Patients undergoing opioid substitution treatment have an increased mortality risk during the induction phase with methadone but not with buprenorphine, a meta-analysis has found. Mortality risk is also raised in the period immediately after leaving treatment with both drugs.

The investigators searched Medline, Embase, PsychINFO and LILACS and identified 19 cohort studies eligible for analysis. The studies were published between 1974 and 2016 and were carried out in high-income countries mainly in Europe, North America and Australia. Methadone was prescribed in 18 of the studies and buprenorphine in three. Standard exclusion criteria such as patients in prison or recently released were applied.

Overall 122,885 patients treated with methadone were followed up over 1.3-13.9 years and 15,831 treated with buprenorphine over 1.1-4.5 years. More than 70% of the participants were men

The pooled all cause mortality rates were 11.3 deaths per 1,000 person-years for those in methadone treatment and 36.1 per 1,000 person-years for those not in treatment, unadjusted out to in rate ratio (RR) 3.20 (95% CI: 2.65-3.86). Equivalent mortality rates for patients in or out of buprenorphine treatment were significantly lower at 4.3 and 9.5 deaths per 1,000 person-years respectively, RR 2.20 (95% CI: 1.34-3.61).

Six methadone cohorts provided all cause mortality data analysed by time interval in and out of treatment. After exclusion of specific, very high-risk patients, the pooled all cause mortality rates were 11.4 and 5.8 deaths per 1,000 person-years during the first four weeks and during the remaining time on methadone treatment respectively. The pooled all cause mortality rate in these cohorts was high in the first four weeks after stopping methadone treatment at

32.1 deaths per 1,000 person-years, but dropped to 13.5 deaths per 1,000 person-years after four weeks.

In the two buprenorphine cohorts reporting data by time in treatment, the pooled all cause mortality was low at 4.5 deaths per 1,000 person-years both during and after the first four weeks of buprenorphine treatment.

The pooled all cause mortality was 32.0 deaths per 1,000 person-years in the first four weeks after stopping buprenorphine treatment, reducing to 10.9 deaths per 1,000 person-years after four weeks.

The findings suggest that opioid substitution treatment with methadone is associated with an average reduction of 25 deaths per 1,000 person-years (95% CI: 14-36). The mortality rate in treatment was less than a third of the rate out of treatment, with the greatest reduction in deaths being from overdose.

The all cause mortality risk during treatment is higher in the first four weeks than in ongoing treatment. Mortality risk is significantly higher in the first four weeks after cessation of treatment than in longer-term out of treatment status.

The study also suggests that treatment with buprenorphine is associated with a reduction in mortality, but unlike methadone there is no increase in risk during the first four weeks in treatment. There is an increased mortality rate in the first four weeks after stopping treatment.

Previous studies of drug users in treatment have not been powerful enough to detect potential differences in mortality between the two drugs, or at different points of a treatment journey.

The authors conclude that retention in opioid substitution treatment with both methadone and buprenorphine is associated with a substantial reduction in the risk for all cause and overdose mortality in opioid dependence.

The induction phase on to methadone treatment and the time immediately after leaving treatment with both drugs are periods of increased mortality risk.

Awareness of the particular stages in treatment journeys that are associated with excess risks can help clinicians to devise strategies for safe opioid substitution treatment dose induction, and treatment and public health services to provide harm minimisation support for those who have recently left treatment.

Dr Jez Thompson

Sordo L, Barrio G, Bravo MJ et al. Mortality risk during and after opioid substitution treatment: systematic review and meta-analysis of cohort studies. BMJ 2017;357:j1550