1. Presented by Robert Dworkin, Ph.D. at the Anesthetic and Life Support Drugs Advisory Committee Meeting on May 16, 2002

2. Evidence that supports separate neuropathic pain indications 1.Distinct patterns of symptoms and signs 2.Unique combinations of pathophysiologic mechanisms 3.Specificity of treatment response

3. “Assuming that pain characteristics may reflect different underlying pain pathophysiologic mechanisms, these data suggest the possibility that the mechanisms that produce PHN pain may be different than those that produce pain in other neuropathic pain syndromes.” Galer BS, Jensen MP. Neurology, 1997;48:332-8 (data also drawn from Carter GT et al. Arch Phys Med Rehabil, 1998;79:1560-4) *Asterisks reflect significant differences among the five groups.

4. Prevalence of Mechanical Allodynia Postherpetic Neuralgia: 58-87% Watson CPN, et al. Pain, 1988;35:289-97. Nurmikko TJ, Bowsher D. J Neurol Neurosurg Psychiatry, 1990;53:135-41. Bowsher D. In CPN Watson, ed. Herpes Zoster and Postherpetic Neuralgia. Amsterdam: Elsevier, 1993:97-107. Painful Diabetic Neuropathy: 20-30% (?) “The mechanical stimuli—paintbrush strokes, pinprick and repeated pinprick—evoked only minimal pain at the first visit…indicating that mechanical allodynia, mechanical hyperalgesia, and ‘wind-up’ phenomenon were negligible.” Eisenberg E, et al. Lamotrigine in the treatment of painful diabetic neuropathy. Eur J Neurol, 1998;5:167-73.

5. Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet, 1999;353:1959-64. Syndrome Symptoms Pathophysiology Aetiology Neuropathic pain Stimulus- independent pain Stimulus dependent pain Mechanisms Metabolic Ischaemic Hereditary Compression Nerve damage Traumatic Toxic Infectious Immune- mediated

6. Costigan M, Woolf CJ. Pain: molecular mechanisms. Journal of Pain, 2000;1(suppl 1):35-44.

7. Modified from Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet, 1999;353:1959-64. Syndrome Symptoms Pathophysiology Aetiology Neuropathic pain Stimulus- independent pain Stimulus dependent pain Mechanisms Metabolic Ischaemic Hereditary Compression Nerve damage Traumatic Toxic Infectious Immune- mediated PHNDPN Phantom TNSFSN FOR ILLUSTRATIVE PURPOSES ONLY:  Central sensitization  Impaired regeneration of small fibers  Reorganization of somatosensory cortex  Na+ channel dependent ectopic discharge  Sprouting of Aß fibers into superficial dorsal horn All material in colors added to original. 

8. The results of placebo-controlled trials and clinical experience have established carbamazepine as first-line therapy for trigeminal neuralgia. Campbell et al, 1966774-period x-over (2 wks/per’d)CBZ > PBO Rockliff et al, 196692-period x-over (3 days/per’d)CBZ > PBO Killian et al, 1968242-period x-over (5 days/per’d)CBZ > PBO ( double-blind patients only) Nicol et al, 1969442-period partial x-overCBZ = PBO But carbamazepine is not considered first- line therapy for any other neuropathic pain syndrome.

9. Amitriptyline is not superior to placebo in painful HIV peripheral neuropathy

10. “In diabetic neuropathy, dextromethorphan decreased pain by a mean of 24% (95% CI: 6% to 42%, p = 0.01), relative to placebo. In postherpetic neuralgia, dextromethorphan did not reduce pain (95% CI: 10% decrease in pain to 14% increase in pain, p = 0.72).” Nelson KA, Park KM, Robinovitz E, Tsigos C, Max MB. High-dose oral dextromethorphan versus placebo in painful diabetic neuropathy and postherpetic neuralgia. Neurology, 1997;48:1212-8. “Dextromethorphan is effective in a dose-related fashion in selected patients with painful diabetic neuropathy. This was not true of PHN, suggesting a difference in pain mechanisms between the two conditions.” Sang CN, Booher, S, Gilron I, Parada S, Max MB. Dextromethorphan and memantine in painful diabetic neuropapthyand postherpeticneuralgia: efficacy and dose-response trials. Anesthesiology, in press.