Mortality Risk of Opioid Substitution Therapy With Methadone Versus Buprenorphine: A Retrospective Cohort Study

Lancet Psychiatry. 2015 Oct;2(10):901-8. doi: 10.1016/S2215-0366(15)00366-1. Epub 2015 Sep 15.


Background: Opioid dependence increases risk of premature mortality. Opioid substitution therapy with methadone or buprenorphine reduces mortality risk, especially for drug-related overdose. Clinical guidelines recommend methadone as the first line of opioid substitution therapy. We aimed to test whether buprenorphine treatment has a lower mortality risk than does methadone treatment by comparing all-cause mortality and drug-related overdose mortality at treatment induction, after in-treatment medication switches, and following treatment cessation.

Methods: We did a retrospective cohort study of all patients with opioid dependency (n=32,033) in New South Wales, Australia, who started a methadone or buprenorphine treatment episode from Aug 1, 2001, to Dec 31, 2010, including 190,232·6 person-years of follow-up. We compared crude mortality rates (CMRs) for all-cause and drug-related overdose mortality, and mortality rate ratios (MRRs) according to age, sex, period in or out of treatment, medication type, and in-treatment switching.

Findings: Patients who initiated with buprenorphine had reduced all-cause and drug-related mortality during the first 4 weeks of treatment compared with those who initiated with methadone (adjusted all-cause MRR 2·17, 95% CI 1·29-3·67; adjusted drug-related MRR 4·88, 1·73-13·69). For the remaining time on treatment, drug-related mortality risk did not differ (adjusted MRR 1·18, 95% CI 0·89-1·56), but weak evidence suggested that all-cause mortality was lower for buprenorphine than methadone (1·66, 1·40-1·96). In the 4 weeks after treatment cessation, all-cause mortality did not differ, but drug-related mortality was lower for methadone (adjusted all-cause MRR 1·12, 0·79-1·59; adjusted drug-related MRR 0·50, 0·29-0·86). Patients who switched from buprenorphine to methadone during treatment had lower mortality in the first 4 weeks of methadone treatment than matched controls who received methadone only (CMR difference 7·1 per 1000 person-years, 95% CI 0·1-14·0); no mortality difference was noted for switches from buprenorphine to methadone or for switches to either medication beyond the first 4 weeks of treatment.

Interpretation: In a setting with high risk of death in the first 4 weeks of opioid substitution therapy, buprenorphine seemed to reduce mortality in this period, but little difference between buprenorphine and methadone was noted thereafter or for in-treatment switching of medications. Cross-cohort corroboration of our findings and further assessment of the stepped treatment model is warranted.

Funding: Australian National Health & Medical Research Council.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Buprenorphine / adverse effects*
  • Cause of Death
  • Cohort Studies
  • Female
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Methadone / adverse effects*
  • Middle Aged
  • Mortality
  • Opiate Substitution Treatment / adverse effects*
  • Opioid-Related Disorders / drug therapy*
  • Opioid-Related Disorders / epidemiology
  • Opioid-Related Disorders / mortality*
  • Retrospective Studies
  • Young Adult


  • Buprenorphine
  • Methadone