Mortality risk of opioid substitution therapy with methadone versus buprenorphine

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.