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

doi:10.1016/S2215-0366(15)00366-1

The Lancet Psychiatry

Volume 2, Issue 10, October 2015, Pages 901-908

https://doi.org/10.1016/S2215-0366(15)00366-1 Get rights and content

Summary

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.

Introduction

Opioid dependence increases risk of premature mortality.¹ Leading causes of death among dependent or regular users of opioids include unintentional drug overdose, suicide and other injury, and sequelae of HIV and hepatitis C infection.¹ Opioid substitution therapy greatly improves survival of individuals with opioid dependency who are in treatment by reducing mortality risk, especially for mortality due to fatal opioid-related overdose.2, 3, 4, 5 Nonetheless, mortality risk remains high during the 4 weeks after treatment induction and treatment cessation.3, 6

Methadone and buprenorphine, two opioid substitution pharmacotherapies, are WHO essential medicines.⁷ As a partial opioid receptor agonist, buprenorphine is less likely to induce respiratory depression than is methadone, and might pose a lower risk of opioid overdose, especially during treatment induction8, 9 or unsanctioned opioid use during opioid substitution therapy.¹⁰ Ecological data from France show a strong correlation between an increase in buprenorphine treatment and reduction in drug overdose deaths.¹¹ However, no direct clinical trial evidence exists that is sufficiently powered to compare risk of death between buprenorphine and methadone.⁶ Previous comparisons suggest that retention might be poorer for buprenorphine than for methadone12, 13, 14, 15 and that patients receiving buprenorphine are more likely to switch medications during treatment.14, 15 Clinical guidance recommends methadone as the first line of treatment instead of buprenorphine because it is more cost effective.16, 17 In the USA, variations in reimbursement of treatment costs have also affected prescribing preferences.18, 19, 20 However, methadone, a full opioid agonist, can cause potentially hazardous respiratory depression during treatment induction. The first 4 weeks of treatment in particular might pose an excess risk of mortality from opioid overdose compared with the remainder of time on treatment.3, 21, 22, 23

To date, however, no well powered studies have been done to directly compare the mortality risks in different periods in and out of treatment for these two medications for use in opioid substitution therapy,⁶ nor to compare in-treatment switching between buprenorphine and methadone. In this study we investigated whether risk of all-cause mortality and unintentional drug-related overdose mortality differed between buprenorphine and methadone at various periods and stages of opioid substitution therapy.

Research in context

Evidence before this study

We searched PubMed from inception up to April 2, 2015, for studies comparing all-cause mortality or drug-related mortality risk of patients on buprenorphine and methadone. We used the search terms “buprenorphine”, “methadone”, and “mortality” with no language restrictions and restricted our search to comparative studies. We reviewed 7 studies from 103 results (appendix) but identified no well powered direct comparison of risk of all-cause or drug-related overdose mortality at different periods of buprenorphine and methadone treatment.

Added value of this study

Only large observational studies can detect a sufficient number of deaths to guide clinicians on which treatments are safest. Our study represents the most detailed and well powered study so far of potential differences in mortality risk between individuals receiving buprenorphine and those receiving methadone for opioid dependence during specific periods in and out of treatment. We report that the risk of drug-related overdose mortality and all-cause mortality during the first 4 weeks of treatment induction is increased for patients commencing methadone compared with those commencing buprenorphine. Sensitivity analyses suggested that this differential mortality risk was unlikely to be caused by unmeasured confounding. For patients who switched to methadone after already having been stabilised on buprenorphine, no such comparative elevation in risk existed. Evidence of differential risk between methadone and buprenorphine in drug-related overdose mortality or all-cause mortality at other periods during and after treatment was less compelling or consistent.

Implications of all available evidence

Our findings have direct clinical relevance, suggesting that induction of patients on to buprenorphine is beneficial in settings in which risk of death is increased in the first 4 weeks of treatment, but thereafter little evidence suggests any difference in mortality risk by treatment type or in switching medications. Cross-cohort analyses to corroborate our findings are warranted. Findings from past research show the importance of treatment duration in reduction of drug-related mortality, and increased average treatment durations for methadone compared with buprenorphine have outweighed the slightly reduced mortality risk during buprenorphine treatment compared with methadone treatment. Our findings are consistent with a stepped approach for methadone treatment whereby patients are first induced on to buprenorphine and then transferred to methadone. Further assessment of optimum induction practice, treatment outcomes, and mortality risk is warranted.

Section snippets

Study population

We used unit records from the Pharmaceutical Drugs of Addiction System (PHDAS; appendix), the administrative database of the New South Wales (NSW) Opioid Substitution Treatment Program, to establish a retrospective cohort of people with opioid dependency who started a treatment episode of opioid substitution therapy from Aug 1, 2001, to Dec 31, 2010. As in previous studies,3, 14 we excluded individuals who did not commence treatment, those in temporary programmes such as interstate patients,

Results

32 033 people entered at least one episode of opioid substitution therapy in NSW between Aug 1, 2001, and Dec 31, 2010, giving a total of 190 232·6 person-years of follow-up (median 6·7 years per person, IQR 3·7–8·4) and 71 439 episodes of treatment. Median length of completed treatment episodes (ie, episodes that were not ongoing at end of follow-up) was 137 days (IQR 22–513) and patients entered a mean of 2·2 (SD 2·0, range 1–24) treatment episodes. Median time out of treatment after leaving

Discussion

We identified strong evidence that the risk of drug-related overdose during the first 4 weeks of treatment induction and stabilisation is almost five times higher, and all-cause mortality double, for patients inducted on to methadone than for those inducted on to buprenorphine. By contrast, if a patient switched to methadone after already having been stabilised on buprenorphine, there was no such comparative elevation in risk. These patients also had a reduced rate of mortality compared with

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

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study population

Results

Discussion

Drug Alcohol Depend

Drug Alcohol Depend

Drug Alcohol Depend

Eur J Pain

Drug Alcohol Depend

J Subst Abuse Treat

Drug Alcohol Depend

Drug Alcohol Depend

Mortality among regular or dependent users of heroin and other opioids: a systematic review and meta-analysis of cohort studies

Addiction

Mortality among opiate users: opioid maintenance therapy, age and causes of death

Addiction

One-year mortality rates of patients receiving methadone and buprenorphine maintenance therapy: a nationally representative cohort study in 2694 patients

J Clin Psychopharmacol

Risk of death during and after opiate substitution treatment in primary care: prospective observational study in UK General Practice Research Database

BMJ

WHO model list of essential medicines

Roles of μ-opioid receptors and nociceptin/orphanin FQ peptide receptors in buprenorphine-induced physiological responses in primates

J Pharmacol Exp Ther

Deaths attributable to methadone vs buprenorphine in France

JAMA

Treatment retention among patients randomized to buprenorphine/naloxone compared to methadone in a multi-site trial

Addiction

Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence

Cochrane Database Syst Rev

Opioid agonist pharmacotherapy in New South Wales from 1985 to 2006: patient characteristics and patterns and predictors of treatment retention

Addiction

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