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Neuropathic Pain And Diabetic Neuropathy

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

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Neuropathic Pain And Diabetic Neuropathy

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

  2. 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 Nociceptive Pain Pain caused by injury to body tissues (musculoskeletal, cutaneous or visceral)2 Mixed Pain Pain with neuropathic and nociceptive components • 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

  3. Trauma Nociceptive Pain Nociceptive pain is an appropriate physiologic response to painful stimuli. Pain Ascending input Descending modulation Dorsal horn Spinothalamic tract Dorsal root ganglion Peripheral nerve Peripheral nociceptors Tortora G, Grabowski SR. Principles of Anatomy and Physiology. 10th ed.2003.

  4. 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

  5. What is pain? “An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” Defining Pain • 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.

  6. 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

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

  8. 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

  9. 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 Neuropathic Pain Causes 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.

  10. Descriptions of Symptoms Reported by Patients with Neuropathic Pain* How would you describe the pain? (n=1172) *Includes peripheral, central and mixed pain states Data on file. Pfizer Inc. Neuropathic Pain Patient Flow Survey.

  11. Signs and Symptoms of Neuropathic Pain 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.

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

  13. 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

  14. Classifications of Pain Acute Duration Chronic Nociceptive Pathophysiology Neuropathic

  15. The Continuum of Pain1 Insult Time to resolution Acute Pain Chronic Pain <1 month 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 • Usually obvious tissue damage • Increased nervous system activity • Pain resolves upon healing • Serves a protective function 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.

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

  17. Peripheral Mechanisms Membrane hyperexcitability Ectopic discharges Peripheral sensitization Central Mechanisms Membrane hyperexcitability Ectopic discharges Wind up Central sensitization Denervation supersensitvity Loss of inhibitory controls Neuropathic Pain: Underlying Mechanisms 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

  18. “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

  19. 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 Neuropathic Pain Causes 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.

  20. 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

  21. Pain Experience in Patients with Neuropathic Pain in EU Survey Pain Severity Index Worst Pain in Last 24 Hours Mild Mild Severe 13% 21% 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

  22. 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

  23. Diabetic Neuropathy

  24. 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

  25. Other Definition “ Clinical or subclinical disorders, including somatic and/or autonomic parts of PNS ” Dyck.P, 2005 American Diabetic Association

  26. Distribution(%) of Symptoms and Signs of Proximal Neuropathies in Diabetes • ------------------------------------------------------------------- • Clinical Presentation VasculitisCIDPMGUSDM • ------------------------------------------------------------------- • DSPN (motor/sensory) 3 91 100 67 • Distal(asymmetric) 27 9 0 0 • Multifocal 70 0 0 33

  27. Differentiation of Distal Symmetric Polyneuropathy from Mono-/Amyoradiculopathies

  28. Common Mononeuropathies • Aaron Vinik, and Anahit Mehrabyan ,American Diabetes Association(2006)

  29. Comparison of features of Mononeuritis & entrapment • Aaron Vinik, and Anahit Mehrabyan ,American Diabetes Association(2006)

  30. Pathogenesis A- Duration and severity of hyperglycemia B- Electrophysiology

  31. 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

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

  33. Initial management of symptomatic neuropathy • 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)

  34. 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.

  35. Oral symptomatic therapy of painful neuropathy

  36. Thank you

  37. 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

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

  39. Pathogenesis A- Duration and severity of hyperglycemia B- Electrophysiology

  40. 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

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

  42. 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

  43. Completed by physician in office Differentiates neuropathic from nociceptive pain 2 pain questions (7 items) 2 skin sensitivity tests (3 items) Validated DN4 Diagnostic Questionnaire DN4: Douleur Neuropathique en 4 questions Bouhassira et al. Pain. 2005;114:29-36

  44. 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) Pain History in Neuropathic Pain 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 1. Jensen and Baron. Pain. 2003;102:1-8

  45. 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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