Background for Fast Fact #171  Prescriptions for methadone have increased in the past few decades (1).    This 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 (Fast Fact #75 and Fast Fact #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.  

Historical Context 

• 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 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 an emerging understanding that opioids can be an effective part of neuropathic pain treatment.  

Basic science data      Methadone inhibits reuptake of norepinephrine and serotonin in a similar manner to many anti-depressants, some of which are effective against neuropathic pain (e.g. duloxetine, 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 (2). 

Patient data      Small controlled studies demonstrated that methadone can reduce neuropathic pain in both cancer and non-cancer patients (3-6). There is no data, for or against the proposition, that methadone is superior to other opioids for neuropathic pain (7).  A 2017 Cochrane Collaborative review found, “The studies provide very limited, very low-quality evidence of the efficacy and safety of methadone for chronic neuropathic pain, and there were too few data for pooled analysis of efficacy or harm, or to have confidence in the results of the individual studies” (8).   

Methadone deaths     There is a growing awareness that the increased prescription of methadone is being paralleled by a similar increase in methadone-related deaths (9,10).  The US Department of Health and Human Services convened an expert panel 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 an observation that methadone, unlike morphine or hydromorphone, can prolong the QTc interval and lead to serious cardiac conduction abnormalities (12-14).  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 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 to treat neuropathic pain compared to other opioids.  The risk of respiratory depression and QTc prolongation should give clinicians pause before prescribing methadone based solely on the theory that it is a superior opioid in neuropathic pain.

References 

1. Warner M, Chen LH, et al. Drug poisoning deaths in the United States, 1980–2008. NCHS Data Brief. 2011; 1-8.
2. Foley KM. Opioids and chronic neuropathic pain. NEJM 2003; 348:1279-1281.
3. 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.
4. Júnior JA, Barbosa MM, Kubota GT, et al. METHA-NeP: effectiveness and safety of methadone for neuropathic pain: a controlled randomized trial. Pain. 2022 May 13:10-97.
5. Gagnon B, et al. Methadone in the treatment of neuropathic pain. Pain Res Manage. 2003; 8:149-154.
6. Moulin DE, et al. Methadone in the management of intractable neuropathic non cancer pain. Can J Neuro Sci.  2005; 32:340-343.
7. Hanna V, Senderovich H. Methadone in pain management: a systematic review. The Journal of Pain 2021; 22(3):233-245.
8. McNicol ED, Ferguson MC, Schumann R. Methadone for neuropathic pain in adults. Cochrane Database of Systematic Reviews. 2017(5).
9. Centers for Disease Control and Prevention (CDC). Vital signs: risk for overdose from methadone used for pain relief – United States, 1999-2010, Morb Mortal Wkly Rep 2012; 61:493-497.
10. Ray WA, Chung CP, Murray KT, et al.  Out-of-hospital mortality among patients receiving methadone for noncancer pain.  JAMA Int Med 2015; 175(3):420-427.
11. US Department of Health and Human Services. Increase in poisoning deaths caused by non-illicit drugs–Utah, 1991-2003. MMWR Weekly. 2005; 54:33-36.
12. Treece JM, Madani MA, Khoury GE, et al. Comprehensive Review on Methadone-Induced QT Prolongation and Torsades. Journal of Pharmacology and Pharmacotherapeutics. 2018;9(2):66-75.
13. Kao D, Bartelson BB, et al.  Trends in reporting methadone-associated cardiac arrhythmia, 1997-2011. Ann of Int Med 2013;158: 735-740.
14. Alinejad S, Kazemi T, Zamani N, Hoffman RS, Mehrpour O. A systematic review of the cardiotoxicity of methadone. EXCLI journal. 2015 May 5;14:577.

Version History:  This Fast Fact was originally edited by David E Weissman MD and published in December 2006.  2nd Edition in April 2009: 3rd Edition in July 2015 by Sean Marks MD; 4th Edition in June 2025.
Conflicts of Interest: None to report.