1 Neuropathic Pain And Diabetic Neuropathy Dr. Awni Khrais Philadelphia University

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Neuropathic Pain AndNeuropathic Pain AndDiabetic NeuropathyDiabetic Neuropathy

Dr. Awni Khrais

Philadelphia University.

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ExamplesPeripheral• Postherpetic neuralgia• Trigeminal neuralgia• Diabetic peripheral neuropathy• Postsurgical neuropathy• Posttraumatic neuropathyCentral• Poststroke painCommon descriptors2

• Burning• Tingling• Hypersensitivity to touch or cold

Examples • Pain due to inflammation• Limb pain after a fracture• Joint pain in osteoarthritis• Postoperative visceral pain Common descriptors2

• Aching• Sharp• Throbbing

Examples • Low back pain with

radiculopathy• Cervical

radiculopathy• Cancer pain• Carpal tunnel

syndrome

Mixed PainPain with

neuropathic and nociceptive components

Neuropathic PainPain initiated or caused by a

primary lesion or dysfunction in the nervous system (either peripheral or

central nervous system)1

Nociceptive PainPain caused by injury to

body tissues (musculoskeletal,

cutaneous or visceral)2

Presentation Across Pain States Varies

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

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Nociceptive Pain

Nociceptive pain is an appropriate physiologic response to painful stimuli.

Tortora G, Grabowski SR. Principles of Anatomy and Physiology. 10th ed.2003.

Trauma

Ascending input Descending modulation

Dorsal root ganglionSpinothalamic tract

Peripheral nociceptors

Peripheral nerve

Dorsal horn

Pain

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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;18:343-349Raja 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.”

Merskey H et al. (Eds) In: Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 1994:209-212.

International Association for the Study of Pain (IASP) 1994

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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;18:343-349Raja et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4th Ed. 1999.;11-57

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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 Increased sensitivity to stimulation, excluding the special senses

HyperpathiaA 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

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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;61:61-83. 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

•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.

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Descriptions of Symptoms Reported by Patients with Neuropathic Pain*

0

5

10

15

20

25

% r

es

po

ns

es

How would you describe the pain? (n=1172)

*Includes peripheral, central and mixed pain statesData 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

Nicholson and Verma. Pain Med. 2004;5 (suppl. 1):S9-S27

Pain

Sleepdisturbances

Anxiety &Depression

Functional impairment

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1.Fishbain DA et al. Pain 1986;26:181-1972.Krishnan KR et al. Pain 1985;22:279-287

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)

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Classifications of Pain

Acute

Chronic

Duration

Nociceptive

Neuropathic

Pathophysiology

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The Continuum of Pain1

<1 month

Time to resolution

3-6 months

AcutePain

ChronicPain

• Usually obvious tissue damage

• Increased nervous system activity

• Pain resolves upon healing

• Serves a protective function

• 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.

Insult

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Development of Neuropathic Pain

Woolf and Mannion. Lancet 1999;353:1959-64

Neuropathic pain

Spontaneous pain Stimulus-evoked pain

Mechanisms

Metabolic Traumatic

ToxicIschemic

Hereditary

Compression

Infectious

Immune-related

Syndrome

Symptoms

Pathophysiology

Etiology

Nerve damage

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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;353:1959-1964. 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

Baron R, Binder A. 2004 Orthopade. 2004;33(5):568-75

Disc

C Fiber

C Fiber

A Fiber

Nociceptive component:Sprouting from C-fibers into the disc

Neuropathic component I:Damage to a branch of the C fiber due to compression and inflammatory mediators

Neuropathic component II: Compression of nerve root

Neuropathic component III: Damage to nerve root by inflammatory mediators

Central sensitization

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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

•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.

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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;353:1959-642. 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

88% of patients reported their worst pain as moderate or severe

Worst Pain in Last 24 Hours Pain Severity Index

Mild

Moderate

Severe

13%

37%

51%

Mild

Moderate

Severe21%

54%

25%

Mild/no: 0-3; Moderate: 4-6; Severe: 7-10

77% of patients reported a pain severity index of moderate or severe

N=602; 93% on Rx medication for pain

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 patientsfail to find adequate relief with existing practicesbecause of a ceiling effect of available drugs; thesepatients often develop significant comorbidity withsizable 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 vastnumber 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

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Differentiation of Distal Symmetric Polyneuropathy from Mono-/Amyoradiculopathies

DSPN Mono-/Amyoradiculopathies

Onset Insidious Acute/sub acute

Distribution Distal/length dependent

Proximal/Asymmetric

Leading signs and symptoms Mild to moderate sensory symptoms(-ve or +ve) & mild motor symptoms

Sever sensory (+ve pain) motor (weakness and atrophy) symptoms

Course of disease Slow progression Monophasic

Glycemic control Dependent Independent

Duration of diabetes Dependent Independent

Association with retinopathy & nephropathy

Associated 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

Aaron Vinik, and Anahit Mehrabyan ,American Diabetes Association (2006)

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

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Pathogenesis

A- Duration and severity of hyperglycemia

B- Electrophysiology

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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

Anticonvulsants 13%

Antidepressants/ mood stab. 4%

Opioids 4%

NSAIDs (incl. COX-II) 41%

Non-narcotic analgesics 21%

Tranquilizers 9%

Local anesthetics 6%

All other 2%

Medications with established efficacy represent a small proportion of Rx

IMS global Rx data 4Q 2003 (n=143 million Rx)

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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)

Initial management of symptomatic neuropathy

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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.

Initial management of symptomatic neuropathy

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Oral symptomatic therapy of painful neuropathy

Drug class Drug Daily dose (mg) Side Effects

Tricyclics Amitriptyline

Imipramine

25-150

25-150

++++

++++

SSRIs Paroxitene

Citalopram

40

40

+++

+++

Anticonvulsants Gabapentin

Lamotrigine

Carbamazepine

900-1,800

200-400

Up to 800

++

++

+++

Antiarrhythmics* Mexilitene Up to 450 +++

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.

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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

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Anticonvulsants 13%


Opioids 4%



Tranquilizers 9%


All other 2%



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Pathogenesis

A- Duration and severity of hyperglycemia

B- Electrophysiology

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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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Anticonvulsants 13%


Opioids 4%



Tranquilizers 9%


All other 2%



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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

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DN4 Diagnostic Questionnaire

DN4: Douleur Neuropathique en 4 questionsBouhassira et al. Pain. 2005;114:29-36

• Completed by physician in office

• Differentiates neuropathic from nociceptive pain

• 2 pain questions (7 items)

• 2 skin sensitivity tests (3 items)

• Validated

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Pain History in Neuropathic Pain

• 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

Identify the following:1 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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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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Sensory Processing and Neuropathic Pain

Adapted from Doubell et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4 th Ed. 1999.;165-182

Nerve function

Stimulus Primary afferent Sensation Mechanism

Normal Innocuousmechanical

A-beta Normal touchNormal function

Noxious, mechanical thermal or chemical

A-delta nociceptorC nociceptor

Normal sharp painNormal burning pain

Decreased Innocuous mechanical

A-betaTactile

hypoanesthesiaDecreased

transmission of impulses



Mechanical, heal, or cold hypoalgesia

Increased Innocuous,mechanical

A-betaDynamic mechanical

allodynia

Many theories (sensitization, etc.)



Mechanical, heat or cold hyperalgesia

Many theories (wind-up, peripheral

sensitization etc.)

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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


Baron R. Clin J Pain. 2000;16:S12-S20. Jensen and Baron. Pain. 2003;102:1-8

*Allodynia: Pain due to a stimulus that does not normally provoke pain

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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 ~46°C


Thermal cold Touch skin with coolants (acetone)


*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 painPain initiated or caused by a primary

lesion or dysfunction in the nervous system

Peripheral neuropathic painPain initiated or caused by a primary

lesion or dysfunction in the peripheral nervous system

Central neuropathic painPain initiated or caused by a primary

lesion or dysfunction in the central nervous system


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Most Patients Currently Receive Rx Medications for Neuropathic Pain

7

93

0 20 40 60 80 100

No

Yes

% of patients on prescription medications (n=602)

Almost all patients were receiving Rx meds for their neuropathic pain

Data on file, Pfizer Inc. European Survey in Painful Neuropathic Disorders

Documents

1 Neuropathic Pain And Diabetic Neuropathy Dr. Awni Khrais Philadelphia University