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Neuropathic Pain And
Diabetic Neuropathy
Dr. Awni Khrais
Philadelphia University.
1
Presentation Across Pain States Varies
Neuropathic Pain
Mixed Pain
Nociceptive Pain
Pain initiated or caused by a
primary lesion or dysfunction
in the nervous system
(either peripheral or
central nervous system)1
Pain with
neuropathic and
nociceptive
components
Pain caused by injury to
body tissues
(musculoskeletal,
cutaneous or visceral)2
Examples
Peripheral
• Postherpetic neuralgia
• Trigeminal neuralgia
• Diabetic peripheral neuropathy
• Postsurgical neuropathy
• Posttraumatic neuropathy
Central
• Poststroke pain
Common descriptors2
• Burning
• Tingling
• Hypersensitivity to touch or cold
Examples
• Low back pain with
radiculopathy
• Cervical
radiculopathy
• Cancer pain
• Carpal tunnel
syndrome
Examples
•
•
•
•
Pain due to inflammation
Limb pain after a fracture
Joint pain in osteoarthritis
Postoperative visceral pain
Common descriptors2
• Aching
• Sharp
• Throbbing
1. International Association for the Study of Pain. IASP Pain Terminology.
2. Raja et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4th Ed. 1999.;11-57
2
Nociceptive Pain
Nociceptive pain is an appropriate physiologic response to painful stimuli.
Pain
Ascending input
Descending modulation
Dorsal horn
Spinothalamic tract
Dorsal root ganglion
Trauma
Peripheral nerve
Peripheral nociceptors
Tortora G, Grabowski SR. Principles of Anatomy and Physiology. 10th ed.2003.
3
Fiber Types Involved in Neuropathic
Pain
• Aβ fibers
— Large diameter, myelinated, fast conduction velocity
— Mechanoreceptors normally activated by non-noxious
mechanical stimuli (touch)
• Aδ fibers
— Large diameter, myelinated, intermediate conduction velocity
— Normally activated by noxious stimuli (transmit sharp pain)
• C fibers
— Small diameter, unmyelinated, slow conduction velocity
— Normally activated by noxious stimuli (responsible for secondary
pain, normally burning, aching pain)
• In neuropathic pain abnormal sensations may be
transmitted along Aβ , Aδ or C fibers
Dworkin Clin J Pain. 2002;18:343-349
Raja et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4th Ed. 1999.;11-57
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Defining Pain
What is pain?
“An unpleasant sensory and emotional
experience associated with actual or potential
tissue damage, or described in terms of such
damage.”
International Association for the Study of
Pain (IASP) 1994
Merskey H et al. (Eds) In: Classification of Chronic Pain:
Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 1994:209-212.
5
Fiber Types Involved in Neuropathic
Pain
• Aβ fibers
— Large diameter, myelinated, fast conduction velocity
— Mechanoreceptors normally activated by non-noxious
mechanical stimuli (touch)
• Aδ fibers
— Large diameter, myelinated, intermediate conduction velocity
— Normally activated by noxious stimuli (transmit sharp pain)
• C fibers
— Small diameter, unmyelinated, slow conduction velocity
— Normally activated by noxious stimuli (responsible for secondary
pain, normally burning, aching pain)
• In neuropathic pain abnormal sensations may be
transmitted along Aβ , Aδ or C fibers
Dworkin Clin J Pain. 2002;18:343-349
Raja et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4th Ed. 1999.;11-57
6
IASP Definitions
Pain term
Definition
Allodynia
Pain due to a stimulus that does not normally provoke pain
Analgesia
Absence of pain in response to stimulation that would normally
be painful
Hyperalgesia
An increased response to a stimulus that is normally painful
Hyperesthesia
Hyperpathia
Increased sensitivity to stimulation, excluding the special
senses
A painful syndrome characterized by an abnormally painful
reaction to a stimulus, especially a repetitive stimulus, as well
as an increased threshold
Hypoalgesia
Diminished pain in response to a normally painful stimulus
Hypoesthesia
Decreased sensitivity to stimulation, excluding the special
senses
Merskey H et al. (Eds) In: Classification of Chronic Pain:
Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 1994:209-212.
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Prevalence/Incidence of Neuropathic
Pain in Different Conditions
• 20-24% of diabetics experience painful DPN1
• 25-50% of patients >50 years with herpes zoster
develop PHN (≥3 months after healing of rash)1
• Up to 20% develop post-mastectomy pain2
• One-third of cancer patients have neuropathic pain
(alone or with nociceptive pain)3
• 7% of patients with low back pain may have
associated neuropathic pain4
1. Schmader. Clin J Pain. 2002;18:350-4. 2. Stevens et al. Pain. 1995;61:61-8
3. Davis and Walsh. Am J Hosp Palliat Care. 2004;21(2):137-42.
4. Deyo and Weinstein. NEJM 2001;344(5):363 - 370
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Neuropathic Pain Causes
Peripheral causes of neuropathic pain
•
Trauma
– e.g. surgery, nerve entrapment, amputation
•
Metabolic disturbances
– e.g. diabetes mellitus, uremia
•
Central causes of neuropathic pain
• Stroke
• Spinal cord lesions
• Multiple sclerosis
• Tumors
Infections
– e.g. herpes zoster (shingles), HIV
•
Toxins
– e.g. chemotherapeutic agents, alcohol
•
Vascular disorders
– e.g. lupus erythematosus, polyarteritis nodosa
•
Nutritional deficiencies
– e.g. niacin, thyamine, pyridoxine
•
Direct effects of cancer
– e.g. metastasis, infiltrative
Wall PD, Melzack R (Eds). Textbook of pain. 4th Ed. 1999; Galer BS, Dworkin RH (Eds) A clinical
guide to neuropathic pain. 2000: Woolf CJ et al. Lancet. 1999;353:1959-1964.
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Descriptions of Symptoms Reported by
Patients with Neuropathic Pain*
How would you describe the pain? (n=1172)
25
% responses
20
15
10
5
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*Includes peripheral, central and mixed pain states
Data on file. Pfizer Inc. Neuropathic Pain Patient Flow Survey.
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Signs and Symptoms of Neuropathic Pain
Sign/Symptom
Description (example)
Spontaneous symptoms
• Spontaneous pain1
Persistent burning, intermittent shock-like or
lancinating pain
• Dysesthesias2
Abnormal unpleasant sensations
e.g. shooting, lancinating, burning
• Parasthesias2
Abnormal, not unpleasant sensations e.g. tingling
Stimulus-evoked
symptoms
• Allodynia2
Painful response to a non-painful stimulus
e.g. warmth, pressure, stroking
• Hyperalgesia2
Heightened response to painful stimulus e.g.
pinprick, cold, heat
• Hyperpathia2
Delayed, explosive response to any painful stimulus
1.Baron. Clin J Pain. 2000;16:S12-S20.
2. Merskey H et al. (Eds) In: Classification of Chronic Pain:
Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 1994:209-212.
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The Inter-Relationship Between Pain,
Sleep, and Anxiety / Depression
Pain
Functional
impairment
Anxiety &
Depression
Nicholson and Verma. Pain Med. 2004;5 (suppl. 1):S9-S27
Sleep
disturbances
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Anxiety and Depression are Prevalent
in Chronic Pain
Anxiety
283 patients evaluated at pain centers1
• 63% significant anxiety symptoms (DSM-III)
• 56% significant depressive symptoms (DSM-III)
Depression
71 patients with chronic low back pain2
• 44% major, 11% minor depression (SADS-L)
1.Fishbain DA et al. Pain 1986;26:181-197
2.Krishnan KR et al. Pain 1985;22:279-287
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Classifications of Pain
Acute
Duration
Chronic
Nociceptive
Pathophysiology
Neuropathic
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The Continuum of Pain1
Insult
Time to resolution
Acute
Pain
<1 month
• Usually obvious tissue damage
• Increased nervous system activity
• Pain resolves upon healing
• Serves a protective function
Chronic
Pain
3-6 months
• Pain for 3-6 months or more2
• Pain beyond expected period
of healing2
• Usually has no protective
function3
• Degrades health and function3
1. Cole BE. Hosp Physician. 2002;38:23-30.
2.Turk and Okifuji. Bonica’s Management of Pain. 2001.
3. Chapman and Stillman. Pain and Touch. 1996.
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Development of Neuropathic Pain
Syndrome
Symptoms
Neuropathic pain
Spontaneous pain
Mechanisms
Pathophysiology
Etiology
Stimulus-evoked pain
Metabolic
Traumatic
Ischemic
Toxic
Hereditary
Infectious
Compression
Immune-related
Nerve damage
Woolf and Mannion. Lancet 1999;353:1959-64
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Neuropathic Pain:
Underlying Mechanisms
Peripheral Mechanisms
• Membrane hyperexcitability
— Ectopic discharges
• Peripheral sensitization
Central Mechanisms
• Membrane hyperexcitability
— Ectopic discharges
• Wind up
• Central sensitization
• Denervation supersensitvity
• Loss of inhibitory controls
Attal N et al. Acta Neurol Scand. 1999;173:12-24. Woolf CJ et al. Lancet. 1999;353:19591964. Roberts et al. In Casey KL (Ed). Pain and central nervous system disease. 1991
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“Sciatica”: Mixed Pain State with Several
Possible Pathological Mechanisms
Nociceptive component:
Sprouting from C-fibers into the disc
Disc
C Fiber
Neuropathic component I:
Damage to a branch of the C fiber
due to compression and
inflammatory mediators
C Fiber
A Fiber
Neuropathic component II:
Compression of nerve root
Neuropathic component III:
Damage to nerve root by inflammatory
mediators
Central sensitization
Baron R, Binder A. 2004 Orthopade. 2004;33(5):568-75
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Neuropathic Pain Causes
Peripheral causes of neuropathic pain
•
Trauma
– e.g. surgery, nerve entrapment, amputation
•
Metabolic disturbances
– e.g. diabetes mellitus, uremia
•
Central causes of neuropathic pain
• Stroke
• Spinal cord lesions
• Multiple sclerosis
• Tumors
Infections
– e.g. herpes zoster (shingles), HIV
•
Toxins
– e.g. chemotherapeutic agents, alcohol
•
Vascular disorders
– e.g. lupus erythematosus, polyarteritis nodosa
•
Nutritional deficiencies
– e.g. niacin, thyamine, pyridoxine
•
Direct effects of cancer
– e.g. metastasis, infiltrative
Wall PD, Melzack R (Eds). Textbook of pain. 4th Ed. 1999; Galer BS, Dworkin RH (Eds) A clinical
guide to neuropathic pain. 2000: Woolf CJ et al. Lancet. 1999;353:1959-1964.
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Challenges in Diagnosing Neuropathic
Pain
• Diverse symptomatology1
• Multiple mechanisms1
• Difficulties in communicating and understanding
symptoms
— Patients may find it difficult to articulate their symptoms
clearly
— Physicians may find it difficult to interpret some of the
terminology patients use to describe their symptoms
• Variable response to treatment2
1. Woolf CJ, Mannion RJ. Lancet. 1999;353:1959-64
2. Bonezzi C, Demartini L. Acta Neurol Scand Suppl. 1999;173:25-3
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Pain Experience in Patients with
Neuropathic Pain in EU Survey
Worst Pain in Last 24 Hours
Pain Severity Index
Mild
Mild
Severe
13%
Severe
25%
21%
51%
37%
54%
Moderate
88% of patients reported their worst pain
as moderate or severe
Moderate
77% of patients reported a pain severity
index of moderate or severe
N=602; 93% on Rx medication for pain
Mild/no: 0-3; Moderate: 4-6; Severe: 7-10
Data on file, Pfizer Inc. European Survey in Painful Neuropathic Disorders
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Current Treatments: Expert Views
“A relatively large number of neuropathic pain patients
fail to find adequate relief with existing practices
because of a ceiling effect of available drugs; these
patients often develop significant comorbidity with
sizable impact on their quality of life”
Smith and Sang. Eur J Pain.2002:6(suppl B):13-18
“We cannot provide adequate treatment to a vast
number of patients with established neuropathic pain”
Taylor BK. Curr Pain and Headache Rep. 2001;5:151-161
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Diabetic Neuropathy
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Diabetic Neuropathies
“ The presence of symptoms and/or
signs of peripheral nerve
dysfunction in people with diabetes
after the exclusion of other causes “
•Boulton . AJM, Diabetic Md.15:508-514, 1998
•Diabetic, American Association
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Other Definition
“ Clinical or subclinical disorders,
including somatic and/or autonomic
parts of PNS ”
Dyck.P, 2005 American Diabetic Association
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Distribution(%) of Symptoms and Signs of
Proximal Neuropathies in Diabetes
-------------------------------------------------------------------
Clinical Presentation Vasculitis CIDP MGUS DM
------------------------------------------------------------------DSPN (motor/sensory)
3
91
100
67
Distal(asymmetric)
27
9
0
0
Multifocal
70
0
0
33
26
Differentiation of Distal Symmetric Polyneuropathy
from Mono-/Amyoradiculopathies
DSPN
Mono/Amyoradiculopathies
Acute/sub acute
Onset
Insidious
Distribution
Proximal/Asymmetric
Course of disease
Distal/length
dependent
Mild to moderate
sensory symptoms(ve or +ve) & mild
motor symptoms
Slow progression
Glycemic control
Dependent
Independent
Duration of diabetes
Dependent
Independent
Leading signs and symptoms
Association with retinopathy & Associated
nephropathy
Sever sensory (+ve pain)
motor (weakness and
atrophy) symptoms
Monophasic
Non Associated
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Common Mononeuropathies
Cranial
3rd, 4th, 6th, 7th
Thoracic
Mononeuritis multiplex
Peripheral
Peroneal
Sural
Sciatic
Aaron Vinik, and Anahit Mehrabyan ,American Diabetes
Association (2006)
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Comparison of features of Mononeuritis
& entrapment
Mononeuritis
Entrapment
Onset
Sudden
Gradual
Pain
Acute
Chronic
Multiplex
Occurs
Rare
Course
Resolves
Persists without
intervention
Treatment Physical therapy Rest/ Splints steroid
and local anesthetic
injections , surgery
Aaron Vinik, and Anahit Mehrabyan ,American Diabetes
Association (2006)
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Pathogenesis
A- Duration and severity of
hyperglycemia
B- Electrophysiology
30
C- Glucose metabolic and transport
dysfunction
Polyol pathway, Myoinsitol, Glyation, Oxidative
stress, Growth factor, Insulin-like growth, c.peptide,
VEGF, Immune Mechansim
American Diabetic Association 2005
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Current Prescription Medication Use Among
Patients Treated for Neuropathic Pain
Medications with established efficacy represent a small proportion of Rx
All other 2%
Anticonvulsants 13%
Local anesthetics 6%
Tranquilizers 9%
Antidepressants/
mood stab. 4%
Opioids 4%
Non-narcotic
analgesics 21%
IMS global Rx data 4Q 2003 (n=143 million Rx)
NSAIDs
(incl. COX-II) 41%
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Initial management of symptomatic neuropathy
1) Exclude nondiabetic causes
•
•
•
•
•
•
Malignant disease (e.g. bronchogenic carcinoma)
Metabolic
Toxic (e.g. alcohol)
Infective (e.g. HIV infection)
Latrogenic (e.g. isoniazid, vinca alkaloids)
Medication related (chemotherapy, HIV
treatment)
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Initial management of symptomatic neuropathy
2) Explanation, support, and practical measures
(e.g. bed cradle to lift bed, clothes off hyperesthetic
skin).
3) Assess level of blood glucose control profiles.
4) Aim for optimal stable control.
5) Consider pharmacological therapy.
34
Oral symptomatic therapy of painful neuropathy
Drug class
Drug
Daily dose (mg)
Side Effects
Tricyclics
Amitriptyline
25-150
++++
SSRIs
Imipramine
Paroxitene
25-150
40
++++
+++
Anticonvulsants
Citalopram
Gabapentin
40
900-1,800
+++
++
Lamotrigine
200-400
++
Carbamazepine
Antiarrhythmics* Mexilitene
Up to 800
Up to 450
+++
+++
Opioids
Tramadol
50-400
+++
Oxycodone CR†
10-60
++++
All medications in the table have demonstrated efficacy in randomized controlled
studies, *Mexilitene should be used with caution & with regular EKG monitoring,
† Oxycodone CR may be useful as an add-in therapy in severe symptomatic
neuropathy.
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Thank you
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Diabetic Neuropathies
“ The presence of symptoms and/or
signs of peripheral nerve
dysfunction in people with diabetes
after the exclusion of other causes “
•Boulton . AJM, Diabetic Md.15:508-514, 1998
•Diabetic, American Association
40
Current Prescription Medication Use Among
Patients Treated for Neuropathic Pain
Medications with established efficacy represent a small proportion of Rx
All other 2%
Anticonvulsants 13%
Local anesthetics 6%
Tranquilizers 9%
Antidepressants/
mood stab. 4%
Opioids 4%
Non-narcotic
analgesics 21%
IMS global Rx data 4Q 2003 (n=143 million Rx)
NSAIDs
(incl. COX-II) 41%
41
Pathogenesis
A- Duration and severity of
hyperglycemia
B- Electrophysiology
42
C- Glucose metabolic and transport
dysfunction
Polyol pathway, Myoinsitol, Glyation, Oxidative
stress, Growth factor, Insulin-like growth, c.peptide,
VEGF, Immune Mechansim
American Diabetic Association 2005
43
Current Prescription Medication Use Among
Patients Treated for Neuropathic Pain
Medications with established efficacy represent a small proportion of Rx
All other 2%
Anticonvulsants 13%
Local anesthetics 6%
Tranquilizers 9%
Antidepressants/
mood stab. 4%
Opioids 4%
Non-narcotic
analgesics 21%
IMS global Rx data 4Q 2003 (n=143 million Rx)
NSAIDs
(incl. COX-II) 41%
44
LANSS Scale
• Completed by physician in office
• Differentiates neuropathic from nociceptive pain
• 5 pain questions and 2 skin sensitivity tests
• Identifies contribution of neuropathic mechanisms to pain
• Validated
Bennett. Pain. 2001;92:147-57
45
DN4 Diagnostic Questionnaire
• Completed by physician in
office
• Differentiates neuropathic
from nociceptive pain
• 2 pain questions (7 items)
• 2 skin sensitivity tests (3
items)
• Validated
DN4: Douleur Neuropathique en 4 questions
Bouhassira et al. Pain. 2005;114:29-36
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Pain History in Neuropathic Pain
Identify the following:1
• Type, distribution and location of
pain
— Character of complaints
• e.g. burning, shock-like, pins
and needles etc.
— Based on anatomic drawing
• Nerve territory
• Extraterritorial spread
• Duration of complaints
• Average intensity of pain in the
last day/week (0-10)
• Extent of interference with daily
activity (0-10)
1. Jensen and Baron. Pain. 2003;102:1-8
Areas of further exploration
• Previous medical history
• Exposure to toxins or other drug
treatment
e.g. taxol, radiation
• Use of pain medications
• Associated psychological and
mood disturbance
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48
Pathophysiology of Neuropathic Pain:
• Neuropathic pain is pain initiated or caused by a primary lesion
or dysfunction in the nervous system
— Peripheral or central in origin
• Peripheral neuropathic pain may often co-exist with nociceptive
pain
• Peripheral and central mechanisms mediate neuropathic pain
independent of aetiology
• Characterized by positive and negative symptoms
— Shared across neuropathic pain states
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50
Sensory Processing and Neuropathic Pain
Nerve
function
Normal
Decreased
Increased
Stimulus
Primary afferent
Sensation
Innocuous
mechanical
A-beta
Normal touch
Noxious, mechanical
thermal or chemical
A-delta nociceptor
C nociceptor
Normal sharp pain
Normal burning pain
Innocuous
mechanical
A-beta
Tactile
hypoanesthesia
Noxious, mechanical
thermal or chemical
A-delta nociceptor
C nociceptor
Mechanical, heal, or
cold hypoalgesia
Innocuous,
mechanical
A-beta
Dynamic mechanical
allodynia
Many theories
(sensitization, etc.)
Mechanical, heat or
cold hyperalgesia
Many theories
(wind-up,
peripheral
sensitization etc.)
Noxious, mechanical
thermal or chemical
A-delta nociceptor
C nociceptor
Mechanism
Normal function
Decreased
transmission of
impulses
Adapted from Doubell et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4th Ed. 1999.;165-182
51
Allodynia*: Simple Tests and Expected
Responses
Type of allodynia
Test
Expected response
Mechanical static
Manual light pressure on
skin
Dull pain
Mechanical punctate
Light manual pinprick with
sharp stick
Sharp, superficial pain
Mechanical dynamic
Stroke skin with brush,
gauze or cotton
Sharp, burning,
superficial pain
Thermal warm
Touch skin with an object
at ~40°C
Painful, burning
sensation
Thermal cold
Touch skin with object ~
20 °C
Painful, burning
sensation
*Allodynia: Pain due to a stimulus that does not normally provoke pain
Baron R. Clin J Pain. 2000;16:S12-S20. Jensen and Baron. Pain. 2003;102:1-8
52
53
Hyperalgesia*: Simple Tests and
Expected Responses
Type of
hyperalgesia
Test
Expected response
Mechanical
pinprick
Manual pinprick with a
safety pin
Sharp, superficial pain
Thermal warm
Touch skin with an object at Painful, burning
~46°C
sensation
Thermal cold
Touch skin with coolants
(acetone)
Painful, burning
sensation
*Hyperalgesia: Increased response to a stimulus which is normally painful
Baron R. Clin J Pain. 2000;16:S12-S20. Jensen and Baron. Pain. 2003;102:1-8
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IASP Definitions: Peripheral Neuropathic and
Central Neuropathic Pain
Neuropathic pain
Pain initiated or caused by a primary
lesion or dysfunction in the nervous system
Peripheral neuropathic pain
Central neuropathic pain
Pain initiated or caused by a primary
lesion or dysfunction in the
peripheral nervous system
Pain initiated or caused by a primary
lesion or dysfunction in the
central nervous system
Merskey H et al. (Eds) In: Classification of Chronic Pain:
Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 1994:209-212.
55
Most Patients Currently Receive Rx
Medications for Neuropathic Pain
Almost all patients were receiving Rx meds for their neuropathic pain
Yes
93
No
7
0
20
40
60
80
100
% of patients on prescription medications (n=602)
Data on file, Pfizer Inc. European Survey in Painful Neuropathic Disorders
56