Meeting the Challenge of Herpesvirus Infections

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Presented by Robert Dworkin, Ph.D. at
the Anesthetic and Life Support Drugs Advisory
Committee Meeting on May 16, 2002
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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, 199748332-8 (data also drawn from
Carter GT et al. Arch Phys Med Rehabil,
1998791560-4) Asterisks reflect significant
differences among the five groups.
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• Prevalence of Mechanical Allodynia
• Postherpetic Neuralgia 58-87
• Watson CPN, et al. Pain, 198835289-97.
• Nurmikko TJ, Bowsher D. J Neurol Neurosurg
  Psychiatry, 199053135-41.
• Bowsher D. In CPN Watson, ed. Herpes Zoster and
  Postherpetic Neuralgia. Amsterdam Elsevier,
  199397-107.
• Painful Diabetic Neuropathy 20-30 (?)
• The mechanical stimulipaintbrush strokes,
  pinprick and repeated pinprickevoked only
  minimal pain at the first visitindicating 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, 19985167-73.

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Syndrome Symptoms Pathophysiology Aetiology
Neuropathic pain
Stimulus- independent pain
Stimulus dependent pain
Mechanisms
Metabolic
Traumatic
Toxic
Ischaemic
Infectious
Hereditary
Immune-mediated
Compression
Woolf CJ, Mannion RJ. Neuropathic pain
aetiology, symptoms, mechanisms, and management.
Lancet, 19993531959-64.
Nerve damage
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Costigan M, Woolf CJ. Pain molecular mechanisms.
Journal of Pain, 20001(suppl 1)35-44.
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PHN
DPN
Phantom
TN
SFSN
Syndrome Symptoms Pathophysiology Aetiology
Neuropathic pain
Stimulus- independent pain
Stimulus dependent pain
Mechanisms
?
?
?
?
?
Metabolic
Traumatic
Toxic
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
Ischaemic
Infectious
Hereditary
Immune-mediated
Compression
Modified from Woolf CJ, Mannion RJ. Neuropathic
pain aetiology, symptoms, mechanisms, and
management. Lancet, 19993531959-64.
Nerve damage
All material in colors added to original.
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• 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/perd) CBZ gt PBO
• Rockliff et al, 1966 9 2-period x-over (3
  days/perd) CBZ gt PBO
• Killian et al, 1968 24 2-period x-over (5
  days/perd) CBZ gt 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.

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Amitriptyline is not superior to placebo in
painful HIV peripheral neuropathy
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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, 1997481212-8. Dextrometh
orphan 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.