Neurology -- Correspondence for Raja et al., 59 (7) 1015-1021

Correspondence published:

Reply to Letter to the Editor: Srinivasa N Raja, Jennifer A Haythornthwaite and Mitchel Max (13 November 2002)

Opioids versus antidepressants in postherpetic neuralgia: A randomized, placebo-controlled tria: Paolo L Manfredi (13 November 2002)

Reply to Letter to the Editor 13 November 2002

Srinivasa N Raja
John Hopkins Hospital Baltimore MD,
Jennifer A Haythornthwaite and Mitchel Max
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Re: Reply to Letter to the Editor

sraja{at}jhmi.edu Srinivasa N Raja, et al.

Dr. Manfredi is accurate in pointing out subtle distinctions in the receptors affected by morphine and methadone in preclinical studies. However, it is not yet clear whether these differences contribute to the analgesic effects of methadone. While experts opine that methadone may be helpful in treating pain unresponsive to pure opioid agonists, this important issue requires systematic study in the context of randomized, controlled trials directly comparing these drugs.
Two findings from our study suggest that methadone may not be a superior agent to pure opioid agonists such as morphine in the treatment of neuropathic pain [3]. First, a subgroup of patients was placed on methadone after developing intolerable side effects to morphine (41%). In this group, dose escalation produced a lower maintenance dose (methadone- 15 mg) than the maintenance dose attained by the subgroup that remained on morphine (91 mg). Since side effects limited dose titration, some patients may be predisposed to side effects from mu opioid agonists and this predisposition may limit the usefulness of this class of drugs in these individuals. Second, the reduction in pain intensity by methadone (1.2) in the same group of patients was lower compared to the analgesic effects of morphine (2.2) in the group who remained on the primary medication. These findings are not consistent with the clinical lore that methadone is helpful in treating pain unresponsive to traditional mu opioid agonists.
The results of our study are consistent with the previous work by Watson and Babul using oxycodone in patients with postherpetic neuralgia [3]. Two different opioid agonists, morphine and oxycodone, have been shown to be effective in reducing neuropathic pain, hence we disagree with the author's conclusion that the results of this study may not be reproducible with pure opioid agonists [1].
References:
1) Reisine, T., and Pasternak, G.W., Opioid analgesics and antagonists. In Goodman & Gilman's: The Pharmacological Basis of Therapeutics, ed. By J.G. Hardman and L.E. Limbird, McGraw-Hill (1996) 521 -556.
2) Raja SN, Haythornthwaite JA, Pappagallo M, Clark MR et al, Opioids versus antidepressants in postherpetic neuralgia: A randomized, placebo- controlled trial. Neurology 2002;59:1015-1021.
3) Watson CP, Babul N. Efficacy of oxycodone in neuropathic pain: A randomized trial in postherpetic neuralgia. Neurology 1998;50:1837-1841.

Opioids versus antidepressants in postherpetic neuralgia: A randomized, placebo-controlled tria 13 November 2002

Paolo L Manfredi
Memorial Sloan Kettering Cancer Center New York NY
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Re: Opioids versus antidepressants in postherpetic neuralgia: A randomized, placebo-controlled tria

manfredp{at}mskcc.org Paolo L Manfredi

In this study, methadone was used by 41% of patients during opioid treatment. Methadone has activity at three different sites: agonistic activity at the mu opioid receptor [2], antagonistic activity at the N- methyl-d-aspartate (NMDA) receptor [3] and inhibitory activity on monoamine re-uptake [4]. These latter two actions are not shared by morphine or by other commonly used opioids such as oxycodone and fentanyl. Methadone's antagonistic activity at the NMDA receptor may result in analgesia against neuropathic pain and other chronic pain states [5]. In addition, the opioid agonist spectrum of methadone is different compared to morphine [6]. Over the last few years, experts in the field of pain management have rediscovered methadone as a very effective analgesic, especially useful for pain unresponsive to other opioids [7, 8, 9]. The analgesic efficacy of opioids seen in Raja et al. study may be at least in part due to methadone's antagonistic activity at the NMDA receptor or its inhibitory activity on mono-amine re-uptake and not solely a result of pure opioid activity [1]. Although the pain in the methadone group decreased less than in the morphine group, the study design selected the methadone patients based on intolerable side effects from a small dose of opioid (morphine 15 mg every 12 hours). Interestingly there was no dose escalation with methadone and a 3-fold dose escalation with morphine. Therefore, methadone is a unique analgesic with actions at three different sites. The results of this study may not be reproducible when pure opioid agonists, such as morphine, oxycodone, and fentanyl are used alone.
References:
1) Raja SN, Haythornthwaite JA, Pappagallo M et al. Opioids versus antidepressants in postherpetic neuralgia. A randomized, placebo controlled trial. Neurology 2002;59: 1015-1021.
2) Reisine, T., and Pasternak, G.W., Opioid analgesics and antagonists. In Goodman & Gilman's: The Pharmacological Basis of Therapeutics, ed. By J.G. Hardman and L.E. Limbird, McGraw-Hill (1996) 521 -556.
3) Gorman, A.L., Elliott, K.J. and Inturrisi, C.E., The d- and l- isomers of methadone bind to the non-competitive sit on the N-methyl-D- aspartate (NMDA) receptor in rat forebrain and spinal cord, Nerurosci Lett 1997;223:5-8.
4) Codd E, Shank R, Schupsky J, Raffia R. serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception. J Pharmacol Exp Ther 1995;274:1263-1270.
5) Davis AM and Inturrisi CE: d-Methadone blocks morphine tolerance and N-Methyl-D-Aspartate (NMDA)-induced hyperalgesia. J. Pharmacol Exp Ther 1999; 289:1048-53.
6) Chang A, Emmel DW, Rossi GC, Pasternak GW. Methadone analgesia in morphine-insensitive CXBK mice. Eur J Pharm 1988;351:189-191.
7) Bruera and Sweeney. Methadone use in cancer patients with pain: a review. J Pall Med 2002; 5:127-138.
8) Davis MP and Walsh D. Methadone for relief of cancer pain: a review of pharmacokinetics, pharmacodynamics, drug interactions and protocols of administration. Support Care Cancer 2001; 9:63-83.
9) Ripamonti and Dickerson. Strategies for the treatment of pain in the new millennium. Drugs 2001;61:955-977.