral for diagnosis and primary treatment of the psychiatric problem concurrent with
therapy for pain. Similarly, patients who have pain and reveal psychological or emotional
disturbances that may reflect comorbid psychiatric pathology, such as a new affective disorder or
an emerging substance use disorder, should be considered for referral to a mental health
professional. One systematic review found that psychological therapies can help people with
chronic pain reduce negative mood (depression and anxiety), disability, and in some cases
pain, but guidance is still required on the best content, duration, intensity, and format of
treatment.10
Rehabilitation and Physical Medicine Approaches
Rehabilitation involves the restoration of lost function and includes physical rehabilitation as well
as occupational, vocational, social, and other forms of rehabilitation. Specific treatment usually
considered under the purview of physical medicine or rehabilitation may be prescribed as part of
a CBT program, or separately. Some patients with acute pains, particularly musculoskeletal pain,
should be given specific instructions for exercise, or referral to a physical therapist, as a first-line
approach to pain therapy with functional restoration. For example, most patients with acute low
back pain should be told to rest for no more than a few days, and then begin gentle exercise,
which has been shown to be as effective as other therapies in resolving the acute pain.11 In
populations with persistent pain, these strategies are especially appropriate when pain is not
related to a serious medical disorder and is associated with impairment in physical functioning
and deconditioning, or more global disability.
Although physicians commonly recommend exercises to patients, a significant need for
conditioning or restoration of function should suggest referral to a trained professional. In some
cases, the best approach is referral to a physician who specializes in physical medicine and
rehabilitation, who can provide a detailed recommendation to a physical therapist or occupational
therapist, a recommendation to a rehabilitation program, or other therapies. In other cases, direct
referral to a physical therapist may be appropriate, particularly if the targets of therapeutic
exercise appear obvious. Therapeutic exercise may focus on general conditioning, gait training,
stretching, specific exercises involving the painful part of the body, specific spinal stabilization
exercises and training, and attention to ergonomics and body mechanics.
In addition to physical therapy and occupational therapy, the category of rehabilitative strategies
for pain usually includes more comprehensive programs and specific modalities. Programs that
may be available through hospitals, free-standing facilities, government services or corporate
entities include vocational assessment and training, job retraining programs, work hardening
programs, and rehabilitation-oriented pain management programs.
In contrast to the broader, function-oriented interventions, physical modalities are used
specifically as an adjunct to other therapies to lessen pain. These modalities include heat, cold,
electricity, vibration, and ultrasound. In transcutaneous electrical nerve stimulation (TENS), a well
known neurostimulatiion therapy, cutaneous stimulation is delivered through a contact pad by an
electrical pulse generator. TENS was developed based on the gate control theory of pain, which
hypothesized that a pain modulating system in the dorsal horn of the spinal cord can be activated
by stimulation of large-diameter non-nociceptive primary afferent neurons (so-called A beta
fibers) and thereby inhibit pain transmission from the periphery to the brain. This theory has
morphed into a broader construct with the identification of dozens of endogenous pain modulating
systems, which function at every level in the periphery and CNS and have numerous and
complex mechanisms. Mechanisms activated by A beta stimulation have been characterized and
provide a rationale for TENS and other neurostimulation therapies. Although there have been
7
many controlled studies of TENS, systematic analyses have concluded that evidence is
insufficient to permit firm characterizations about its effectiveness for the treatment of either acute
or chronic pain.12,13 Nonetheless, the safety of the approach, combined with favorable anecdotal
experiences, leads many experts to continue recommending a trial of TENS in the clinical setting
for patients with focal or regional chronic pain.
Pharmacologic Strategies
Analgesic drug therapy involves the administration of nonopioid and opioid analgesics, and a
diverse group of drugs often called the adjuvant analgesics. The latter drugs were originally
conceptualized as a group of agents that have indications other than pain but may be analgesic in
specific circumstances. Historically, they were considered to be useful adjuvants when combined
with other analgesics. During the past decades, however, research has characterized the
analgesic potential of many drugs and led to the use of some, such as selected antidepressants
and antiepileptic drugs, as primary therapies for pain. Accordingly, the term adjuvant analgesic
is actually a misnomer applied generically to a large and diverse group of drugs that vary in
evidence and utility as analgesics.
There is no one systematic approach to the use of drugs for pain control. Many disease-specific
or syndrome-specific guidelines have been published, some of which are based on good
evidence and some of which have become widely accepted. For example, in 1986, the World
Health Organization (WHO) developed a 3-step conceptual model (Figure: World Health
Organization Analgesic Ladder) to guide the management of cancer pain, which suggests that
the overall severity of the pain should be used to guide the selection of an analgesic (e.g.,
NSAID, so-called weak opioid, and so-called strong opioid for mild, moderate and severe pain,
respectively).14 This broad recommendation has been useful over the years as a tool for
developing policies and education, and for structuring more specific guidelines for cancer pain
management.15-17 As a guideline, it is generally accepted as applying to patients with active
cancer and patients with advanced illnesses of other types, such HIV/AIDS. It should not be
applied to all chronic pain. The current view and application of the WHO ladder to treating cancer
pain has been modified in recent years, at least in the Unites States, with a better understanding
of the disadvantages that can accompany the clinical use of codeine, and the lack of
pharmacologic basis for classifying the combination of pure opioid agonists such as hydrocodone
pain. Prescribed alone, these agents can relieve many types of mild to moderate pain.
Alternatively, for moderate to severe pain, they can be used in combination with opioid drugs to
enhance pain relief. These agents differ from opioid analgesics in several ways: (1) they have a
ceiling effect to analgesia; (2) they do not produce tolerance or physical dependence and are not
associated with abuse or addiction; (3) they are antipyretic and all except acetaminophen are
anti-inflammatory; and (4) their primary mechanism of action is inhibition of prostaglandin
formation.23
marketed in the U.S. is celecoxib (Celebrex). The U.S. Food and Drug Administration requires a
boxed warning for all NSAIDs reminding clinicians of both cardiovascular and gastrointestinal risk.
Acetaminophen inhibits COX in a cell-specific manner, including the central nervous system. It is
relatively inactive as an anti-inflammatory agent, but is an effective antipyretic and analgesic
agent. In contrast to the NSAIDs, acetaminophen does not cause gastric ulceration or inhibit
platelet aggregation. Acetaminophen does not act as a competitive COX inhibitor, but rather
appears to interfere with the oxidative state of COX, an action that itself is reversed or prevented
by the tissue peroxide tone and which explains acetaminophens relative lack of antiinflammatory effects.25-27
usual maximum dose (3000 mg per day) and has asked manufacturers of prescription
combination products to limit the amount of acetaminophen to 325 mg. Patients should be
warned about the risk of unintentional overdose and told to avoid consumption of acetaminophen
from various sources unless they clearly understand the recommended limits from all sources.
Although it does not affect platelet activity, acetaminophen has been reported to potentiate anticoagulation when administered to patients taking warfarin.30 Chronic excessive use of
acetaminophen may impair renal function, although markedly less than NSAIDs.
Acetaminophen Considerations
Dosage limits have been considered to be 4000 mg/ day but the
FDA is now recommending 3,000 mg/day
Drug-Drug Interactions
As a class, most NSAIDs bind tightly to plasma proteins, and thus, drug-drug interactions can
occur when there is competition for binding sites. Because many patients with persistent pain are
elderly and receiving other drug therapy, the potential for drug interactions is significant. The most
common drug interactions of NSAIDs and other medications are listed in the Table, Potential
Drug Interactions with NSAID Analgesics.45 As described previously, recent studies also have
demonstrated an important pharmacodynamic action between specific NSAIDs, including
ibuprofen and naproxen, and aspirin.45 Specifically, these and probably other NSAIDs, have the
potential to block aspirins effect on platelets. As a result, there is a theoretical concern that
regular NSAID use may compromise the therapeutic effects of low-dose aspirin on the prevention
of cerebrovascular and heart disease. The extent of this risk, in terms of cardiovascular events, is
not known and drug-specific effects are uncertain.46 Because these data are limited, the proper
advice to give patients is not clear. The role of naproxen, for example, is especially uncertain, as
the data suggesting a lower risk of NSAID-induced cardiovascular toxicity would appear to conflict
with data suggesting inhibition of the aspirin protective effect. Accordingly, the most prudent
approach at this time would be to consider aspirin prophylaxis as another relative contraindication
to the long-term use of a NSAID, to perhaps avoid ibuprofen (the best studied and clearest
offender) if aspirin-treated patients would benefit from an NSAID, and encourage patients to take
their daily dose of aspirin several hours before their daily dose of the NSAID on the assumption
that the interaction would have the least impact with this timing.
Given these toxicities, the decision to undertake NSAID therapy must first consider the overall
risk: benefit ratio. The inclination to prescribe is generally higher with inflammatory pain or bone
pain. Concern about risk should be relatively high in patients with factors that predispose to GI
toxicity or cardiovascular toxicity, or who have renal insufficiency or a bleeding diathesis. If the
decision is made to use an NSAID, it is reasonable to consider a COX-2 selective drug in those
predisposed to GI toxicity, or to consider co-administration of a gastroprotective agent,
specifically a proton pump inhibitor or misoprostol. In those predisposed to atherothrombotic
cardiovascular toxicity, it may be reasonable to consider naproxen. In all cases, it is reasonable to
consider choosing NSAIDs with relatively good safety profiles, such as celecoxib, naproxen or
naproxen sodium, or ibuprofen, ketoprofen, diclofenac, etodolac, nabumetone, meloxicam, or one
of the nonacetylated salicylates, and to use the lowest effective dose for the shortest duration of
therapy.
Intravenous (Ofirmev)
Salicylates
aspirin (Bayer, Ecotrin, Genecote,
Norwich Aspirin)
choline magnesium trisalicylate*
(Tricosol, Trilisate)
diflunisal* ( Dolobid, Diflunisal
Tablets)
magnesium salicylate* (Doans
Caplets, Keygesic-10, Momentum,
Mobidin)
salsalate (Argesic SA, Disalcid,
Salflex, Salsitab, Mono Gesic)
sodium salicylate*
4000 mg
1000-1500 mg PO q 12 hrs
3000 mg
1500 mg
1000-1500 mg PO q 12 hrs
3000 mg
14
Other NSAIDs
sulindac* (Clinoril)
diclofenac potassium* (Cataflam)
etodolac* (Lodine, Etodolac ExtendedRelease)
fenoprofen calcium* (Nalfon)
ibuprofen* (Advil, Genpril, Haltran,
Ibu-Tab, IBU, Menadol, Motrin)
ibuprofen i.v. (Caldolor)
indomethacin* (Indocin)
ketoprofen* (Actron, Ketoprofen
Capsules, Orudis, Orudis KT, Oruvail)
ketorolac tromethamine*
(Toradol)
400 mg
200-600 mg PO q 6 hrs
400-800 mg PO q 6-8 hrs
2400 mg
3200 mg
3200 mg
150 mg
300 mg
150 mg
1200 mg
Modified from Institute for Clinical Improvements, October 2002. *Available by nonproprietary name.
Effect
Oral anticoagulants
with all NSAIDs
Antihypertensive agents
(beta-blockers, ACE inhibitors, vasodilators, diuretics) with several NSAIDs
Management
Options/Considerations
Monitor prothrombin time and for
occult blood in stool and urine
Avoid concurrent use of aspirin
Monitor lithium concentrations
carefully
Interactions less likely with aspirin
than naproxen sodium or
ibuprofen
Monitor blood pressure and
cardiac function
Monitor potassium concentration
Low-dose aspirin (e.g., 75 mg/day)
may not interact with ACE inhibitor
Monitor digoxin concentrations
Adjust dose as necessary
15
&
Source: American Hospital Formulary Service. Drug Information. American Society of HealthSystem Pharmacists. 2011. Bethesda, MD.
&
#
Reduced absorption of other NSAIDs also but not to the same extent
Probenecid reduces the renal clearance of certain other NSAIDs as well
16
Agonist drugs may be further divided into immediate-release short-acting preparations and longacting drugs, based on their time-action properties.13 For example, morphine is a short-acting
opioid and, as such, requires frequent dosing to maintain analgesia. Extended-release oral (e.g.,
morphine, oxycodone, oxymorphone, hydromorphone,) and transdermal (e.g., fentanyl,
buprenorphine) formulations, and oral opioids with long half-lives (e.g., methadone, levorphanol)
are alternatives to short-acting opioids. They typically are used when around-the-clock dosing is
required and in patients who are opioid tolerant.
Long-acting preparations are not indicated for the management of acute or intermittent pain, postoperative pain, or in patients who require opioid analgesics for only a short period of time. Some
extended release/long-acting opioids (ER/LA) are labeled for use only in opioid tolerant patients
and others are not recommended as initial opioid therapy. A few ER/LA products carry FDAapproved product labeling indicating they could be used in opioid naive patients starting with the
lowest dose recommended for initial dose titration (Table Long Acting/Extended Release
Opioids). However, most pain experts avoid initial use of these products in such patients.
17
Dosage Form
Strengths
12,25,50,75,100
mcg/hr
Dosing
Interval
3 days
5,10,20 mcg/hr
(10 and 20 mcg
dosage forms for
use in opioid
tolerant patients
only)
5 and 10 mg
tablets. Initial
dose in opioid
non-tolerant
patients 2.5 to 10
mg.
7 days
Morphine sulfate ER
Avinza
30,45,60,75,90,1
20 mg caps
24 hrs
Morphine
MS Contin
8-12 hrs
10,20,30,50,60,8
0,100, and 200
mg caps
12-24 hrs
15,30,60,100 mg
tabs
8-12 hrs
12-24 hrs
Oxycodone CR
Oxycontin
20,30,50,60,80,
100 mg caps
with amounts
of naltrexone
(0.8 to 4 mg)
10,15,20,30,40,
60,80 mg tabs
Oxymorphone ER
(Opana)
5,7.5,10,15,20,
30,40 mg tabs
12 hrs
Hydromorphone ER
(Exalgo)
8,12,16 mg tabs
24 hrs
Tapentadol ER
Nucynta
50,100,150,200,
and 250 mg
12 hrs
Fentanyl*
DuragesicTM
Buprenorphine
Butrans
Methadone
Embeda (MS ER
with naltrexone
8-12 hrs
12 hrs
tabs. Maximujm
daily dose = 500
mg
patients. Max daily dose = 500 mg. Lifethreatening serotonin syndrome can occur with
use of SSRIs, SNRIs, TCAs, MAOIs, and triptans.
No data on conversion from other opioids.
Each product has specific features that govern safe use including dosing instructions, titration
intervals, drug interactions or other concerns. The ER/LA opioids are now associated with anFDA
class-wide risk evaluation and mitigations strategies (REMS) program, which stresses voluntary
education about risks.
Medications
Codeine
Hydrocodone
Dihydrocodeine
Morphine
Hydromorphone
Fentanyl
Oxycodone
Oxymorphone
Levorphanol
Methadone
Meperidine
Notes
No clinically relevant ceiling effect to analgesia; as dose
is raised, analgesic effects increase until analgesia is
achieved or dose-limiting side effects supervene.
Codeine, hydrocodone, oxycodone combination
products are most widely prescribed and used for
short-term and long-term management of
moderate to severe pain. Codeine not preferred
because of variation in metabolic conversion to
active metabolite. Dosing of combination products
limited by safety of the nonopioid constituent.
Single entity formulations, particularly long-acting
versions, are mainstay of therapy for long-term
moderate to severe cancer pain.
Meperidine is generally not used due to potential effects
of toxic metabolites.
Methadone must be used with caution; only clinicians
who are knowledgeable about the risks posed by long
and variable half-life, unpredictable potency, respiratory
depression, and potential for QTc prolongation should
use this drug without guidance.
Agonist-antagonists
Partial agonists
Buprenorphine
Mixed agonist-antagonists
Butorphanol
Nalbuphine
Pentazocine
Importantly, long acting and extended-release products are the opioid analgesics that have been
most commonly implicated in unintentional overdoses, poisonings, and deaths in recent years.
Tramadol and tapentadol are centrally-acting analgesics that activate the mu opioid receptor and
also inhibit the neuronal reuptake of monoamines. Tramadol is unscheduled and considered for
19
has a far longer half-life than meperidine and can accumulate during repeated doses. The
concentration of the metabolite compared to the parent compound is relatively greater in the
elderly and in those with renal impairment, two populations that are at particular risk from
normeperidine toxicity. Meperidine is not favored by pain experts in the U.S. and it generally
should not be used for more than a few days.
The use of transmucosal immediate-release fentanyl products (TIRF) is limited to the
management of breakthrough pain in adults with cancer who are routinely taking other opioid pain
medicines around-the-clock for pain. Breakthrough pain is pain that comes on suddenly for short
periods of time and is not alleviated by a patients normal pain management plan. TIRF products
are intended for use only in patients who are opioid tolerant based on the concurrent regular use
of another opioid medication. The FDA definition of patients considered opioid tolerant are those
who are taking at least 60 mg oral morphine daily, 25 mcg transdermal fentanyl/hr, 30 mg oral
oxycodone or 8 mg oral oxymorphone daily, or an equianalgesic dose of another opioid for one
week. All TIRF products are subject to a class-wide REMS program (Table Transmucosal
Immediate Release Fentanyl Products).
Formulation
Abstral
Sublingual tablet
Actiq
(generics
available)
Fentora
Lazanda
Onsolis
21
Opioids are absorbed from the GI tract after oral or rectal administration. Orally-administered
opioids are subject to the first-pass metabolism in the liver; thus, larger doses would be required
compared to parenteral routes to produce the same analgesia. Most immediate-release oral
opioids require 20 to 40 minutes for onset of action, with peak analgesia reached within 45 to 60
minutes. Intravenous administration yields peak analgesia in a range of almost immediately to as
long as 20 minutes depending on the characteristics of the specific drug. Intramuscular
administration is not generally recommended due to its multiple disadvantages: painful
administration, unpredictable absorption, and complications involving tissue fibrosis and
abscesses. Subcutaneous (SC) administration, which has kinetics similar to the IM route, is not
associated with these problems and is preferred.
Risk Assessment
Opioid medications are the mainstay therapies for acute severe pain and moderate to severe
persistent pain due to active cancer or other advanced illnesses. During the last few decades,
growing numbers of patients with other types of persistent pain also have been offered long-term
opioid therapy (see Module 7). Increased access to these drugs has been paralleled by a large
increase in adverse consequences, including drug abuse, addiction, diversion and
overdose/mortality.
The statistics demonstrate a serious public health concern: During the past decade, the number
of patients seeking substance abuse treatment for the primary abuse of prescription pain relievers
has increased six-fold. Drug overdoses deaths in the United States also have increased steadily
and now exceed 38,000 annually.50 Prescription drugs are involved in more than 57% of such
deaths (~22,000) with opioids involved in 75% of the prescription drug overdose deaths reported
in 2010 or about 43% of drug overdose deaths overall.50
The estimated number of emergency department (ED) visits related to the nonmedical use of
opioid analgesics increased 79% from 201,280 in 2006 to 359,921 in 2010, according to the most
recent data from the Drug Abuse Warning Network (DAWN). 51 The greatest increases were seen
in buprenorphine, hydromorphone, and oxycodone-related ED visits. With respect to the broader
public health impact, the proportion of individuals 12 and older who are using prescription pain
relievers in a nonmedical fashion is substantially larger. 52 For each ED visit, 15 others use
prescription pain relievers nonmedically some time in their lifetime. These trends have continued
to increase for prescription opioids except for methadone which has shown a decrease in
unintentional overdoses since 2007.53
Among patients on chronic opioid therapy, the relative risk of an overdose increases with the
average daily dose and use of multiple prescribers .54-56 Demographic variables (e.g., Caucasian,
male sex, age 30-54, state and residence in a non-metro county, lower income) and personal
characteristics (e.g., history of nonmedical use or substance abuse, other mental health
diagnosis, route of administration) also are markers for overdose risk.54-58
The medical community must be a partner in a multi-pronged effort to reduce the adverse
consequences related to prescription drug abuse. Numerous federal and state actions have
begun, such as the FDA REMS for long-acting opioids, state-based initiatives designed to more
tightly regulate opioid use, and federal support for requiring mandatory education for DEA
registration. Given the likelihood that part of the problem relates to poor patient selection for
treatment, inappropriate drug selection or dosing, inadequate monitoring, or failure to address
clinical problems when they occur, clinician education is essential.
The assessment of risks related to prescription drug abuse, addiction, diversion and unintentional
overdose must be considered whenever opioid drugs are considered for use. Clinicians must
have a working knowledge of these outcomes, an understanding of medically-relevant definitions,
and basic skills in the elements of risk assessment and management that constitute a universal
precautions approach. Risk assessment and management must be viewed as a necessary part
22
of all opioid prescribing. At the same time, clinicians must not conclude that opioids should be
avoided even when there is a generally accepted indication (e.g., acute pain or chronic pain
related to active cancer or other serious illness) or never used when there is a more controversial
indication (selected patients with so-called chronic non-cancer pain).
The goal from the clinical perspective is a balanced approach by which clinicians neither reject
the use of opioids nor use them without due regard for the risks associated with abuse, addiction,
diversion and unintentional overdose.
23
Details
Comments
Oral (PO)
Rectal (PR)
Intramuscular (IM)
Intravenous (IV)
Subcutaneous (SC)
Transdermal (TD)
Modified with permission from Berry PH, Chapman CR, Covington EC, et al. Pain: Current Understanding of Assessment,
Management, and Treatments. Reston, VA: National Pharmaceutical Council and the Joint Commission for Accreditation of Healthcare
31
Organizations; December, 2001.
24
The assessment of all patients with pain should include a personal and family history of
substance use, including tobacco, alcohol, prescription drugs and illicit drugs. This understanding
is a key foundation of the universal precautions approach to risk assessment and management
described previously.
For patients with pain due to serious illness and a small minority of other patients, long-term
opioid therapy is considered, trialed and continues. The following section outlines the general
principles of opioid use, and provides further details about the approach to risk assessment and
risk stratification, and structuring therapy when chronic opioid therapy is undertaken. For further
information on issues related to the use of opioids in patients with persistent pain see
Module 7.
If the patient has a disorder for which opioid therapy is widely considered the mainstay approach,
such as advanced cancer or HIV/AIDS, healthcare providers should follow established guidelines
for pharmacologic management.61,62 The universal precautions approach still applies, with risk
stratification and the use of specific interventions (required consultations, monitoring with urine or
saliva drug screening, use of one pharmacy, pill counts and other approaches) applied as
appropriate to the clinical situation to ensure that monitoring of drug-related behavior is
appropriate and the patient is assisted in controlling drug use (see discussion on Structuring
Therapy).
Risk Assessment and Stratification
The population of prescription opioid users is heterogeneous. Among patients with well
characterized chronic pain syndromes, there are those who are responsive to the medication and
adherent, others who are so-called chemical copers, and some who develop problems with
substance use disorders or addiction. Nonmedical users also are heterogeneous. Some are selftreating pain or a psychiatric disorder, others are using drugs in a recreational pattern, and some
develop an addictive pattern of use characterized by a loss of control, craving, a compulsion to
use, or the continued use of the drug despite harm. Because the extant data do not allow certain
prediction of future nonadherence, all patients who are being considered for treatment with an
opioid or other potentially abusable drug should be stratified for risk, and should treatment be
26
undertaken, the type of controls built into the treatment plan should be commensurate with this
risk.
Studies have evaluated numerous factors as potential predictors of problematic drug-related
behavior, including abuse and addiction. The most consistent are a prior or current history of
alcohol or drug abuse, a family history of alcohol or drug abuse, and a history of major psychiatric
disorder.63 The presence of one or more of these factors should indicate that the patient may be
at relatively high risk of problematic drug use, an important consideration in the decision to
proceed with therapy, and if this is done, in the decisions that must be made about the degree of
structure and control that should be incorporated (see Structuring Therapy).
Conceptually, patients can be divided or triaged into two (low and high) or three (low, medium
and high) risk groups (see Table-Risk Assessment and Stratification in Clinical Practice).
Those with a low risk usually can be managed by primary care physicians using the basic
elements of a universal precautions approach. Those at moderate risk require more controls
incorporated into the prescribing and monitoring approach; when managed by a primary care
physician, some of these patients may benefit from consultation with appropriate specialist
support. Those patients at high risk of opioid abuseshould they be judged candidates for opioid
treatmentrequire a careful approach to prescribing and monitoring, and should be considered
for referral to a specialist in addiction medicine, or in some cases, pain medicine. Additional
screening tools can help identify patients at risk for misuse.
is given a score, and then the scores are summed, with scores in the 03 range associated with
low risk, 47 with moderate risk, and 8 and over with high risk. Although the ORT is useful due to
its brevity and ease of scoring, the validation is limited. Its face validity is reassuring, but also
raises concern about the potential for deception. Other tools also are available (e.g., COMM,
DIRE) to monitor for misuse and aberrant behaviors (see below).
that clinicians structure care to reduce risks and monitor all patients carefully. Some patients
need no special monitoring (low risk). Others (moderate to high risk) need more extensive
structure to assist them in adhering to the pain management therapy and to increase the
likelihood that any problems are identified promptly. The latter structure may include frequent
visits, prescription of small amounts of opioids, use of an opioid agreement (describing
expectations and consequences of problematic behavior), occasional biofluid drug screening,
requiring consultations or co-therapy with mental health care providers, and other similar
strategies (See Table. Tailor Monitoring to Patients Risk of Opioid Misuse, Abuse or
Diversion). Clinicians who cannot establish structured approaches should not independently
treat patients who require such an approach.
Monitoring Outcomes
During a trial of long-acting therapy, and thereafter should treatment be continued, safe and
effective management requires a patient-centered treatment plan and ongoing assessment of a
range of critical outcomes. These outcomes include: 1) analgesia (goal: continuing satisfactory
relief of pain, 2) side effects (goal: tolerable and manageable, and producing a degree of burden
clearly outweighed by the benefit of therapy, 3) physical and psychosocial functioning (goal:
stable or improved function in one or more meaningful domains), and 4) therapeutic adherence
(goal: lack of aberrant drug-related behaviors) (see the 4 As). Functional outcomes often are
more objective and verifiable, and in patients with pain associated with disability, functional
improvement can be designated as a therapeutic goal as important, or more important, than relief
of pain.
It is critically important to monitor these outcomes systematically, and to change therapy if an
indication to do so arises. These outcomes should be documented in the medical record
repeatedly over time, whether or not patients have relatively increased risk for aberrant drugrelated behavior.59 In monitoring the latter behaviors, there is an expectation that the occurrence
of any problem should be documented and followed by an evaluation to appropriately interpret its
naturefor example, addiction vs. some other psychiatric disorder vs. bothand management
should be pursued based on this interpretation, the seriousness of the behavior, and the skills of
the clinician.59
The 4 As
A useful mnemonic has been applied to the four key outcomes of long-term opioid therapy: the
4As
Analgesia. The effectiveness of the opioid for its primary indication, pain, should be assessed at
regular intervals.
Adverse effects. Opioids carry a substantial side effect liability and therapy should not be
continued if the burden posed by side effects is excessive.
Activities. Physical and psychosocial functioning must be assessed and documented during
opioid therapy. During successful therapy, patients maintain their level of function or improve;
therapy is unsuccessful if function declines. Use of an activity monitoring form can be instructive.
Aberrant drug-related behavior. Therapeutic adherence is essential for safe care. Problematic
behaviors may be characterized as misuse, abuse, or addiction, or possibly indicate diversion;
these behaviors occur on a continuum and must be carefully assessed in order to clarify their
seriousness and resolve the differential diagnosis. Relatively mild problems, such as the
occasional use of an extra dose (particularly if not cautioned against this), must be contrasted
with serious events which are more indicative of addiction, such as repeated requests for early
refills, acquisition of prescription opioids from multiple sources, or the concurrent use of illicit
drugs (Table - Aberrant Drug-Related Behaviors That May Occur During Long-Term Opioid
Therapy). Aberrant drug behaviors can be relatively less or more suggestive of addiction in
association with long-term opioid therapy. Once aberrant behavior is identified, an assessment is
29
needed to interpret it appropriately.59 There are recognized risk factors for the development of
aberrant behaviors (Table- Patient Risk Factors for Aberrant Behaviors/Harm).
As mentioned above, validated instruments may be useful in screening patients or monitoring
drug-related behavior during therapy. The Current Opioid Misuse Measure (COMM) assists in
identifying whether a patient, currently on long-term opioid therapy, may be exhibiting aberrant
behaviors associated with misuse of opioid medications. 69 In contrast, the previously described
Screener and Opioid Assessment for Patients with Pain (SOAPP) is intended to predict which
patients being considered for long-term opioid therapy, may exhibit aberrant medication
behaviors in the future. Since the COMM examines concurrent misuse, it is more suited for
helping clinicians monitor patients' aberrant medication-related behaviors over the course of
treatment. Another screening tool, the Diagnosis, Intractability, Risk, Efficacy (DIRE) score, was
designed to predict analgesia and adherence during long-term opioid treatment, but also may be
useful during ongoing treatment.70 Each category (diagnosis, intractability, efficacy, and risk
[psychological, chemical health, reliability, and social support]) is rated from 1 to 3, with higher
scores indicating a greater possibility of successful opioid therapy. The tool requires a good
history and a good relationship with the patient, and requires less than 2 minutes to complete.
The Addiction Behavior Checklist (ABC) also may be useful in evaluating adverse behaviors and
inappropriate opioid use in chronic pain. 71 See Module 4 for more discussion on the use of these
screening instruments.
In addition to the use of these instruments, data obtained from state-based PDMP reports and the
use of biofluid drug testing are important monitoring activities. Medication reconciliation, pill
counts, and consultation with family members are additional approaches that can be part of the
evaluation of patient behavior.
Table. Suggested Strategies in Tailoring Monitoring to Patients Assessed Risk of Opioid
Misuse, Abuse or Diversion
Monitoring
Action
Sole Prescriber
Frequency of
Visits
Lowest Level of
Monitoring:
Very Low Risk
Required
Q 6 months
minimum
Moderate Level of
Monitoring:
Significant Risk
Required
Q 2 weeks to
start
Q 2 weeks after
med change
Q 3 months if
stable after 6
months if NO
aberrant
behaviors
Encourage
family or friend
to attend
appointments
Commonly used
Opioid Pain
Care
Agreement
Opioid
prescribing
limits
Optional
30 day supply
Biofluid Drug
Testing
Commonly used
approach is
Common practice is
initial visit plus randomly
Commonly used
Specialty
Referral
on a semiannual or
quarterly basis
thereafter, and after the
occurrence of any
aberrant behavior
Consider behavioral
health/Pain evaluation
Others as needed
*Monitoring measures should be modified based upon the condition of the patient.
Patients who are very ill or declining rapidly will not need the same level of assessment and monitoring as
patients with a longer life expectancy.
31
Biological
Age <45 years
Male sex
Family history of
prescription drug or
alcohol abuse
Cigarette smoking
Physical illnesses
Pain severity
Psychiatric
Substance use disorder
Preadolescent sexual
abuse (in women)
Major psychiatric disorder
(e.g., personality disorder,
anxiety or depressive
disorder, bipolar disorder)
Social
Prior legal problems
History of motor vehicle
accidents
Poor family support
Involvement in a
problematic subculture
Unemployed
Isolation
32
Dosing
Individualization of the dose through the process of gradual dose titration is the key principle in
attaining a favorable balance between analgesia and side effects. Full mu opioid agonists, such
as morphine, have a fairly linear dose response curve and upward dose titration can be done until
either satisfactory analgesia is reported or the patient experiences an intolerable and
unmanageable side effect. The latter scenario is known as poor responsiveness and should be
considered specific for the particular opioid and route of administration.29
Clinically, the potency and effectiveness of mu receptor agonists can vary unpredictably among
patients, with some patients achieving excellent relief with one agent, while other patients require
a different drug. Side effects such as nausea and vomiting also differ among individuals. If side
effects become problematic during dose titration, it is reasonable to consider a change in the
drug.
Part of the explanation may lie in the fact that the mu opioid receptor gene generates a variety of
different mu opioid receptor subtypes in the form of splice variants with different response
characteristics, the pattern of which varies among individuals. 74-76 Thus, the most effective drug
for one patient may not be the best one for another individual. The presence of incomplete cross
tolerance among mu opioids is another example of differences among the drugs. Patients highly
tolerant to one mu opioid may regain their sensitivity when switched to another mu opioid, an
observation which has led to the practice of opioid rotation.
Morphine sulfate is regarded as the prototype opioid drug, and the potency of other members of
the class are typically compared to a 10-mg parenteral dose of morphine (Table: Equianalgesic
Dosing of Opioid Analgesics). Although the variation in potency is very large (e.g., microgram
quantities of fentanyl yield effects comparable to many milligrams of morphine), clinicians are
able to select appropriate starting doses in the patient who is relatively opioid-nave by consulting
the package insert. In the patient who is already taking an opioid, a change in the opioida
technique called opioid rotationcan begin with a starting dose by cautiously applying the
information in the equianalgesic dose table. The data in the table is only a guide, however, and
cannot be used without adjustments, nor do they guarantee safety. A variety of factors alters the
ratios, including variation in bioavailability when a route other than the intravenous route is used,
and often more important, shifts in relative potency between drugs that occur as tolerance
develops during long-term therapy. It must be understood that the data that have been codified in
the equianalgesic dose table reflect studies that were done on populations with limited opioid
exposure, and that differences in cross-tolerance to analgesia and other effects may greatly
influence the effects produced when drugs are changed during long-term treatment.
When comparing intravenous morphine and hydromorphone, for example, the equianalgesic table
relies on early studies showing that 10 mg of the former provides roughly the same analgesia
as 1.5 mg of the latter. This reflects a potency difference in a population with little opioid
exposure. During chronic therapy with one or the other drug, however, the relative potency
can shift, necessitating caution when changing drugs in the clinical setting. It is important that the
clinician always consult the equianalgesic dose table prior to switching opioid drugs or routes of
administration, and very importantly, use these values only as a broad guide. A protocol for opioid
rotation that incorporates judicious reduction in the calculated equianalgesic dose to maintain
safety should be followed.72
33
Analgesic
Morphine*
oxycodone
levorphanol
hydromorphone
Fentanyl
hydrocodone
oxymorphone
methadone
codeine
meperidine
Parenteral Dose
SC, IM, IV(mg)
10
NA
2
1.5
0.1
NA
1
10
120
100
In short, the use of an equianalgesic table to help guide switching is based on the best available
science but has inherent limitations based on the populations and types of pain evaluated,
73
duration of treatment, formulations that have been studied, and the directionality of the switch.
Therefore, all equivalents should be considered approximations only and can be affected by
interpatient variability, type of pain (i.e., acute vs chronic), chronicity of treatment, tolerance, and
incomplete cross tolerance. An alternate approach that obviates the need to consult
equianalgesic table has recently been offered (please see Module 7 for further discussion). In
any event, patients should be monitored for efficacy and adverse reactions and the dose adjusted
accordingly.
Fentanyl. Although the parenteral morphine:fentanyl ratio in the Table is shown as 10:0.1 (or a
100:1 ratio), in clinical practice the ratio has been described as anywhere between 15 and
112.5:1; many clinicians use an equivalency of 4 mg/hr IV morphine equivalent to 100 mcg/hr
parenteral or transdermal fentanyl. Transdermal fentanyl 25 mcg/hr used for chronic pain is
roughly equivalent to 50 mg oral morphine/day, however, when converting from morphine
equivalents per day to transdermal fentanyl, the fentanyl dose in adjusted in 25 mcg/hr
increments over approximately a 90 mg morphine range. These conversions are in the package
insert.
variable half-life, complex metabolism and risk of drug-drug interactions, potential to prolong the
QTc interval, and relative potency ratios with other opioids that change with the dose and duration
of treatment at the time of a switch to methadone therapy. The analgesic effects of methadone
persist for up to 4 to 6 hours, therefore it usually must be administered three times daily. For
patients who are opioid-nave or have very limited prior opioid exposure, methadone can be
initiated at doses of 2.5-5 mg tid, with the smaller and less frequent doses reserved for those with
chronic illness or more than 70 years of age. Patients should be warned that initial pain relief
may be inadequate and not to take extra methadone. A short-acting opioid can be used initially
for augmentation and breakthrough pain. See Module 7 for further discussion on methadone.
For those patients receiving higher opioid doses, there are a number of strategies that can be
used to safely change to methadone. One approach starts with the calculated equianalgesic dose
and then reduces the starting dose of methadone by 75-90% depending on the size of the dose,
the medical frailty of the patient and the severity of the pain. Another approach calculates the
starting dose of methadone in ranges determined by the dose of the prior drug, and then adds a
safety factor. A table of conversions from oral morphine illustrates this (see below).
After estimating the equianalgesic dose, a safety factor is introduced by identifying an automatic
does reduction of 25%-50% with the larger reduction intended for patients receiving relatively
high doses, non-Caucasian race, or is elderly or medically frail.
For individuals on very high opioid doses (e.g., 1,000 mg morphine equivalents/ day or higher)
great caution should be exercised in converting to methadone. Based on clinical experience,
some experts advocate never starting a dose above 40 mg per day; others suggest that a higher
starting dose can be done but strongly consider doing so in a monitored setting.
Dose Titration
Initial oral dosing regimens typically utilize a short-acting, immediate-release preparation and the
dose is titrated upward to determine the optimal dosage. Dose titration for immediate release
preparations should be accomplished by increasing the dose as a percentage of the total daily
dose. An increase of 25% to 50% usually is safe. Thus, a patient with inadequate pain relief with
30 mg morphine can receive 45 mg, while a patient on a dosage of 300 mg may require an
increase to 450 mg with careful monitoring of the patient for side effects. Frequent reassessment
is invaluable in ensuring appropriate and adequate dosing.
Patients prescribed short-acting drugs may require multiple doses throughout the day, which can
be inconvenient and reduce adherence. If pain is constant or recurs frequently, opioids should be
administered on a time-contingent (regularly scheduled) basis and this is usually best
accomplished with a long-acting opioid. Once the total dose of an immediate-release formulation
is determined, the regimen can be converted to a modified-release opioid formulation or
methadone.
35
Modified-release preparations of morphine increase the drugs duration from 2 to 4 hours (for
short-acting agents) to 8 to 12 hour for some formulations and 24 hours for others. Modifiedrelease oral formulations are also available for oxycodone, oxymorphone, hydromorphone, and
tapentadol (oral), and modified-release transdermal formulations are available for fentanyl and
buprenorphine. When patients are switched to one of these drugs, they should be warned that
initial pain relief may be inadequate; a short-acting opioid can be used initially for augmentation
and breakthrough pain.
The occurrence of tolerance to analgesic effects of opioid drugs can occur, and is a common
worry of clinicians and patients alike. Tolerance to analgesic effects and tolerance to other
effects, such as respiratory depression and constipation, occur at different rates and to varying
extents. Only tolerance to analgesia poses an issue clinically. Observational data based on case
series or open-label extension studies support the view that some patients can be maintained on
low to moderate doses for several months to years; 77-80 others require periodic dose changes that
can be accommodated by the clinician and patient. Randomized clinical trial data have not
adequately characterized the long-term outcomes of opioid therapy in heterogeneous populations
with chronic pain. Epidemiological evaluations based on administrative and clinical data derived
from large population-based studies have tended to suggest a lack of efficacy or functional
improvement with long term use (see Module 7 for further discussion on the evidence related
to long term opioid therapy). These data do not exclude the potential for significant benefit in a
subset of patients managed in careful practice settings. Large epidemiologic studies also include
patients who have dose escalated and are not doing well, and perhaps reflect a pattern of opioid
use for a wider range of diagnoses. 54,56,57,81-84 The extant data suggest that some patients reach a
low stable dose, others escalate their dose but eventually stabilize, but many others never seem
85
to stabilize. Importantly, benefits do not seem to last and functional improvement is not apparent
in most of those who dose escalate.86 Regardless, many patients who are started on chronic
opioid therapy eventually discontinue either because of adverse effects or inadequate pain relief
(see Module 7).
Another concern that relates to opioid titration is the potential for opioid-induced hyperalgesia, a
state of nociceptive sensitization caused by exposure to opioids. The phenomenon, which has
been well characterized in animal models, would be clinically manifest by the occurrence in
patients treated with opioids of greater sensitivity to noxious stimuli or more clinical pain.87,88
Although there are observations that suggest that this occurs in patients (see Module 7), it is
difficult to distinguish it from tolerance or other explanations for increasing pain, including disease
progression and anxiety. A recent controlled clinical trial demonstrated that tolerance occurred
after a month of chronic opioid treatment in patients with back pain, but hyperalgesia could not be
demonstrated.89
Breakthrough pain is common in populations with cancer pain and non-cancer pain.90,91 The coadministration of an immediate-release, short-acting rescue dose is now the standard approach
when treating persistent pain in the cancer population. In the population with opioid-treated
noncancer pain, the rescue dose is used commonly, but should not be considered the standard of
care; patients should be carefully assessed to determine whether the potential benefits of this
additional opioid outweigh any risks. A typical rescue dose consists of 5% to 15% of the patients
24-hour dose of medication or the equivalent dose of a different drug, as calculated from
analgesic conversion charts (Table: Equianalgesic Dosing of Opioid Analgesics). The only
exception to this is provided by oral transmucosal immediate release fentanyl products which
should be initiated at low doses in all patients, and then titrated upward as needed. This is a key
element of the FDA REMS program for the transmucosal immediate-release formulations.
binding to mu2 opioid receptors in the GI tract. Unfortunately, this often continues as a significant
problem as patients either fail to develop tolerance or experience concomitant causes. A
prophylactic bowel regimen should be considered in patients who are predisposed to this side
effect, such as the elderly, sedentary patients, patients with poor oral intake, and patients treated
with other constipating drugs. Peristaltic stimulants, such as senna concentrate or bisacodyl are
routinely recommended, unless use of these agents is contraindicated. Numerous other laxative
options exist, including commonly-used osmotic agents such as lactulose or polyethylene glycol.
Methylnaltrexone, an injectable opioid antagonist that does not cross the blood-brain barrier, is
FDA-approved for refractory opioid-induced constipation. Occasional patients are offered oral
naloxone, which has very poor oral bioavailability and also has been used to treat opioid-induced
constipation.
Nausea and vomiting, which may be related to direct drug effect in the brainstem, to
gastroparesis, or to sensitization of the labyrinthine-vestibular system, is a problem for a
substantial minority of patients at the start of therapy. Some patients, however, report persistent
nausea during chronic therapy. Although nausea often resolves spontaneously, some patients
may require an antiemetic. If the nausea appears to be mediated by activation of a
chemoreceptor trigger zone in the medulla, centrally-acting antiemetics, such as
prochlorperazine, are the most effective. Patients with nausea associated with vertigo or
aggravated by motion, may be helped with an antivertiginous drug (e.g., cyclizine, scopolamine,
meclizine). If the nausea is most prominent after eating and is associated with early satiety or
post-prandial distension, a trial of metaclopramide is reasonable given its dual central effects on
dopamine receptors and gastrokinetic properties.
Constipation
Nausea and vomiting
Sedation
Mental clouding
Hypogonadism
Sleep-disordered breathing
Respiratory depression
Opioid-induced sedation and mental clouding occur in a dose-dependent fashion and are most
common when treatment is initiated. The risk of respiratory depression also is greatest when
dosing is initiated in the patient who is relatively opioid-nave. Sedation and other cognitive effects
typically wane over time.
However, some patients experience persistent sedation or cognitive impairment. If this occurs, a
change in therapy is indicated. In the medically ill, co-administration of a psychostimulant, such
as dextroamphetamine, methylphenidate hydrochloride, or modafinil, often is tried. The use of
psychostimulants may be associated with side effects, however, and must be carefully monitored.
Respiratory depression during opioid therapy occurs rarely if appropriate doses are administered
and monitoring is appropriate. The risk is greatest when opioid-naive patients are first exposed to
relatively large doses of these drugs or doses are escalated too rapidly, especially with
methadone. The initiation of therapy and dose titration should be undertaken with particular
caution in patients with serious pulmonary dysfunction. Tolerance to the respiratory effect of
37
opioids typically occurs with chronic therapy, but presumably, tolerance is incomplete and
residual respiratory depressant effects are demonstrable by a shift in the CO 2-response curve but
not clinically.
This phenomenon would explain the response to naloxone that usually is seen when an opioidtreated patient develops compromised respirations as a result of a new cardiopulmonary event,
such as pulmonary embolism or respiratory infection. Clinicians should be aware that respiratory
depression is dose-related and does not occur if a patient has demonstrated an ability to tolerate
a dose at a steady-state level. If a patient who is stable develops late respiratory depression, a
new cardiopulmonary insult should be sought even if there is a response to naloxone. Moreover,
opioid-induced respiratory depression does not occur with tachypnea or dyspnea; these findings
also indicate a high likelihood of a new cardiopulmonary insult, again even if there is a response
to naloxone. Concomitant use of benzodiazepines increases the risk of respiratory
depression in patients receiving opioid analgesics..
Other potential consequences of long-term opioid therapy include neuroendocrine effects
(hypogonadism potentially causing fatigue, mood change, sexual dysfunction, osteoporosis,
infertility, and amenorrhea) and urinary retention. Some opioids can cause histamine release
producing sweating, flushing, pruritus, and urticaria; true anaphylactic reactions are extremely
rare. Some patients also may experience problems with dental hygeine and oral health due to
opioid-induced xerostomia. Opioid-related dysimmune effects have been reported but have
uncertain clinical relevance.
Although liver dysfunction usually must be severe to affect opioid pharmacokinetics, the potential
for pharmacodynamic changes suggests that they should be used cautiously in patients with
hepatic disease. Opioids have the potential to interact with a variety of medications, primarily
other CNS depressants with which additive effects occur. Increased sedation is a frequent
interaction that has been reported with alcohol, benzodiazepines, butyrophenones,
phenothiazines, sedative-hypnotics, tricyclic antidepressants, and anticonvulsants. Drug
interactions and relevant notations regarding specific hepatic cytochrome P450 isozymes are
summarized in the table (Table: Important Opioid Drug Interactions).
Interacting drug(s)
First generation antihistamines
Effect
Increased sedation
Controlled-release opioids
metoclopramide
Codeine, tramadol
Oxycodone, hydrocodone
Fentanyl, methadone
Oxycodone, tramadol,
buprenorphine
Fentanyl, meperidine, tramadol
38
days
Meperidine, morphine
cimetidine
desipramine
Methadone
Tramadol
Tapentadol
MAO inhibitors
Source: Jackson KC, Lipman AG. Opioid Analgesics. In: Tallison CD, Satterwaite JR, Tollison JW, eds. Practical Pain Management. 3rd ed.
Philadelphia: Lippincott Williams & Wilkins; 2001; 216-231.
Summary
Safe and effective use of opioid analgesics requires proper patient selection and risk assessment
including the use of universal precautions, development of a patient-centered treatment plan,
periodic review using the 4 As, and reassessment of underlying disease if symptoms or response
to treatment changes. Ongoing monitoring for compliance and evaluation of drug-related behavior
is essential. Opioid analgesics are but one component of a comprehensive treatment plan. When
contemplating use in patients with persistent pain, opioids should only be prescribed on a trial
basis. Each visit requires reassessment of continuing need and safety. Opioid therapy is
modifiable through dose titration, rotation and conversion, or discontinuation based on individual
variability and response.
Adjuvant Analgesics
Adjuvant analgesics (Table: Examples of Adjuvant Analgesic Use) were historically defined as
drugs that are used primarily for treating conditions other than pain, but may be analgesic in
selected circumstances.92 They now include some drugs (selected antidepressants and
antiepileptic drugs) that are primarily approved for specific types of pain). Adjuvant analgesics
include agents useful in all types of pain (such as antidepressants), analgesics for neuropathic
pain (such as the antidepressants, and selected antiepileptic drugs (AEDs), and analgesics
typically used for musculoskeletal pain (such as so-called muscle relaxants).
Antidepressants have been used for decades as primary analgesics. They may be considered
multipurpose analgesics, appropriate for a trial in any persistent pain condition. The tricyclic
antidepressants have been well studied and are most likely to be effective. Their side effect
liability is higher than newer drugs. The selective serotonin and norepinephrine reuptake
inhibitors (SNRIs) appear to be more effective analgesics than the selective serotonin reuptake
inhibitors (SSRIs). Duloxetine and minalcipran have FDA-approved labeling for treatment of
specific pain syndromes, including diabetic painful neuropathy and fibromyalgia. Drugs that are
predominantly noradrenergic, such as bupropion, also may be analgesic.
The secondary amine tricyclic antidepressants, such as desipramine and nortriptyline, have a
relatively favorable side effect profile and are generally preferred when an antidepressant of this
type is tried for pain. These drugs are well absorbed from the GI tract and have long half-lives,
making single daily doses effective. A low starting dose (e.g., 25 mg in adults and 10 mg in the
elderly) should be gradually titrated upward. The usual effective dose range is 50-150 mg per
day. Side effects include dry mouth, urinary retention, constipation, sedation, and orthostatic
hypotension. The most serious side effects are cardiac rhythm disturbances, and patients should
be carefully evaluated for cardiac abnormalities prior to initiating therapy. One of the SNRIs
39
should be considered if the tricyclic is not tolerated or the risk of adverse effects is judged to be
too high for a trial.
Antiepileptic agents are commonly used to treat neuropathic pain. 32 Gabapentin and pregabalin
are currently the most commonly prescribed drugs for this indication. Gabapentin has FDAapproved labeling for the treatment of postherpetic neuralgia (PHN) and pregabalin is FDA
approved for diabetic painful polyneuropathy (DPN), PHN, spinal cord injury pain, and
fibromyalgia. Pregabalin has more stable pharmacokinetics than gabapentin and should be more
simple to use. Other antiepileptics, such as phenytoin, carbamazepine, clonazepam and sodium
divalproex, and newer drugs, such as lamotrigine, topiramate, tiagabine, lacosamide, and
oxcarbazepine, also are used as analgesics for refractory neuropathic pain. All of these drugs
should be dosed and monitored in a manner similar to their use in seizure prevention. Although
all can cause sedation and mental clouding, other side effects vary and clinicians should become
familiar with their guidelines for use before adopting them in the treatment of persistent
neuropathic pain. Lidocaine (5%) and capsaicin (8%) patches are FDA-approved for PHN.
Many other drugs categorized broadly under the so-called adjuvant analgesics may be
considered for trials in patients with refractory neuropathic pain. These drugs, most of which are
approved for indications other than pain, include numerous agents in many classes, a large
number of which may be tried for neuropathic pain (see Table: Examples of Adjuvant
Analgesic Use). In addition to the analgesic antidepressants, gabapentinoids, other antiepileptic
Table: Examples of Adjuvant Analgesic Use
Indication
Examples
Multiple types of pain syndromes
Corticosteroids (dexamethasone, prednisone )
Tricyclic antidepressants*
amitriptyline
desipramine
nortriptyline
Selective serotonin and norepinephrine reuptake
inhibitor (SSRI/SNRIs) antidepressants*
duloxetine
venlafaxine
minalcipran
paroxetine
citalopram
Other
bupropion
Alpha-2-adrenergic agonists
tizanidine*
clonidine
Topical therapies
lidocaine patch (5%)
capsaicin patch (8%)
doxepin or another compounded tricyclic
Gabapentinoids (gabapentin, pregabalin)
Other anticonvulsants
carbamazepine
lacosamide
sodium divalproex
lamotrigine
oxcarbazepine
topiramate
NMDA receptor antagonists
memantine
ketamine
dextromethorphan
amantadine
Oral sodium channel blockers
mexiletine
tocainide
GABA Agonists
baclofen
clonzaepam
40
Calcitonin
Clonidine
Bisphosphonates (e.g.,pamidronate)
Calcitonin
Radiopharmaceuticals
drugs and topical treatment noted previously, this category includes 1) alpha-2 adrenergic
agonists such as tizanidine and clonidine, 2) sodium channel blockers such as mexiletine (and
the novel lacosamide, which is a sodium channel modulator approved for the treatment of
epilepsy), 3) other GABA agonists such as baclofen, 4) N-methyl-D-aspartate antagonists such
as memantine, and 5) cannabinoids such as tetrahydrocannabinol and nabilone. See Module 9
for further information on the use of adjuvant analgesics.
Summary
Based on the comprehensive assessment, one or more than one treatment strategy should be
selected. Often, the goals of therapy are both pain relief and functional restoration. If
pharmacotherapy is used, clinicians should have an understanding of the approaches used to
optimize treatment with NSAIDs, adjuvant analgesics, and opioids.
References
1. Christo PJ, Mazloomdoost D. Interventional pain treatments for cancer pain. Ann N Y Acad
Sci. 2008;1138:299-328.
2. Eidelman A, White T, Swarm RA. Interventional therapies for cancer pain management:
important adjuvants to systemic analgesics. J Natl Compr Canc Netw. 2007;5:753-760.
3. Loeser JD, Turk DC. Multidisciplinary pain management. In: Loeser JD, Butler SH, Chapman
CR, Turk DC, eds. Bonicas Management of Pain. Philadelphia, PA: Lippincott Williams &
Wilkins; 2001:2069-2079.
4. Parrott T. Pain Management in Primary-Care Medical Practice. In: Tollison CD,
Satterthwaithe JR, Tollison JW, eds. Practical Pain Management. 3rd ed. Philadelphia, PA:
Lippincott Williams & Wilkins; 2002:729-759.
5. Sanders SH, Harden RN, Vicente PJ. Evidence-based clinical practice guidelines for
interdisciplinary rehabilitation of chronic nonmalignant pain syndrome patients. Pain Pract.
2005 5:303-315.
6. Guzman J, Esmail R, Karjalainen K, et al. Multidisciplinary bio-psycho-social rehabilitation for
chronic low back pain. Cochrane Database Syst Rev. 2002;(1):CD000963.
7. Johnson RE, Jones GT, Wiles NJ, et al. Active exercise, education, and cognitive behavioral
therapy for persistent disabling low back pain: a randomized controlled trial. Spine.
2007;32:1578-1585.
8. Hoffman BM, Paps R, Chatkoff DK, Kerns RD. Meta-analysis of psychological interventions
for chronic low back pain. Health Psychol. 2007;26:10-12.
9. Wetering EJ, Lemmens KM, Nieboer AP, Huijsman R. Cognitive and behavioral interventions
for the management of chronic neuropathic pain in adults a systematic review. Eur J Pain.
2010;14:670-81.
10. Eccleston C, William SC, Morley S. Psychological therapies for the management of chronic
pain (excluding headache) in adults. Cochrane Database Syst Rev. 2009;15(2):CD0077407.
11. Hayden JA, van Tulder MW, Malmivaara AV, Koes BW. Meta-analysis: exercise therapy for
nonspecific low back pain. Ann Intern Med. 2005;142:765-775
12. Nnoaham KE, Kumbang J. Transcutaneous electrical nerve stimulation (TENS) for chronic
pain. Cochrane Database Syst Rev. 2008 Jul 16;(3):CD003222. Update of: Cochrane
Database Syst Rev. 2001;(3):CD003222. PMID: 11687055.
13. Walsh DM, Howe TE, Johnson MI, Sluka KA. Transcutaneous electrical nerve stimulation for
acute pain. Cochrane Database Syst Rev. 2009 Apr 15;(2):CD006142.
14. World Health Organization: Cancer Pain Relief, 2nd ed, with a Guide to Opioid Availability.
2nd ed. Geneva:, United nations, World Health Organization, 1996.
41
15. American Pain Society. Principles of Analgesic Use in the Treatment of Acute Pain and
Cancer Pain (6th ed). Glenview, IL: American Pain Society, 2008.
16. Adult Cancer Pain. NCCN Clinical Practice Guidelines in Oncology. Version 1.2013 Available
at: www.nccn.org.
17. Jost L, Roila F; ESMO Guidelines Working Group. Management of cancer pain: ESMO
clinical recommendations. Ann Oncol. 2008;19 Suppl 2:ii119-121.
18. Dworkin RH, OConnor AB, Backonja M, et al: Pharmacologic management of neuropathic
pain: evidence-based recommendations. Pain. 2007;132:237-251.
19. Simon LS, Lipman AG, Caudill-Slosberg M, et al. Guideline for the Management of Pain in
Osteoarthritis, Rheumatoid Arthritis, and Juvenile Chronic Arthritis. 2nd ed. Glenview, Ill:
American Pain Society, 2002.
20. Zhang W, Moskowitz RW, Nuki G, et al. OARSI recommendations for the management of hip
and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines.
Osteoarthritis Cartilage. 2008;16:137-162.
21. American Academy of Orthopedic Surgeons. Clinical practice guideline on the treatment of
osteoarthritis of the knee (non-arthroplasty). 2008. American Academy of Orthopaedic
Surgeons. Rosemont, IL.
22. Hochberg MC, Altman RA, Toupin April K, et al. American College of Rheumatology 2012
recommendations for the use of nonpharmacologic and pharmacologic therapies in
osteoarthritis of the hand, hip, and knee. Arthritis Care Res. 2012;64:464-474.
23. Fitzgerald GA. Prostaglandins, aspirin and other NSAIDS. In Goldman L, Ausiello D, eds.
Cecil Textbook of Medicine, 22nd ed. London: Elsevier Science; 2004:155-161.
24. Vane, J .R. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like
drugs. Nature New Biology. 1971 Jun 23; 231:232-235.
25. Kis B, Snipes JA, Busija DW. Acetaminophen and the cyclooxygenase-3 puzzle: sorting out
facts, fictions, and uncertainties. J Pharmacol Ther. 2005;315:1-7.
26. Boutand O, Aronoff DM, Richardson JH, Marnett LJ, Opates JA. Determinants of the cellular
specificity of acetaminophen as an inhibitor of prostaglandin H92) synthases. Proc Natl Acad
Sci USA. 2002;99:7130-7135.
27. Aronoff DM, Oates JA, Buotand O. New insights into the mechanism of action of
acetaminophen. Its clinical pharmacologic characteristics reflect its inhibition of the two
prostaglandin H2 synthases. Clin Pharmacol Ther. 2006;79:9-19.
28. Jahr JS, Lee VK: Intravenous acetaminophen. Anesthesiol Clin 2010; 28;619-645)
29. Food and Drug Administration Drug Safety Communication on Acetaminophen.
http://www.fda.gov/Drugs/DrugSafety/ucm239821.htm. Accessed August 26, 2012.
30. Hylek EM, Heiman H, Skates SJ, Sheehan MA, Singer DE. Acetaminophen and other risk
factors for excessive warfarin anticoagulation. JAMA. 1998;279:657-662.
31. Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications
related to use of nonsteroidal anti- inflammatory drugs. A meta-analysis. Ann Intern Med.
1991;115: 787-796.
32. Dubois RW, Melmed GY, Henning JM, Bernal M. Risk of upper gastrointestinal injury and
events in patients treated with cyclooxygenase (COX)-1/COX-2 nonsteroidal antiinflammatory drugs (NSAIDs), COX-2 selective NSAIDs, and gastroprotective co-therapy: An
appraisal of the literature. J Clin Rheumatol. 2004;10:178-189.
33. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs
nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS
study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA.
2000;284: 1247-1255.
34. Singh G, Fort JG, Goldstein JL, et al. Celecoxib versus naproxen and diclofenac in
osteoarthritis patients: SUCCESS-I Study. Am J Med. 2006;119:255266.
35. Chan FK, Lanas A, Scheiman J, Berger MF, Nguyen H, Goldstein JL. Celecoxib versus
omeprazole and diclofenac in patients with osteoarthritis and rheumatoid arthritis (CONDOR:
a randomised trial. Lancet. 2010;376(9736):173-179.
36. Mallen SR, Essex MN, Zhang R. Gastrointestinal tolerability of NSAIDs in elderly patients: a
pooled analysis of 21 randomized clinical trials with celecoxib and nonselective NSAIDs. Curr
Med Res Opin. 2011;27:1359-1366.
42
37. Moore RA, Derry S, Phillips CJ, et al. Nonsteroidal anti-inflammatory drugs (NSAIDs),
cyxlooxygenase-2 selective inhibitors (coxibs) and gastrointestinal harm: Review of clinical
trials and clinical practice. BMC Musculoskelet Disord 2006;7:79.
38. Van der Linden MW, Gaugris S, Kuipers EJ, et al. COX-2 inhibitors: complex association with
lower risk of hospitalization for gastrointestinal events compared to traditional NSAIDs plus
proton inhibitors. Pharmacoepidemiol Drug Saf. 2009;18:880-890.
39. Brown TJ, Hooper L, Elliott RA, et al. Comparison of the cost-effectiveness of five strategies
for the prevention of non-steroidal anti-inflammatory drug-induced gastrointestinal toxicity: a
systematic review with economic modeling. Health Technol Assess. 2006;10:iii-iv, xi-xiii, 1183.
40. Scheiman JM, Hindley CE. Strategies to optimize treatment with NSAIDs in patients at risk
for gastrointestinal and cardiovascular adverse events. ClinTher. 2010;32:667-677.
41. Rostom A, Moayyedi P, Hunt R, Canadian Association of Gastroenterology Consensus
Group. Canadian consensus guidelines on long-term nonsteroidal anti-inflammatory drug
therapy and the need for gastroprotection: benefits versus risks. Aliment Pharmacol Ther.
2009;29:481-496.
42. Farkouh ME, Greenberg BP. An evidence-based review of the cardiovascular risks of the
nonsteroidal anti-inflammatory drugs. Am J Cardiol. 2009;103:1227-1237.
43. Schjerning Olsen AM, Fosbol EL, Lindhardsen J et al. Long-term cardiovascular risk of
NSAID use according to time passed after first-time myocardial infarction: A nationwide
study. Circulation. 2012;126:1955-63.
44. Sowers JR, White WB, Pitt B, et al. The Effects of cyclooxygenase-2 inhibitors and
nonsteroidal anti-inflammatory therapy on 24-hour blood pressure in patients with
hypertension, osteoarthritis, and type 2 diabetes mellitus. Arch Intern Med. 2005;165:161168.
45. Allen LV, Berardi RR, Desimone EM, et al., eds. Handbook of Nonprescription Drugs. 12th
ed. Washington, DC: American Pharmaceutical Association; 2000.
46. Gladding PA, Webster MW, Farrell HB, et al. The antiplatelet effect of six non-steroidal antiinflammatory drugs and their pharmacodynamic interaction with aspirin in healthy volunteers.
Am J Cardiol. 2008 Apr 1;101:1060-1063.
47. Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL. Opioid and nonopioid
components independently contribute to the mechanism of action of tramadol, an atypical
opioid analgesic. J Pharmacol Exp Ther. 1992;260:275-285.
48. Lotsch J, Rohrbacher M, Schmidt H, et al. Can extremely low or high morphine formation
from codeine be predicted prior to therapy initiation? Pain 2009;144:119-124
49. Crews KR, Gaedigk A, Dunnenberger HM, et al. Clinical pharmacogenetics implementation
consortium (CPIC) guidelines for codeine therapy in the context of cytochromeP4502D6
(CYP2D6) genotype. Clin Pharmacol Therap. 2012;91:321-326
50. Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose death, United States, 2010.
JAMA. 2013;309:657-658..
51. Substance Abuse and Mental Health Services Administration. 2011. Drug Abuse Warning
Network, 2009: National Estimates of Drug-Related Emergency Department Visits, Table 19.
Rockville, MD.
http://www.samhsa.gov/data/2k11/DAWN/2k9DAWNED/HTML/DAWN2k9ED.htm#Tab19.
Accessed on March 30, 2012
52. Substance Abuse and Mental Health Services Administration. 2011. Results from the 2010
National Survey on Drug Use and Health: Detailed Table, Table 7.1.a. Rockville, MD.
http://www.samhsa.gov/data/NSDUH/2k10NSDUH/tabs/Sect7peTabs1to45.htm#Tab7.1A.
Accessed on March 30, 2012.
53. National Vital Statistics System. Methadone mortality.
54. Dunn KM, Saunders KW, Rutter CM et al. Opioid prescriptions for chronic pain and overdose:
a cohort study. Ann Intern Med. 2010 Jan 19;152:85-92.
55. Braden JB, Russo J, Fan MY, et al. Emergency department visits among recipients of chronic
opioid therapy. Arch Intern Med. 2010 Sep 13;170:1425-32.
43
56. Bohnert AS, Valenstein M, Bair MJ, et al. Association between opioid prescribing patterns
and opioid overdose-related deaths. JAMA. 2011 Apr 6;305:1315-21.
57. Paulozzi et al. Paulozzi LJ, Kilbourne EM, et al. A history of being prescribed controlled
substances and risk of drug overdose death. Pain Med. 2012;13:87-95.
58. Toblin RL, Paulozzi LJ, Logan JE, Hall AJ, Kaplan JA. Mental illness and psychotropic drug
use among prescription drug overdose deaths: a medical examiner chart review. J Clin
Psychiatry. 2010;71:491-6.
59. Portenoy RK, Payne R, Passik S: Acute and chronic pain. In Lowinson JH, Ruiz P, Millman
RB, eds. Comprehensive Textbook of Substance Abuse. Fourth Edition. Baltimore: Williams
and Wilkins; 2005:863-903.
60. Gourlay DL, Heit H, Amahrezi A. Universal precautions in pain medicine: A rational approach
to the treatment of pain. Pain Med. 2005;6:107-112.
61. American Pain Society. Principles of Analgesic Use in the Treatment of Acute Pain and
Cancer Pain (6th ed). Glenview, IL: American Pain Society, 2008.
62. Fine P, Portenoy RK: Opioid analgesia. New York: McGraw Hill, 2004. (http://
www.stoppain.org/pcd/content/forpros/opioidbook.asp).
63. Webster LR, Webster RM. Predicting aberrant behaviors in opioid-treated patients:
preliminary validation of the Opioid Risk Tool. Pain Med. 2005;6:432-442.
64. Butler SF, Budman SH, Fernandez K, et al. Validation of a screener and opioid assessment
measure for patients with chronic pain. Pain. 2004;112:6575.
http://painedu.org/soapp.asp?gclid=CJfdirDimK4CFU
65. Butler SF, Fernandez K, Benoit C, et al. Validation of the revised Screener and Opioid
Assessment for Patients with Pain (SOAPP-R). J Pain. 2008;9:360372.
66. Alliance of States with Prescription Monitoring Programs. http://www.pmpalliance.org/.
Accessed August 26, 2012.
67. Brandeis University. Schneider Institutes for Health Policy. Prescription Monitoring Program
Center of Excellence Briefing on PMP Effectiveness.
http://www.pmpexcellence.org/sites/all/pdfs/pmp_effectiveness_brief_revised_3_29_12.pdf.
Accessed August 26, 2012.
68. Reifler LM. Droz D, Bailey JE et al. Do Prescription Monitoring Programs Impact State Trends
in Opioid Abuse/Misuse? Pain Medicine. 2012;13:434-442.
69. Butler SF, Budman SH, Fernandez KC, et al. Development and validation of the Current
Opioid Misuse Measure. Pain. 2007;130:144156.
70. Belgrade MJ, Schamber CD, Lindgren BR. The DIRE score: predicting outcomes of opioid
prescribing for chronic pain. J Pain. 2006;7:671681.
71. Wu SM, Compton P, Bolus R, et al. The addiction behaviors checklist: validation of a new
clinician-based measure of inappropriate opioid use in chronic pain. J Pain Symptom
Manage. 2006;32:342-351.
72. Fine PG, Portenoy RK, and the Ad Hoc Expert Panel on Evidence Review and Guidelines for
Opioid Rotation. Establishing best practices for opioid rotation: conclusions of an expert
panel. J Pain Symptom Manage 2009;38:418-25
73. Knotkova H, Fine PG, Portenoy RK: Opioid rotation: the science and limitations of the
equianalgesic dose table. J Pain Symptom Manage. 2009;38:426-39.
74. Shabalina S, Zaykin DV, Gris P et al. Expansion of the human opioid receptor gene
architecture: novel functional variats. Hum Molec Genet. 2009;18:1037-1051.
75. Pasternak GW. Molecular insights into opioid pharmacology: From the clinic to the bench.
Clin J Pain. 2010;26(Suppl 10)S3-S9.
76. Argoff CE. Clinical implications of opioid pharmacogenetics. Clin J Pain. 21010;26(Suppl
10)S16-S20.
77. Ballantyne, Shin. Efficacy of opioids for chronic pain: a review of the evidence. Clin J Pain.
2008;24:469-478.
78. Portenoy R, Farrar J, Backonja M, et al. Long-term use of controlled-release oxycodone for
noncancer pain: Results of a 3-year registry study. Clin J Pain. 2007;23:287-299.
79. Furlan AD, Sandoval JA, Mailis-Gagnon A, Tunks E. Opioids for chronic noncancer pain: a
meta-analysis of effectiveness and side effects. CMAJ. 2006 May 23;174:1589-94.
44
80. Meredith Noble, Jonathan R Treadwell, Stephen J Tregear, et al. Long-term opioid
management for chronic noncancer pain. Cochrane Database of Systematic Reviews 2010,
Issue 1. Art. No.: CD006605. DOI:10.1002/14651858.CD006605.pub2.
81. Eriksen J, Sjogren P, Bruera E, Ekholm O, Rasmussen NK. Critical issues on opioids in
chronic non-cancer pain: An epidemiological study. Pain. 2006;125:172-179.
82. Volinn E, Fargo JD, Fine PG. Opioid therapy for nonspecific low back pain and the outcome
of chronic work loss. Pain. 2009 Apr;142:194-201.
83. Dillie KS, Fleming MF, Mundt MP, French MT. Quality of life associated with daily opioid
therapy in a primary care chronic pain sample. J Am Board Fam Med. 2008;21:108-117.
84. Webster BS, Verma SK, Gatchel RJ. Relationship between early opioid prescribing for acute
occupational low back pain and disability duration, medical costs, subsequent surgery and
late opioid use. Spine. 2007;32:2127-32.
85. Schneider JP, Kirsh KL. Defining clinical issues around tolerance, hyperalgesia, and
addiction: A quantitative and qualitative outcome study of long-term opioid dosing in a chronic
pain practice. J Opioid Manag. 2010;6:385-396.
86. Naliboff BD, Wu SM, Schieffer B, Bolus R, Pham Q, Baria A, Aragaki D, Van Vort W, Davis F,
Shekelle P. A randomized trial of 2 prescription strategies for opioid treatment of chronic
nonmalignant pain. J Pain. 2011;12:288-96
87. Lee M, Silverman S, Hansen H, Patel V, Manchikanti L. A Comprehensive Review of OpioidInduced Hyperalgesia. Pain Physician 2011;14:145-161.
88. Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review.
Anesthesiology. 2006;104:570-587.
89. Chu LF, DArcy N, Brady C et al. Analgesic tolerance without demonstrable opioid-induced
hyperalgesia: a double-blinded, randomized, placebo-controlled trial of sustained-release
morphine for treatment of chronic nonradicular low-back pain. Pain. 2012;153:1583-92.
90. Portenoy RK, Hagen NA. Breakthrough pain: definition, prevalence and characteristics. Pain.
1990;41:273-281.
91. Portenoy RK, Bennett DS, Rauck R, et al: The prevalence and characteristics of
breakthrough pain in opioid-treated patients with chronic non-cancer pain. J Pain.
2006;7:583-591.
92. Lussier D, Portenoy RK: Adjuvant analgesics. In Hanks G, Cherny NI, Christakis N, Fallon M,
Kaasa S, Portenoy RK (eds): Oxford Textbook of Palliative Medicine. Fourth Ed. Oxford:
Oxford University Press. 2012.
45