Mortality risk during and after opioid substitution treatment: systematic review and meta-analysis of cohort studies

Objective To compare the risk for all cause and overdose mortality in people with opioid dependence during and after substitution treatment with methadone or buprenorphine and to characterise trends in risk of mortality after initiation and cessation of treatment. Design Systematic review and meta-analysis. Data sources Medline, Embase, PsycINFO, and LILACS to September 2016. Study selection Prospective or retrospective cohort studies in people with opioid dependence that reported deaths from all causes or overdose during follow-up periods in and out of opioid substitution treatment with methadone or buprenorphine. Data extraction and synthesis Two independent reviewers performed data extraction and assessed study quality. Mortality rates in and out of treatment were jointly combined across methadone or buprenorphine cohorts by using multivariate random effects meta-analysis. Results There were 19 eligible cohorts, following 122 885 people treated with methadone over 1.3-13.9 years and 15 831 people treated with buprenorphine over 1.1-4.5 years. Pooled all cause mortality rates were 11.3 and 36.1 per 1000 person years in and out of methadone treatment (unadjusted out-to-in rate ratio 3.20, 95% confidence interval 2.65 to 3.86) and reduced to 4.3 and 9.5 in and out of buprenorphine treatment (2.20, 1.34 to 3.61). In pooled trend analysis, all cause mortality dropped sharply over the first four weeks of methadone treatment and decreased gradually two weeks after leaving treatment. All cause mortality remained stable during induction and remaining time on buprenorphine treatment. Overdose mortality evolved similarly, with pooled overdose mortality rates of 2.6 and 12.7 per 1000 person years in and out of methadone treatment (unadjusted out-to-in rate ratio 4.80, 2.90 to 7.96) and 1.4 and 4.6 in and out of buprenorphine treatment. Conclusions Retention in methadone and buprenorphine treatment is associated with substantial reductions in the risk for all cause and overdose mortality in people dependent on opioids. The induction phase onto methadone treatment and the time immediately after leaving treatment with both drugs are periods of particularly increased mortality risk, which should be dealt with by both public health and clinical strategies to mitigate such risk. These findings are potentially important, but further research must be conducted to properly account for potential confounding and selection bias in comparisons of mortality risk between opioid substitution treatments, as well as throughout periods in and out of each treatment.

[1]  Rose A Rudd,et al.  Increases in Drug and Opioid-Involved Overdose Deaths - United States, 2010-2015. , 2016, MMWR. Morbidity and mortality weekly report.

[2]  R. Rosenheck,et al.  Characteristics of veterans receiving buprenorphine vs. methadone for opioid use disorder nationally in the Veterans Health Administration. , 2016, Drug and alcohol dependence.

[3]  T. Fahey,et al.  Risk of mortality on and off methadone substitution treatment in primary care: a national cohort study. , 2016, Addiction.

[4]  J. Macleod,et al.  Commentary on Cousins et al. (2016): Accumulating evidence on risk of mortality on and off opioid substitution treatment. , 2016, Addiction.

[5]  M. Herdener,et al.  A comprehensive model of treatment participation in chronic disease allowed prediction of opioid substitution treatment participation in Zurich, 1992-2012. , 2015, Journal of clinical epidemiology.

[6]  J. Bell,et al.  Understanding Heroin Overdose: A Study of the Acute Respiratory Depressant Effects of Injected Pharmaceutical Heroin , 2015, PloS one.

[7]  D. Randall,et al.  Mortality risk of opioid substitution therapy with methadone versus buprenorphine: a retrospective cohort study. , 2015, The lancet. Psychiatry.

[8]  J. Montaner,et al.  The Effects of Opioid Substitution Treatment and Highly Active Antiretroviral Therapy on the Cause-Specific Risk of Mortality Among HIV-Positive People Who Inject Drugs. , 2015, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[9]  Y. Hser,et al.  Mortality among individuals accessing pharmacological treatment for opioid dependence in California, 2006-10. , 2015, Addiction.

[10]  K. Mills,et al.  Long-term mortality, remission, criminality and psychiatric comorbidity of heroin dependence: 11-year findings from the Australian Treatment Outcome Study. , 2015, Addiction.

[11]  W. Ling,et al.  Long-Term Course of Opioid Addiction , 2015, Harvard review of psychiatry.

[12]  P. Sebastiani,et al.  Prenatal buprenorphine versus methadone exposure and neonatal outcomes: systematic review and meta-analysis. , 2014, American journal of epidemiology.

[13]  T. Vos,et al.  The global epidemiology and burden of opioid dependence: results from the global burden of disease 2010 study. , 2014, Addiction.

[14]  C. Thomas,et al.  Medication-assisted treatment with buprenorphine: assessing the evidence. , 2014, Psychiatric services.

[15]  P. Tugwell,et al.  The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised Studies in Meta-Analyses , 2014 .

[16]  Shane R. Mueller,et al.  Mortality After Prison Release: Opioid Overdose and Other Causes of Death, Risk Factors, and Time Trends From 1999 to 2009 , 2013, Annals of Internal Medicine.

[17]  S. Bird,et al.  A record-linkage study of drug-related death and suicide after hospital discharge among drug-treatment clients in Scotland, 1996-2006. , 2013, Addiction.

[18]  A Gasparrini,et al.  Multivariate meta-analysis for non-linear and other multi-parameter associations , 2012, Statistics in medicine.

[19]  I. White,et al.  Quantifying the impact of between-study heterogeneity in multivariate meta-analyses , 2012, Statistics in medicine.

[20]  The EMA has strengthened information sharing arrangements with the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). , 2012, Reactions Weekly.

[21]  C. Teljeur,et al.  Risk of drug-related mortality during periods of transition in methadone maintenance treatment: a cohort study. , 2011, Journal of substance abuse treatment.

[22]  J. Rich,et al.  Buprenorphine and buprenorphine/naloxone diversion, misuse, and illicit use: an international review. , 2011, Current drug abuse reviews.

[23]  Dan Jackson,et al.  Multivariate meta-analysis: Potential and promise , 2011, Statistics in medicine.

[24]  L. Degenhardt,et al.  Mortality among regular or dependent users of heroin and other opioids: a systematic review and meta-analysis of cohort studies. , 2011, Addiction.

[25]  Rosie P Cornish,et al.  Risk of death during and after opiate substitution treatment in primary care: prospective observational study in UK General Practice Research Database , 2010, BMJ : British Medical Journal.

[26]  M. Farrell,et al.  Meta-analysis of drug-related deaths soon after release from prison , 2010, Addiction.

[27]  Matthew Hickman,et al.  HIV prevention, treatment, and care services for people who inject drugs: a systematic review of global, regional, and national coverage , 2010, The Lancet.

[28]  S. Schreiber,et al.  15-Year survival and retention of patients in a general hospital-affiliated methadone maintenance treatment (MMT) center in Israel. , 2010, Drug and alcohol dependence.

[29]  A. Reece.  Favorable Mortality Profile of Naltrexone Implants for Opiate Addiction , 2010, Journal of addictive diseases.

[30]  D. Moher,et al.  Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. , 2010, International journal of surgery.

[31]  W. Hall,et al.  Mortality among clients of a state-wide opioid pharmacotherapy program over 20 years: risk factors and lives saved. , 2009, Drug and alcohol dependence.

[32]  J. Bell,et al.  Comparing overdose mortality associated with methadone and buprenorphine treatment. , 2009, Drug and alcohol dependence.

[33]  J. Bell,et al.  Comparing retention in treatment and mortality in people after initial entry to methadone and buprenorphine treatment. , 2009, Addiction.

[34]  D. Moher,et al.  Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement , 2009, BMJ : British Medical Journal.

[35]  T Fahey,et al.  Factors associated with mortality in Scottish patients receiving methadone in primary care: retrospective cohort study , 2009, BMJ : British Medical Journal.

[36]  D. Moher,et al.  Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. , 2009, Journal of clinical epidemiology.

[37]  R. Ali,et al.  Key findings from the WHO collaborative study on substitution therapy for opioid dependence and HIV/AIDS. , 2008, Addiction.

[38]  T. Clausen,et al.  Mortality prior to, during and after opioid maintenance treatment (OMT): a national prospective cross-registry study. , 2008, Drug and alcohol dependence.

[39]  H. Kleber.  Pharmacologic treatments for opioid dependence: detoxification and maintenance options , 2007, Dialogues in clinical neuroscience.

[40]  Federica Vigna-Taglianti,et al.  Risk of fatal overdose during and after specialist drug treatment: the VEdeTTE study, a national multi-site prospective cohort study. , 2007, Addiction.

[41]  I. Thiblin,et al.  Methadone maintenance treatment: the balance between life-saving treatment and fatal poisonings. , 2007, Addiction.

[42]  C. Rück,et al.  A stepped care strategy using buprenorphine and methadone versus conventional methadone maintenance in heroin dependence: a randomized controlled trial. , 2007, The American journal of psychiatry.

[43]  H. Wittchen,et al.  One-year Mortality Rates of Patients Receiving Methadone and Buprenorphine Maintenance Therapy: A Nationally Representative Cohort Study in 2694 Patients , 2006, Journal of clinical psychopharmacology.

[44]  J. Bell,et al.  Cycling in and out of treatment; participation in methadone treatment in NSW, 1990-2002. , 2006, Drug and alcohol dependence.

[45]  M. Brugal,et al.  Evaluating the impact of methadone maintenance programmes on mortality due to overdose and aids in a cohort of heroin users in Spain. , 2005, Addiction.

[46]  F. Baud,et al.  A critical review of the causes of death among post-mortem toxicological investigations: analysis of 34 buprenorphine-associated and 35 methadone-associated deaths. , 2004, Addiction.

[47]  R P Mattick,et al.  Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. , 2008, The Cochrane database of systematic reviews.

[48]  R P Mattick,et al.  Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. , 2009, The Cochrane database of systematic reviews.

[49]  N. Scherbaum,et al.  Senkt die Methadonsubstitutionsbehandlung die Mortalität Opiatabhängiger? , 2002 .

[50]  W. van den Brink,et al.  An increase in overdose mortality during the first 2 weeks after entering or re-entering methadone treatment in Amsterdam. , 2002, Addiction.

[51]  Julie M. Miller.  The Scottish Intercollegiate Guidelines Network (SIGN) , 2002 .

[52]  N. Scherbaum,et al.  [Does maintenance treatment reduce the mortality rate of opioid addicts?]. , 2002, Fortschritte der Neurologie-Psychiatrie.

[53]  Duncan Stewart,et al.  A prospective study of mortality among drug misusers during a 4-year period after seeking treatment. , 2002, Addiction.

[54]  T. Buclin,et al.  Interindividual Variability of the Clinical Pharmacokinetics of Methadone , 2002, Clinical pharmacokinetics.

[55]  J. Tignol,et al.  Garlic as a Tick Repellent—Reply , 2001 .

[56]  J. Robins,et al.  Marginal Structural Models and Causal Inference in Epidemiology , 2000, Epidemiology.

[57]  S. Sunjic,et al.  Deaths in methadone maintenance treatment in New South Wales, Australia 1990-1995. , 2000, Addiction.

[58]  J. White,et al.  Mechanisms of fatal opioid overdose. , 1999, Addiction.

[59]  Jeff Ward,et al.  Role of maintenance treatment in opioid dependence , 1999, The Lancet.

[60]  S. Sharp,et al.  Explaining heterogeneity in meta-analysis: a comparison of methods. , 1997, Statistics in medicine.

[61]  F Mosteller,et al.  Meta-analysis of multiple outcomes by regression with random effects. , 1998, Statistics in medicine.

[62]  A. Romelsjö,et al.  Changes in mortality, arrests, and hospitalizations in nonvoluntarily treated heroin addicts in relation to methadone treatment. , 1998, Substance use & misuse.

[63]  G. Smith,et al.  Bias in meta-analysis detected by a simple, graphical test , 1997, BMJ.

[64]  J. Caplehorn,et al.  Methadone maintenance and addicts' risk of fatal heroin overdose. , 1996, Substance use & misuse.

[65]  S. Greenland.  Dose‐Response and Trend Analysis in Epidemiology: Alternatives to Categorical Analysis , 1995, Epidemiology.

[66]  J. Rajs,et al.  Mortality among HIV-infected intravenous drug addicts in Stockholm in relation to methadone treatment. , 1995, Addiction.

[67]  J. Caplehorn,et al.  Retention in methadone maintenance and heroin addicts' risk of death. , 1994, Addiction.

[68]  L. Öhlund,et al.  Mortality in heroin addiction: impact of methadone treatment , 1990, Acta psychiatrica Scandinavica.

[69]  P. Cushman.  Ten years of methadone maintenance treatment: some clinical observations. , 1977, The American journal of drug and alcohol abuse.

[70]  M. Schweitzer,et al.  An epidemiologic evaluation of long-term methadone maintenance treatment for heroin addiction. , 1974, American journal of epidemiology.