By: Neal Shah, PharmD, MD/PhD Student c/o 2021, West Virginia University School of Medicine

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Methadone is a powerful long-acting mu-opioid agonist that has been traditionally used in the management of chronic pain, treatment of pain refractory to certain opioid agents, and maintenance of opioid addiction.^1-5 While neuropathic pain is not traditionally linked to mu-opioid receptors, spontaneous neuropathic pain has been successfully treated with opioids. However, no improvements in emotional or physical functioning were seen.⁶

Neuropathic pain is classically linked to N-methyl-D-aspartate (NMDA), serotonin (5HT), and norepinephrine (NE) receptors. NMDA receptors are antagonized by agents such as ketamine, and 5HT and NE reuptake into neurons are inhibited by agents such as duloxetine and amitriptyline.⁷ Some mu-opioid agonists, like tramadol, have dual 5HT/NE reuptake inhibition; methadone possesses these characteristics as well as additional NMDA antagonism.^8,9 Agonism of NMDA receptors causes a down-regulation of mu-opioid receptors. Therefore, by antagonizing NMDA receptors, mu-opioid agonists are able to exert analgesic effects.⁸ The combination of these effects makes methadone an excellent and efficacious option in managing neuropathic pain in both cancerous and noncancer settings, such as in diabetic neuropathy.^9,10

A retrospective chart review compared the visual analog scale (VAS) scores of pain from 18 patients (15 with various cancers, 3 with diabetes mellitus) before and after methadone treatment. Doses ranging from 15 mg to 60 mg of methadone daily lowered the VAS from an average of 7.5 to 1.5.¹¹ Another retrospective assessment of 50 noncancer patients with various intractable neuropathies (nerve root fibrosis, peripheral neuropathy, post-herpetic neuralgia, etc.) showed that out of the 26 patients that completed therapy and questionnaires, 15 had “moderate” pain relief, and 6 had “marked” pain relief.⁹ Two drawbacks of using mu-opioid agonists are their addictiveness and their overdose potential. In 2007, West Virginia ranked first for deaths involving overdoses on methadone.⁴

Additionally, since methadone involves the inhibition of 5HT reuptake, serotonin syndrome is possible. A woman taking concomitant methadone, olanzapine, and venlafaxine developed symptoms consistent with serotonin syndrome, which resolved when venlafaxine and olanzapine were discontinued.¹² Furthermore, selective serotonin reuptake inhibitors such as fluvoxamine and fluoxetine inhibit one pathway of the metabolism of methadone by CYP2D6, which may elevate the risk of developing serotonin syndrome.¹³

Methadone remains a valid choice to use in refractory neuropathic pain in many patient conditions; however, it must be administered with caution in patients at a high risk for drug abuse or overdose, and when concomitantly given with drugs affecting serotonin pathways.

SOURCES:

1. Baxter LE Sr, Campbell A, Deshields M et al. Safe methadone induction and stabilization: report of an expert panel. J Addict Med. 2013 Nov-Dec;7(6):377-86. doi: 10.1097/01.ADM.0000435321.39251.d7.
2. Shaiova L. The role of methadone in the treatment of moderate to severe cancer pain. Support Cancer Ther. 2005 Apr 1;2(3):176-80. doi: 10.3816/SCT.2005.n.010.
3. Kilonzo I, Twomey F. Rotating to oral methadone in advanced cancer patients: a case series. J Palliat Med. 2013 Sep;16(9):1154-7. doi: 10.1089/jpm.2012.0594. Epub 2013 Apr 30.
4. Terpening CM, Johnson WM. Methadone as an analgesic: a review of the risks and benefits. W V Med J. 2007 Jan-Feb;103(1):14-8.
5. Rhondali W, Tremellat F, Ledoux M et al.  Methadone Rotation for Cancer Patients with Refractory Pain in a Palliative Care Unit: An Observational Study. J Palliat Med. 2013 Oct 12. [Epub ahead of print]
6. McNicol ED, Midbari A, Eisenberg E. Opioids for neuropathic pain. Cochrane Database Syst Rev. 2013 Aug 29;8:CD006146. doi: 10.1002/14651858.CD006146.pub2.
7. Vranken JH. Elucidation of pathophysiology and treatment of neuropathic pain. Cent Nerv Syst Agents Med Chem. 2012 Dec;12(4):304-14.
8. Mizoguchi H, Watanabe C, Yonezawa A et al. New therapy for neuropathic pain. Int Rev Neurobiol. 2009;85:249-60. doi: 10.1016/S0074-7742(09)85019-8.
9. Moulin DE, Palma D, Watling C et al. Methadone in the management of intractable neuropathic noncancer pain. Can J Neurol Sci. 2005 Aug;32(3):340-3.
10. Hays L, Reid C, Doran M et al. Use of methadone for the treatment of diabetic neuropathy. Diabetes Care. 2005 Feb;28(2):485-7.
11. Gagnon B, Almahrezi A, Schreier G. Methadone in the treatment of neuropathic pain. Pain Res Manag. 2003 Fall;8(3):149-54.
12. Dvir Y, Smallwood P. Serotonin syndrome: a complex but easily avoidable condition. Gen Hosp Psychiatry. 2008 May-Jun;30(3):284-7. doi: 10.1016/j.genhosppsych.2007.09.007.
13. Bush E, Miller C, Friedman I. A case of serotonin syndrome and mutism associated with methadone. J Palliat Med. 2006 Dec;9(6):1257-9.

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