Author(s): David E Weissman MD
Background Prescriptions for methadone have greatly increased in the past six years (1). The reason for this increase is likely related to two factors: reduced cost relative to other potent opioids and basic science data suggesting that methadone may be particularly useful in treating neuropathic pain. Two previous Fast Facts #75, 86) reviewed methadone’s pharmacological properties. This Fast Fact examines the research base regarding methadone and neuropathic pain and reviews the rise in methadone-related deaths.
Prior to 1985, when long-acting morphine preparations were introduced, methadone was commonly prescribed for cancer-related pain as it had a longer duration of action than morphine. However, it was well appreciated that methadone had a higher risk of respiratory depression due to drug accumulation with chronic dosing – an effect not associated with other opioids, for which there is no drug accumulation in the setting of normal renal function.
Prior to 1990 there was a widespread belief that opioids were relatively ineffective in treating neuropathic pain. Since then, there been a much greater understanding that opioids are an effective part of neuropathic pain treatment.
Basic science data Methadone inhibits reuptake of norepinephrine and serotonin in a similar manner to newer anti-depressants, some of which are effective against neuropathic pain (e.g. venlafaxine). Also, methadone binds to the NMDA receptor, a known modulator of neuropathic pain. Finally, methadone has demonstrated efficacy in animal models of neuropathic pain (1).
Patient data Small non-controlled case series and at least one small randomized study (methadone vs. placebo) have demonstrated that methadone can reduce neuropathic pain in both cancer and non-cancer patients (2-5). There is no data, for or against the proposition, that methadone is superior to other opioids for neuropathic pain. A 2004 Cochrane Collaborative review found, “there is no trial evidence to support the proposal that methadone has a particular role in neuropathic pain of malignant origin” (6). Furthermore, the review cautioned clinicians about the danger of methadone-induced respiratory depression due to its long terminal half-life.
Methadone deaths There is a growing awareness that the increased prescription of methadone is being paralleled by a similar increase in methadone-related deaths. Florida, Utah, North Carolina, Oregon, Indiana, Maryland, Alabama and West Virginia have all reported a spike in deaths related to methadone since 2000 (7,8). The US Department of Health and Human Services convened an expert panel in 2003 to investigate the rise in methadone deaths and concluded that the rise was largely due to the increasing use of methadone as an analgesic (9). The Center for Disease Control published a report detailing data from Utah in 2005, suggesting that part of the problem was due to increased prescribing (10). The current data seem to suggest that the general increased supply of methadone, via legitimate prescribing, is leading to deaths due to accidental overdose through improper prescribing or illicit diversion/recreational use. In addition to concern about respiratory depression, there has been a relatively recent observation that methadone, unlike morphine or hydromorphone, can prolong the QTc interval and lead to serious cardiac conduction abnormalities. Note: the overall number of opioid-related deaths has increased, not just from methadone. Note: there are no data on untimely deaths related to methadone prescribing in hospice/palliative care patients.
Summary The renewed interest in an old drug based on new science holds exciting promise of benefit for the many patients with neuropathic pain. However, clinical research has yet to confirm or deny a unique clinical role for methadone compared to other opioids. The risk of respiratory depression should give clinicians pause before prescribing methadone based solely on the theory that it is a superior opioid in neuropathic pain. Furthermore, given that diversion of legitimate opioid prescriptions to the illicit market can occur, even in the practice of hospice and palliative care, physicians and hospice agencies need to recognize they also have a larger social responsibility to the public welfare, and prescribe methadone with care and caution.
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Morley JS, et al. Low-dose methadone has an analgesic effect in neuropathic pain: a double-blind randomized controlled crossover trial. Pall Med. 2003; 17:576-587.
Altier N, et al. Management of chronic neuropathic pain with methadone: a review of 13 cases. Clin J Pain. 2005; 21:364-369.
Gagnon B, et al. Methadone in the treatment of neuropathic pain. Pain Res Manage. 2003; 8:149-154.
Moulin DE, et al. Methadone in the management of intractable neuropathic non cancer pain. Can J Neuro Sci. 2005; 32:340-343.
Nichloson AB. Methadone for cancer pain: Review. Cochrane Database of systematic reviews. 2004;2:CD003971.
Google Search: ‘Methadone deaths.’ December 2007.
Finn S, Tuckwiller S. Feds act on methadone deaths. West Virginia Gazette. July 23 2006.
Increase in poisoning deaths caused by non-illicit drugs--Utah, 1991-2003. MMWR Weekly. 2005; 54:33-36.
US Department of Health and Human Services – Division on Pharmacologic Therapies. Report on Methadone Mortality (http://dpt.samhsa.gov/reports/methodone_mortality-05.htm - no longer publicly available). Updated Report available at: http://www.dpt.samhsa.gov/pdf/MethadoneBackgroundPaper_72007_2_.pdf.
Fast Facts and Concepts are edited by Drew A Rosielle MD, Palliative Care Center, Medical College of Wisconsin. For more information write to: firstname.lastname@example.org. More information, as well as the complete set of Fast Facts, are available at EPERC: www.eperc.mcw.edu.
Version History: This Fast Fact was originally edited by David E Weissman MD and published in December 2006. Current version re-copy-edited in April 2009; web-links updated.
Copyright/Referencing Information: Users are free to download and distribute Fast Facts for educational purposes only. Weissman DE. Methadone for Neuropathic Pain. Fast Facts and Concepts. December 2006; 171. Available at: http://www.eperc.mcw.edu/FastFactsIndex/ff_171.htm.
Disclaimer: Fast Facts and Concepts provide educational information. This information is not medical advice. Health care providers should exercise their own independent clinical judgment. Some Fast Facts cite the use of a product in a dosage, for an indication, or in a manner other than that recommended in the product labeling. Accordingly, the official prescribing information should be consulted before any such product is used.
ACGME Competencies: Medical Knowledge, Patient Care
Keyword(s): Pain – Opioids