Methadone use for non-cancer pain associated with increased mortality

1. Methadone is an opioid analgesic often prescribed for pain management; however side effects include potentially fatal respiratory depression and ventricular arrhythmia.

2. In this study, methadone was found to be associated with increased all-cause mortality as compared to morphine sustained-release when used in non-cancer patients.

Evidence Rating Level: 2 (Good)       

Study Rundown: Methadone use has expanded beyond those receiving treatment for narcotic addiction. Due to its low cost, it is becoming a popular treatment for chronic pain. Unfortunately, this drug is characterized by variable pharmacokinetics and a long half-life, which has the potential to cause sustained respiratory depression. It can also prolong the QT interval and cause ventricular arrhythmias and sudden cardiac death. This retrospective cohort sought to investigate the effect of methadone use on all-cause mortality in patients with non-cancer pain. The investigators found that in non-cancer patients, there was an increased risk of all-cause mortality associated with methadone use as compared to morphine sustained-release (morphine SR).

This study made significant efforts to reduce and adjust for confounding factors, however more than half of the cohort also was concurrently using another drug in addition to either methadone or morphine SR. Moreover, the entire study population was comprised of Tennessee Medicaid enrollees, which could possibly limit generalizability. However, roughly one-fourth of the patients received either methadone or morphine prior to the study period, which could have eliminated patients who were more susceptible to the adverse effects. Further studies are necessary to reconcile this report with others that have found no significant increase in mortality as a result of methadone analgesic use.

Click to read the study in JAMA Internal Medicine

Relevant Reading: Comparative mortality among Department of Veterans Affairs patients prescribed methadone or long-acting morphine for chronic pain.

In-Depth [retrospective cohort]: This study used records of 38,756 Tennessee Medicaid enrollees aged 30 to 74 years with filled prescriptions for either methadone or morphine SR between 1997 and 2009. Exclusion criteria were created in an attempt to minimize confounding from deaths related to terminal diseases such as cancer. Patients older than 75 years old and nursing home residents were also excluded, as were patients with a history of drug abuse at risk for overdose. The primary end point of the study was all deaths outside the hospital, classified into three subgroups based on death certificates: sudden unexpected deaths consistent with either opioid overdose or life-threatening arrhythmias, other cardiac or respiratory deaths for which opioid involvement was possible but not definitive, and deaths not as likely to be related to the drugs.

The most common indication for taking the study opioid was for either back or musculoskeletal pain (90%). Patients who took methadone had a 46% increased risk of death compared to morphine SR during the follow-up period of this study, with an adjusted hazard ratio of 1.46 (95%CI 1.17-1.83; p<0.001). The lowest quartile of methadone dose (<20mg/dL), when compared with an equivalent dose of morphine SR (<60 mg/dL), was also associated with an increased risk of death with an adjusted hazard ratio of 1.59 (95%CI 1.01-2.51; p=0.046). The hazard ratios calculated in this study were adjusted for covariants including patient demographics, indication for opioid treatment, psychiatric and cardiovascular conditions, and other comorbidities.

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