Cited by 1,816Opioid Use Disorder TreatmentSubstance Abuse Treatment and OutcomesHIV, Drug Use, Sexual Risk

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

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Sordo, Luis, Barrio, Gregorio, Bravo, Maria J, Indave, B Iciar, Degenhardt, Louisa, Wiessing, Lucas, Ferri, Marica, Pastor-Barriuso, Roberto·2017·BMJ

DOI 10.1136/bmj.j1550PMC PMC5421454

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Abstract

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.

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“Finally, the multiple benefits of OAT use, such as improved functional outcomes [40] and reductions in injecting risk behaviour [39], criminal activity [41], overdose and all-cause mortality [42], may lead to better engagement in services and a greater readiness to test, and be treated, for HIV.”
Background
Voting with their feet: Social factors linked with treatment for opioid use disorder using same-day buprenorphine delivered in California hospitals
Kalmin, M. M., Goodman‐Meza, D., Anderson, E. S., Abid, A., Speener, M., Snyder, H. R., Campbell, A., Moulin, A. K., SHOPTAW, S. J., & Herring, A. A. (2021) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2021.108673 · Cited by 18
Addiction Medicine Practice-Based Research Network (AMNet): Assessment Tools and Quality Measures
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A comparison of office-based buprenorphine treatment outcomes in Bronx community clinics before versus during the COVID-19 pandemic
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“…& Gregg, 2021; Clark et al., 2021; Samuels et al., 2020; Wang et al., 2021), to our knowledge, only two manuscripts have reported patient outcomes (Nordeck et al., 2020; Tofighi et al., 2021), and none have compared the full cascade of OUD treatment outcomes before versus during the pandemic.”
Influential
‘Not at all what I had expected’: Discontinuing treatment with extended-release naltrexone (XR-NTX): A qualitative study
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Factors associated with discontinuation of methadone maintenance therapy (MMT) among persons who use alcohol in Vancouver, Canada
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Opioid agonist treatment reduces losses in quality of life and quality-adjusted life expectancy in heroin users: Evidence from real world data
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Methadone‐related deaths among youth and young adults in Sweden 2006–15
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Retention in Care as a Quality Measure for Opioid use Disorder
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Clinical Perspective on Opioids in the Context of Suicide Risk
Nestadt, P. S., & Bohnert, A. S. B. (2020) · FOCUS The Journal of Lifelong Learning in Psychiatry · doi:10.1176/appi.focus.20200003 · Cited by 18
Relative Cost Differences of Initial Treatment Strategies for Newly Diagnosed Opioid Use Disorder
Larochelle, M. R., Wakeman, S. E., Ameli, O., Chaisson, C. E., McPheeters, J., Crown, W. H., Azocar, F., & Sanghavi, D. M. (2020) · Medical Care · doi:10.1097/mlr.0000000000001394 · Cited by 17
Prevalence and correlates of multiple non-fatal opioid overdoses among people who inject drugs who utilise needle syringe programs in Australia
Geddes, L., Iversen, J., Darke, S. G., Dietze, P., & Maher, L. (2021) · International Journal of Drug Policy · doi:10.1016/j.drugpo.2021.103245 · Cited by 17
Trends in pharmacy-based dispensing of buprenorphine, extended-release naltrexone, and naloxone during the COVID-19 pandemic by age and sex – United States, March 2019 – December 2020
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Mini review: Potential therapeutic values of mitragynine as an opioid substitution therapy
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Opioid Use Disorder Diagnosis and Management
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Application of the COM-B model to patient barriers and facilitators of retention in medication treatment for opioid use disorder in rural Northeastern United States: A qualitative study
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“Individuals face elevated risk of illicit opioid use (Bentzley et al., 2015) and overdose mortality (Sordo et al., 2017) in the first month following MOUD dropout.”
Background
Risk of Experiencing an Overdose Event for Patients Undergoing Treatment With Medication for Opioid Use Disorder
Brandt, L., Hu, M., Liu, Y., Castillo, F., Odom, G., Balise, R. R., Feaster, D. J., Nunes, E. V., & Luo, S. X. (2023) · American Journal of Psychiatry · doi:10.1176/appi.ajp.20220312 · Cited by 17
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Williams, A. R., Aronowitz, S. V., Rowe, C. L., Gallagher, R., Behar, E., & Bisaga, A. M. (2023) · The American Journal of Drug and Alcohol Abuse · doi:10.1080/00952990.2023.2180382 · Cited by 17
“Retention on MOUD is critical for reducing mortality as days covered by MOUD is associated with 66–80% (10,11) reductions in both overdose and all-cause mortality.”
Background
Women's experiences in injectable opioid agonist treatment programs in Vancouver, Canada
Mayer, S., Boyd, J., Fairbairn, N. S., Chapman, J., Brohman, I., Jenkins, E., & McNeil, R. (2023) · International Journal of Drug Policy · doi:10.1016/j.drugpo.2023.104054 · Cited by 17
Relationship between medication adherence for opioid use disorder and health care costs and health care events in a claims dataset
Liao, S. X., Jang, S., Tharp, J. A., & Lester, N. A. (2023) · Journal of Substance Use and Addiction Treatment · doi:10.1016/j.josat.2023.209139 · Cited by 17
Patient navigation for pregnant individuals with opioid use disorder: Results of a randomized multi‐site pilot trial
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Scaling Emergency Department Opioid Use Disorder Treatment Across California to Reduce Overdose Deaths, 2019–2023
Samuels, E. A., Rosen, A. D., Speener, M., Kaleekal, J., Kalmin, M. M., Goodman‐Meza, D., SHOPTAW, S. J., Clayton, S., Lin, C., Campbell, A., et al. (2024) · American Journal of Public Health · doi:10.2105/ajph.2024.307710 · Cited by 17
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McMaster, J., & Abeysundera, H. (2024) · Australasian Psychiatry · doi:10.1177/10398562241295872 · Cited by 17
A comparison of buprenorphine and psychosocial treatment outcomes in psychosocial and medical settings
Presnall, N. J., Wolf, D. A. P. S., Brown, D. S., Beeler‐Stinn, S., & Grucza, R. A. (2019) · Journal of Substance Abuse Treatment · doi:10.1016/j.jsat.2019.06.010 · Cited by 17
“Treatment with either medication is associated with a reduction in mortality risk compared to being out of treatment (Sordo et al., 2017) and methadone has been shown to be associated with decreased criminal activity and disease transmission (Marsch, 1998; Sordo et al.”
BackgroundInfluential
Optimizing HIV prevention and treatment outcomes for persons with substance use in Central Asia
Deryabina, A. P., & El-Sadr, W. M. (2019) · Current Opinion in HIV and AIDS · doi:10.1097/coh.0000000000000565 · Cited by 17
Patients With Opioid Use Disorder Deserve Trained Providers
Weimer, M. B., Tetrault, J. M., & Fiellin, D. A. (2019) · Annals of Internal Medicine · doi:10.7326/m19-2303 · Cited by 17
“They may be unaware of the evidence demonstrating that detoxification alone increases mortality (10).”
Background
Outpatient care for opioid use disorder among the commercially insured: Use of medication and psychosocial treatment
Busch, A. B., Greenfield, S. F., Reif, S., Normand, S. T., & Huskamp, H. A. (2020) · Journal of Substance Abuse Treatment · doi:10.1016/j.jsat.2020.108040 · Cited by 17
“MOUD improve treatment retention, and reduce opioid use and mortality (Sordo et al., 2017; Timko, Schultz, Cucciare, Vittorio, & Garrison-Diehn, 2016).”
Background
Transporting to treatment: Evaluating the effectiveness of a mobile engagement unit
Stewart, R. E., Shen, L., Kwon, N., Vigderman, J., Kramer, S., Mandell, D. S., Candon, M. K., Lamb, R., & Rothbard, A. B. (2021) · Journal of Substance Abuse Treatment · doi:10.1016/j.jsat.2021.108377 · Cited by 17
Mortality in homeless people enrolled in the French housing first randomized controlled trial: a secondary outcome analysis of predictors and causes of death
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“All MOUD have a toxicity and can potentially cause death [57] but continued heroin use is associated with higher risks: mortality risks among opioid users during MOUD is less than a third of that expected in the absence of medications [48].”
Background
Implementation of a comprehensive hospitalist‐led initiative to improve care for patients with opioid use disorder
Clifton, D., Ivey, N., Poley, S., O’Regan, A., Raman, S. R., Frascino, N., Hamilton, S., & Setji, N. (2022) · Journal of Hospital Medicine · doi:10.1002/jhm.12837 · Cited by 16
Determining the effective dose of street-level heroin: A new way to consider fluctuations in heroin purity, mass and potential contribution to overdose
Stam, N. C., Gerostamoulos, D., Gerstner-Stevens, J., Scott, N., Smith, K. L., Drummer, O. H., & Schumann, J. (2018) · Forensic Science International · doi:10.1016/j.forsciint.2018.07.009 · Cited by 18
One opioid user saving another: the first study of an opioid overdose-reversal and naloxone distribution program addressing hard-to-reach drug scenes in Denmark
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Injectable-Only Overlapping Buprenorphine Starting Protocol in a Low-Threshold Setting
Waters, R. C., Hoog, J., Bell, C., Toland, P., Valley, J., Hurtado, L., Kallsen, M. A., Johnson, T., Gerard, A., Fockele, C. E., et al. (2025) · JAMA Network Open · doi:10.1001/jamanetworkopen.2025.27016 · Cited by 16
Expanding Treatment Opportunities for Hospitalized Patients with Opioid Use Disorders
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Trajectories of Retention in Opioid Agonist Therapy and Overdose Risk During a Community-Wide Overdose Epidemic in a Canadian Setting
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Implementation of buprenorphine services in NYC syringe services programs: a qualitative process evaluation
Jakubowski, A. U., Rath, C., Harocopos, A., Wright, M., Welch, A. E., Kattan, J. A., Behrends, C. N., López‐Castro, T., & Fox, A. D. (2022) · Harm Reduction Journal · doi:10.1186/s12954-022-00654-0 · Cited by 16
“Buprenorphine is a safe and effective medication treatment for OUD that reduces non-prescribed opioid use [2], HIV risk behaviors [3], and opioid overdose mortality [4].”
Background
Anterior cingulate cortex and its projections to the ventral tegmental area regulate opioid withdrawal, the formation of opioid context associations and context-induced drug seeking
McKendrick, G., McDevitt, D. S., Shafeek, P., Cottrill, A. R., & Graziane, N. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.972658 · Cited by 17
“, methadone and buprenorphine) have shown promise in reducing mortality, relapse, and prolonging abstinence (Mattick et al., 2014; Connery, 2015; Sordo et al., 2017).”
Background
Expert Panel Consensus on State-Level Policies to Improve Engagement and Retention in Treatment for Opioid Use Disorder
Smart, R., Grant, S., Gordon, A. J., Pacula, R. L., & Stein, B. D. (2022) · JAMA Health Forum · doi:10.1001/jamahealthforum.2022.3285 · Cited by 18
Initiation of opioid agonist therapy after hospital visits for opioid poisonings in Ontario
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Trauma exposure across the lifespan among individuals engaged in treatment with medication for opioid use disorder: differences by gender, PTSD status, and chronic pain
Rodríguez, M. N., Colgan, D. D., Leyde, S. E., Pike, K. C., Merrill, J. O., & Price, C. J. (2024) · Substance Abuse Treatment Prevention and Policy · doi:10.1186/s13011-024-00608-8 · Cited by 16
“These medications are associated with substantial reductions in overdose mortality [5].”
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The Gut-Brain Axis in Opioid Use Disorder: Exploring the Bidirectional Influence of Opioids and the Gut Microbiome—A Comprehensive Review
Barkus, A., Baltrūnienė, V., Baušienė, J., Baltrūnas, T., Barkienė, L., Kazlauskaitė, P., & Baušys, A. (2024) · Life · doi:10.3390/life14101227 · Cited by 18
“These medications not only reduce cravings but also mitigate the risk of overdose and all-cause mortality [3–6].”
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Nowhere to go? Examining facility acceptance levels for serving individuals using medications for opioid used disorder
Kepple, N. J., Parker, A., Whitmore, S., & Comtois, M. (2019) · Journal of Substance Abuse Treatment · doi:10.1016/j.jsat.2019.06.004 · Cited by 17
ACMT Position Statement: Remove the Waiver Requirement for Prescribing Buprenorphine for Opioid Use Disorder
Marino, R. T., Perrone, J., Nelson, L. S., Wiegand, T. J., Schwarz, E. S., Wax, P. M., & Stolbach, A. I. (2019) · Journal of Medical Toxicology · doi:10.1007/s13181-019-00728-9 · Cited by 16

Authors: Sordo, L., Barrio, G., Bravo, M. J., Indave, B. I., Degenhardt, L., Wiessing, L., Ferri, M., & Pastor-Barriuso, R.
Affiliations: Universidad Complutense de Madrid (ES)
Instituto de Salud Carlos III (ES)
The University of Melbourne (AU)
European Monitoring Centre for Drugs and Drug Addiction (PT)
Corresponding author: Barrio, Gregorio
ORCID: Sordo, Luis
Barrio, Gregorio
Degenhardt, Louisa
Wiessing, Lucas
Ferri, Marica
Venue: BMJ
Publisher: BMJ
Published: 2017-04-26
Volume: 357
Pages: j1550
ISSN: 1756-1833 (ISSN-L)
0959-8138
DOI: 10.1136/bmj.j1550
PMC: PMC5421454
OpenAlex: W2608446001
Cited by: 1,816
References: 76
Citations by year: 2026: 156 · 2025: 194 · 2024: 201 · 2023: 239 · 2022: 228 · 2021: 261 · 2020: 213 · 2019: 187 · 2018: 99 · 2017: 32
FWCI: 23.58
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc
www.bmj.org/licenses/tdm/1.0/terms-and-conditions.html (tdm)
Locations: BMJ (publishedVersion, cc-by-nc)
Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
PubMed Central (publishedVersion, cc-by-nc)
PubMed (publishedVersion)
LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-sa)
Minerva Access (University of Melbourne) (submittedVersion, cc-by-nc)
HighWire Press Open Archive (submittedVersion)
Topics: Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Opioid Use Disorder Treatment
Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
Health Sciences › Medicine › Epidemiology › HIV, Drug Use, Sexual Risk
Keywords: opioid substitution therapy, methadone, buprenorphine, opioid use disorder, all-cause mortality, drug overdose deaths, treatment retention, treatment discontinuation, harm reduction, opioid antagonists
MeSH terms: Buprenorphine, Humans, Methadone, Opioid-Related Disorders, Narcotics, Risk, Opiate Substitution Treatment, Drug Overdose

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

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