Mortality risk of opioid substitution therapy with methadone versus buprenorphine: a retrospective cohort study

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.