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

Presented by Robert Dworkin, Ph.D.

at theAnesthetic and Life Support Drugs

Advisory Committee Meetingon May 16, 2002

Evidence that supports separateneuropathic pain indications

1. Distinct patterns of symptoms and signs

2. Unique combinations of pathophysiologic mechanisms

3. Specificity of treatment response

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Sharp* Hot Dull Cold* Sensitive* Itchy* Deep Surface*

PHN

CRPS-I (RSD)

Diabetic neuropathy

Peripheral nerve injury

Charcot-Marie-Tooth

“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.

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 painfuldiabetic neuropathy. Eur J Neurol, 1998;5:167-73.

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

Stimulusdependent pain

Mechanisms

Metabolic

Ischaemic

Hereditary

Compression

Nerve damage

Traumatic

Toxic

Infectious

Immune-mediated

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

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

Stimulusdependent pain

Mechanisms

Metabolic

Ischaemic

Hereditary

Compression

Nerve damage

Traumatic

Toxic

Infectious

Immune-mediated

PHN DPN Phantom TN SFSN

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.

The results of placebo-controlled trials and clinical experience have established carbamazepine as first-line therapy for trigeminal neuralgia.

• Campbell et al, 1966 77 4-period x-over (2 wks/per’d) CBZ >

PBO

• Rockliff et al, 1966 9 2-period x-over (3 days/per’d) CBZ >

PBO

• Killian et al, 1968 24 2-period x-over (5 days/per’d) CBZ >

PBO (double-blind patients only)

• Nicol et al, 1969 44 2-period partial x-over CBZ =

PBO

But carbamazepine is not considered first-line therapy for any other neuropathic pain syndrome.

Amitriptyline is not superior to placeboin painful HIV peripheral neuropathy

“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 memantinein painful diabetic neuropapthyand postherpeticneuralgia: efficacy

and dose-response trials. Anesthesiology, in press.