Out-of-Hospital Mortality among Patients Receiving Methadone for Non-Cancer Pain

Methadone, a µ-opioid agonist long used as evidence-based treatment for opioid dependence,1 has been increasingly prescribed for chronic pain. In 2009, 4.4 million methadone prescriptions in the U.S. were for treatment of pain, accounting for 9% of prescribed opioid analgesics on a dose-adjusted basis.1 Methadone's primary advantages as an analgesic are a long elimination half-life,2 and low cost;1 however, its efficacy is comparable to that of other long-acting opioids.3 There are major concerns regarding methadone's relative safety. The risk for accidental overdose and lethal respiratory depression may be greater than that for other long-acting opioids. Because the duration of methadone's respiratory depressant effects is longer than that for its analgesic effects,4;5 inadvertent intoxication can occur as dose is increased to provide greater pain relief. This risk may be exacerbated by methadone's highly variable pharmacokinetics.4;5 In 2006, the FDA issued an advisory and the label was modified to warn of the potential for unintentional overdose.5–7 This concern was reinforced by autopsy series of opioid overdose deaths with over-representation of methadone-related cases8;9 and a U.S. study demonstrating a disproportionate number of prescription-opioid-related overdose deaths with methadone involvement.1 Methadone also has adverse cardiac effects. It prolongs the QT interval10 and has been implicated in numerous case reports of life-threatening ventricular arrhythmias.10–13 Cases of sudden cardiac death, the majority of which are due to ventricular arrhythmias,14;15 have been reported in methadone patients.16 These data have led to questions regarding the appropriateness of the widespread use of methadone for the treatment of chronic pain, particularly given other equally effective alternatives.1;3;17 However, the one cohort study comparing methadone to sustained-release (SR) morphine unexpectedly found that adjusted overall mortality was 44% lower for the methadone users.18 Given this controversy, we conducted a cohort study of patients receiving either methadone or morphine SR for non-cancer pain. Given the multiple mechanisms by which an opioid could increase mortality, the primary endpoint was total mortality during study followup.