Diabetic Pain Peripheral Neuropathy

Agus Yuwono

ULIN Hospital Lambung Mangkurat
University
1. INTRODUCTION
2. PATHOFISIOLOGY
3. ASSESSMENT
4. MANAGEMENT & GUIDELINES


TOPICS
ASK-DNC
2
(Tjokroprawiro, 1993, Revised : 1998, 2002)
Chronic Diabetic Complications and Provided Information
Retinopathy : "The Window of Microangiopathy" CHD : "The Window of Macroangiopathy"
Microalbuminuria (30-299 mg/day or 20-199 mg/min) : is referred to as having Incipient Nephropathy
Microangiopathy : Retinopathy, Nephropathy, Neuropathy Macroangiopathy : CHD, Stroke, PVD
Inability to achieve or maintain an erection sufficient
for satisfactory sexual performance
Erectile Dysfunction = ED (NIH-Consensus 1993)
IIEF 1997 : Score < 21
:
*) + 5% of this Prevalence : PDN
%
67.0
51.4
50.9
27.2
25.5
16.3
12.8
12.1
10.0
5.7
4.2
3.8
3.0
Retinopathy
Joint Manifestation
Cataract
Pulmonary Tbc
Hypertension (WHO,1983)
CHD
Clinical Nephropathy
Stroke
Cellulitis - Gangrene
Symptomatic Gall Stone
0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0
Dyslipidemia
Hypertension in Europe : 30 %
(Williams, 1991)
Commulative Prevalence of CVD : 63.0%
(in line with Dyslipidemia)
30 million in USA
(FELDMAN, et al 1994)
Erectile Dysfunction
Symptomatic Neuropathy*)
PERIPHERAL NEUROPATHY AND
PAIN ARE FREQUENT IN DM
Diabetic neuropathies are group of disorders in which
nerve are damaged as a consequence of high blood sugar

51,4% of DM: Diabetic Peripheral Neuropathy (DPN)
Similar rates in type 1 and type 2 diabetes
longer duration of diabetes
poor glucose control

30% to 60% DPN: Painfull Neuropathy
Boulton et al, 2004
CLASSIFICATION OF DIABETIC NEUROPATHY
Sensorimotor neuropathy
Distal symmetric polyneuropathy
Focal neuropathy
Diabetic mononeuropathy (cranial,
truncal, peripheral nerves)
Mononeuropathy multiplex
Diabetic amyotrophy
Autonomic neuropathy
Hypoglycemic unawareness
Abnormal pupillary function
Cardiovascular autonomic neuropathy
Vasomotor neuropathy
Sudomotor neuropathy (sweat glands)
Genitourinary autonomic neuropathy


Boulton et al, 2005/ADA, 2005
Generalized symmetric polyneuropathies
Acute sensory
Chronic sensory motor
Autonomic
Focal and multifocal neuropathies
Cranial
Truncal
Focal limb
Proximal motor (amyotrophy)
Coexisting Chronic Inflammatory
Demyelinating Polyneuropathy
(CIDP)
Aring et al, 2005
CLASSIFICATION OF DIABETIC
NEUROPATHY
A. Symmetric neuropathies
1. Distal symmetric sensorimotor polyneuropathy
2. Autonomic neuropathy
3. Acute painful neuropathy
4. Hyperglycemic neuropathy
5. Tratment-induced neuropathy
6. Symmetric proximal lower extremity neuropathy
B. Focal and multifocal neuropathy
1. Cranial neuropathy
2. Thoracoabdominal
3. Focal limb
4. Diabetic amyotrophy
Freeman, 2005
CLASSIFICATION OF DIABETIC
NEUROPATHY
Peripheral neuropathy
a. distal symmetrical sensory loss
b. motor neuropathy
foot drop,wrist drop
diabetic amyotrophy
Cranial neuropathy
cranial nerves affected 111,1V,V1,V11
Autonomic neuropathy
a. postural hypotension
b. resting tachycardia
c. loss of sweating
d. gastrointestinal neuropathy
gastroparesis,diabetic diarrhea
e. urinary bladder atony
f. erectile dysfunction

PERIPHERAL POLYNEUROPATHY
Vinik, 2006
large fiber neuropathies
C-fiber function in vasodilation
Vinik, 2006
Clinical presentation of small fiber neuropathy
The signs of this disorder:
Pain (C-fiber type, burning and
superficial),
late hypoalgesia,
hypoesthesia,
impaired warm thermal perception,
decreased sweating,
impaired cutaneous blood flow (the
cold foot).
The risks are foot ulcers,
gangrene, and amputations.
Vinik, 2006
FEATURES NEUROPATHY
Burning or lancinating
Hyperesthesia
Paresthesia
Loss of Pain and
Temperature
Dysautonomia
Foot Ulceration
Loss of visceral pain
Loss of position and
vibration sensation
Areflexia
Nerve-conduction
abnormalities
SMALL - FIBER
LARGE - FIBER
Boulton et al, 2005/ADA, 2005
Gejala Peripheral:
mati rasa / kesemutan di kaki sensitivitas, kram, /
ketidakpekaan menyentuh, kehilangan keseimbangan /
koordinasi
Otonom gejala:
inkontinensia urin, hilangnya respon seksual, stasis lambung
(gastropaty), hipotensi ortostatik.Etiologi tidak diketahui
Diabetic Neuropathy. July 2005 (updated 2006). NIDDK publication NIH 93-3185.
Vinik AI et al. In: Diabetes Mellitus. 2006:737-751.

CLINICAL PATHWAYS LEADING
TO FOOT ULCERATION
Diabetes Mellitus
Peripheral Vascular Disease
Neuropathy
Ischemic Foot
FOOT ULCERATION
Trauma
Motor Sensory
Decreased
pain & position
sensation
Motor dysfunction
High plantar foot pressures
Autonomic
Intrinsic
muscle
wasting
Foot
deformity
Limited
joint mobility
Decreased
sweat production
Dry skin
Fissures
Callus
AV shunting
Charcot joint
disease
Cigarette smoking
dyslipidemia
Using a goniometer, the flexion: at least 90.
Force of the ground up
Abnormal
contracture of
tendon achilles
Upper extremity features of large fiber
neuropathies.
Lower extremity features of large
fiber neuropathies.
SYMPTOMS OF DIABETIC PERIPHERAL
NEUROPATHY
Numbness or loss of feeling
Pickling/Tingling (mengeras)
Aching (sakit)
Burning Pain
Lancinating Pain
Unusual sensitivity or tenderness when feet are touched
(allodynia) adalah nyeri akibat stimulus yang biasanya tidak
memprovokasi rasa sakit

Negative emotions
Depression
Anxiety
Poor Sleep
Decreased quality of life
Existential Suffering
May lead patients to want to
actively
end their life
1. INTRODUCTION
2. PATHOFISIOLOGY
3. ASSESSMENT
4. MANAGEMENT & GUIDELINES


TOPICS
ASK-DNC
Schiff Base
(Hours)

Amadori Products
(Days)

AGEs
(Week-Months)
PHASE-1


PHASE-2


PHASE-3


AGE-Protein
(Brownlee, 1995)

Nucleic Acid Histones

Mutation

Gene Expression
Cancer
3
Pancreatic Ca Liver Ca
Microvascular Damage
DIABETIC NEUROPATHY
Aminoguanidine*
)

(Kowluru et al 1999)
Excellent
Glycemic Control
Macrophage
RAGE (SR1, SR2)

TNF, IL-1, IGF-1
Production

Proliferation of
Cells and Matrix
2


Endothelial Cell
RAGE (R1, R2, R3)
Oxidative Stress
Endothelin-1
Tissue Factor Production
Vasoconstriction
Focal Thrombosis
1
Adhesion Mol.
Expression
(Lopes-Virella et al 1999)
3
Clinical Staging of Hyperglycemia
Microvascular and Diabetic Neuropathy
(Summarized : Tjokroprawiro 1994, 1995, 1996, 1997, 1999, 2001, 2002, 2003, 2004)
*) AGE and Oxidative Stress
Hyperglycemia
-Linolenic
Acid
Ischemia
hypoxia
Lipolysis
AGE-RAGE-NF-B
Polyol pathway
Protein kinase C
Autooxidation
Growth
Factor
Immune-
mediated
inflammatory
response
Lipid Peroxidation DNA damage
( DRG; Schawn cell; terminals)
Length-dependent
sensory neuropathy
Genetic +
Figure: Suggested pathogenesis of
diabetic neuropathy
Low, 2005
Vinik, 2001
1. INTRODUCTION
2. PATHOFISIOLOGY
3. ASSESSMENT
4. GUIDELINES


TOPICS
ASSESSMENT
monofilament test
vibratory
pinprick tests
Reflexes and the strength and
flexibility of the toes, foot, and ankle
should also be assessed
signs of ulcer risk (eg, hammer toes,
bunions, calluses, tender areas).
Assessing for signs and symptoms
of peripheral vascular disease,
including pedal pulse quality,
capillary refill, skin color and moisture,
and ankle-brachial index,
1. INTRODUCTION
2. PATHOFISIOLOGY
3. ASSESSMENT
4. MANAGEMENT & GUIDELINES


TOPICS
TREATMENT GOALS
Halt progressive nerve fiber loss
Early intervention
Good glycemic control
Decrease symptoms, especially pain
Prevent ulcers and Amputation
Descending Inhibition
Brain
TCA
SSRI
SNRI
Tramadol
Opiates
COX-2 inhibitor
TCA
SSRI
SNRI
Tramadol
Opiates
COX-2 inhibitor
Spinal Cord
Gabapentin
Pregabalin
Oxcarbazepine
Ketamine
Dextropethorphan
Amantadine
Memantine
Topiramate
Opiates
COX-2 inhibitor
TCA
Opiates
Venlafaxine
Duloxetine
Locally
COX-2 inhibitor
Local anesthetic
Capsaicin
Cold
Peripheral Nervous
System
Carbamazepine
Oxcarbazepine
TCA
Topiramate
Mexiletine
Lidocaine

Pharmacologic Approach to Treatment
EFNS guidelines for the treatment of
painful polyneuropathy
Drugs with established efficacy include PREGABALIN,
gabapentin, TCAs, SNRIs,, strong opioids and tramadol
EFNS: European Federation of Neurological Societies, 2006
First line therapy
PREGABALIN/gabapentin or TCAs/SNRIs
(evidence level A)
Second line therapy Opioids and lamotrigine (evidence level B)
Lack of or
weak efficacy
SSRIs, capsaicin, mexiletine, oxcarbazepine and
topiramate (evidence level A)
Low strength evidence
or safety concerns
Carbamazepine and valproate
Recommendations:
Algorithm for management of symptomatic DPN (1). Note that nonpharmacological, topical,
or physical therapies might be useful at any stage. These include acupuncture, capsaicin,
glyceryl trinitrate spray/patches etc (2)
Symptomatic neuropathy
Exclude nondiabetic etiologies
Stabilize glycemic control (insulin not always required in type 2 diabetes)
Tricyclic drugs (e.g., Amitriptyline 25-150 mg before bed)
Anticonvulsants (e.g., Gabapentin, typical dose 1.8 g/day),
PREGABALIN
Opioid or opioid-like drug (e.g., Tramadol, Oxycodone)
Consider pain clinic referral
Boulton et al, 2005
ADA,2005
Pregabalin Effective in DPN: Rapid
Reduction in Pain
***
***
*** ***
***
*** **
**
**P<0.01; ***P<0.001 vs. placebo
***
EP
Rosenstock et al. Pain.2004;110:628-38
-3
-2.5
-2
-1.5
-1
-0.5
0
0 1 2
3 4 5 6 7 8 9
Week
M
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a
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c
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i
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p
a
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s
c
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e

Placebo (n=70)
Pregabalin 300 mg/day (n=76)
Pregabalin & Venlafaxine Study: Rapid
Improvement in HAM-A Score with Pregabalin
-18
-16
-14
-12
-10
-8
-6
-4
-2
0
0 1 2 3 4 5 6 7
M
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a
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c
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a
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f
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o
m

b
a
s
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i
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e
Placebo (n=100)
Pregabalin 400 mg/day (n=94)
Pregabalin 600 mg/day (n=104)
Venlafaxine IR 75 mg/day (n=110)
EP
*P<0.05, 400 mg vs. pbo
P<0.05, 600 mg & venlafaxine vs. pbo
Montgomery et al.
J Clin Psychiatry. 2006: In press
Week
Mean HAM-A baseline score = 26.5
*
*P<0.05, 400 & 600 mg
vs. pbo week 1
*
*
*





*
pregabalin memberikan efek independent pada
perbaikan ansietas.