1

Presentation Across Pain States Varies
Neuropathic Pain
Pain initiated or caused by a primary lesion or dysfunction in the nervous system
(either peripheral or central nervous system) 1
Mixed Pain
Pain with neuropathic and nociceptive components
Nociceptive Pain
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 descriptors 2
•
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 descriptors 2
•
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 is an appropriate physiologic response to painful stimuli.
Pain
Ascending input
Spinothalamic tract
Descending modulation
Dorsal horn
Dorsal root ganglion
Peripheral nociceptors
Trauma
Peripheral nerve
Tortora G, Grabowski SR. Principles of Anatomy and Physiology. 10th ed.2003.
3

• 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. 4 th Ed. 1999.;11-57
4

“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

• 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. 4 th Ed. 1999.;11-57
6

Pain term Definition
Allodynia
Analgesia
Pain due to a stimulus that does not normally provoke pain
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.
7

• 20-24% of diabetics experience painful DPN 1
• 25-50% of patients >50 years with herpes zoster develop PHN ( ≥3 months after healing of rash) 1
• Up to 20% develop post-mastectomy pain 2
• 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 pain 4
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 8

Peripheral causes of neuropathic pain
• Trauma
– e.g. surgery, nerve entrapment, amputation
• Metabolic disturbances
– e.g. diabetes mellitus, uremia
• 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
Central causes of neuropathic pain
• Stroke
• Spinal cord lesions
• Multiple sclerosis
• Tumors
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.
9

Descriptions of Symptoms Reported by
Patients with Neuropathic Pain*
How would you describe the pain? (n=1172)
25
20
15
10
5
0
La nc in at in g
D ee p
S ha rp
A ch in g
B ur ni ng
S ho ot in g s an d ne ed le s
R ad
P in ia tin g
C ut tin g
P ric ki ng
N um b
D ul l
B ur st in g
D ril lin g
C ra m pi ng
S ta bb in g
G na w in g
*Includes peripheral, central and mixed pain states
Data on file. Pfizer Inc. Neuropathic Pain Patient Flow Survey. 10

Signs and Symptoms of Neuropathic Pain
Sign/Symptom Description (example)
Spontaneous symptoms
• Spontaneous pain 1
• Dysesthesias 2
Persistent burning, intermittent shock-like or lancinating pain
Abnormal unpleasant sensations e.g. shooting, lancinating, burning
Abnormal, not unpleasant sensations e.g. tingling • Parasthesias 2
Stimulus-evoked symptoms
• Allodynia 2
• Hyperalgesia
• Hyperpathia 2
2
Painful response to a non-painful stimulus e.g. warmth, pressure, stroking
Heightened response to painful stimulus e.g. pinprick, cold, heat
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.
11

Pain
Functional impairment
Anxiety &
Depression
Nicholson and Verma. Pain Med. 2004;5 (suppl. 1):S9-S27
Sleep disturbances
12

Anxiety
283 patients evaluated at pain centers 1
• 63% significant anxiety symptoms (DSM-III)
• 56% significant depressive symptoms (DSM-III)
Depression
71 patients with chronic low back pain 2
• 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 13

Duration
Acute
Chronic
Nociceptive
Pathophysiology
Neuropathic
14

1
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 more 2
•
Pain beyond expected period of healing 2
•
Usually has no protective function 3
•
Degrades health and function 3
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.
15

Syndrome
Neuropathic pain
Symptoms
Pathophysiology
Spontaneous pain Stimulus-evoked pain
Mechanisms
Etiology
Metabolic
Ischemic
Hereditary
Compression
Traumatic
Toxic
Infectious
Immune-related
Nerve damage
Woolf and Mannion. Lancet 1999;353:1959-64
16

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;353:1959-
1964. Roberts et al. In Casey KL (Ed). Pain and central nervous system disease. 1991 17

“Sciatica”: Mixed Pain State with Several
Possible Pathological Mechanisms
Disc
Nociceptive component:
Sprouting from C-fibers into the 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
18

Peripheral causes of neuropathic pain
• Trauma
– e.g. surgery, nerve entrapment, amputation
• Metabolic disturbances
– e.g. diabetes mellitus, uremia
• 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
Central causes of neuropathic pain
• Stroke
• Spinal cord lesions
• Multiple sclerosis
• Tumors
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.
19

• Diverse symptomatology 1
• Multiple mechanisms 1
• 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 treatment 2
1. Woolf CJ, Mannion RJ. Lancet. 1999;353:1959-64
2. Bonezzi C, Demartini L. Acta Neurol Scand Suppl. 1999;173:25-3
20

Worst Pain in Last 24 Hours Pain Severity Index
Mild
13%
Severe
21%
Mild
25%
Severe 51%
37%
54%
Moderate Moderate
88% of patients reported their worst pain as moderate or severe
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
21

“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
22

23

“
“
•Boulton . AJM, Diabetic Md.15:508-514, 1998
•Diabetic, American Association
24

Dyck.P, 2005 American Diabetic Association
25

-------------------------------------------------------------------
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
Onset
DSPN
Insidious
Distribution Distal/length dependent
Leading signs and symptoms Mild to moderate sensory symptoms(ve or +ve) & mild motor symptoms
Course of disease Slow progression
Mono-
/Amyoradiculopathies
Acute/sub acute
Proximal/Asymmetric
Sever sensory (+ve pain) motor (weakness and atrophy) symptoms
Monophasic
Independent Glycemic control
Duration of diabetes
Dependent
Dependent Independent
Association with retinopathy & nephropathy
Associated Non Associated
27

Cranial 3 rd , 4 th , 6 th , 7 th
Thoracic Mononeuritis multiplex
Peripheral Peroneal
Sural
Sciatic
Aaron Vinik, and Anahit Mehrabyan ,American Diabetes
Association (2006)
28

Mononeuritis Entrapment
Onset
Pain
Sudden
Acute
Gradual
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)
29

30

Polyol pathway, Myoinsitol, Glyation, Oxidative stress, Growth factor, Insulin-like growth, c.peptide,
VEGF, Immune Mechansim
American Diabetic Association 2005
31

Current Prescription Medication Use Among
Patients Treated for Neuropathic Pain
Medications with established efficacy represent a small proportion of Rx
All other 2%
Local anesthetics 6%
Tranquilizers 9%
Anticonvulsants 13%
Antidepressants/ mood stab. 4%
Opioids 4%
NSAIDs
(incl. COX-II) 41%
Non-narcotic analgesics 21%
IMS global Rx data 4Q 2003 (n=143 million Rx)
32

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)
33

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
Tricyclics Amitriptyline
SSRIs
Imipramine
Paroxitene
Citalopram
Anticonvulsants Gabapentin
Lamotrigine
Carbamazepine
Antiarrhythmics* Mexilitene
Daily dose (mg)
25-150
25-150
40
40
900-1,800
200-400
Up to 800
Up to 450
Side Effects
++++
++++
+++
+++
++
++
+++
+++
Opioids Tramadol
Oxycodone CR
†
50-400
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.
35

36

37

38

39

“
“
•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%
Local anesthetics 6%
Tranquilizers 9%
Anticonvulsants 13%
Antidepressants/ mood stab. 4%
Opioids 4%
NSAIDs
(incl. COX-II) 41%
Non-narcotic analgesics 21%
IMS global Rx data 4Q 2003 (n=143 million Rx)
41

42

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%
Local anesthetics 6%
Tranquilizers 9%
Anticonvulsants 13%
Antidepressants/ mood stab. 4%
Opioids 4%
NSAIDs
(incl. COX-II) 41%
Non-narcotic analgesics 21%
IMS global Rx data 4Q 2003 (n=143 million Rx)
44

• 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

• 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 46

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)
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
1. Jensen and Baron. Pain. 2003;102:1-8
47

48

• 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
49

50

Sensory Processing and Neuropathic Pain
Nerve function
Normal
Decreased
Increased
Stimulus Primary afferent Sensation Mechanism
Innocuous mechanical
A-beta Normal touch
Noxious, mechanical thermal or chemical
A-delta nociceptor
C nociceptor
Normal sharp pain
Normal burning pain
Normal function
Innocuous mechanical
A-beta
Noxious, mechanical thermal or chemical
A-delta nociceptor
C nociceptor
Innocuous, mechanical
A-beta
Noxious, mechanical thermal or chemical
A-delta nociceptor
C nociceptor
Tactile hypoanesthesia
Decreased transmission of impulses
Mechanical, heal, or cold hypoalgesia
Dynamic mechanical allodynia
Many theories
(sensitization, etc.)
Mechanical, heat or cold hyperalgesia
Many theories
(wind-up, peripheral sensitization etc.)
Adapted from Doubell et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4 th
51

Type of allodynia Expected response
Mechanical static
Test
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
Thermal cold
Touch skin with an object at ~40 °C
Painful, burning sensation
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

Type of hyperalgesia
Mechanical pinprick
Test
Manual pinprick with a safety pin
Expected response
Sharp, superficial pain
Thermal warm
Thermal cold
Touch skin with an object at
~46 °C
Painful, burning sensation
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 54

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
Pain initiated or caused by a primary lesion or dysfunction in the
peripheral nervous system
Central neuropathic pain
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
% of patients on prescription medications (n=602)
100
Data on file, Pfizer Inc. European Survey in Painful Neuropathic Disorders
56