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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BackgroundInfluential
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Time to address addiction treatment inequality in hospital settings
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“Medications are highly effective in treating opioid use disorder (OUD) but generally require long-term use to prevent relapse and fatalities.(1,2) Health insurance disenrollment poses a significant challenge to sustaining treatment and can lead to highrisk treatment discontinuation and transitions in care.”
Background
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Khatri, U. G., Lee, K., Lin, T. C., D’Orazio, J. L., Patel, M. S., Shofer, F. S., & Perrone, J. (2022) · Journal of Medical Toxicology · doi:10.1007/s13181-022-00890-7 · Cited by 7
“Patients who receive buprenorphine are less likely to suffer a non-fatal or fatal overdose, use illicit opioids, develop Hepatitis C or HIV, suffer other infectious complications, or have contacts with the criminal justice system [8, 9].”
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Levin, J. S., Landis, R. K., Sorbero, M., Dick, A. W., Saloner, B. K., & Stein, B. D. (2022) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2022.109510 · Cited by 8
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“Medications for opioid use disorder (OUD) reduce overdose deaths and opioid-related acute care episodes (Sordo et al., 2017; Wakeman et al., 2020) but only one-fifth of treatment-seeking people with OUD receive treatment, and even fewer retain in long-term care (Wu et al., 2016).”
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“For example, between 46 and 65% of patients who initiate methadone OAT discontinue treatment in the first year and relapse to opioid use—a period of high risk for fatal overdose [35].”
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Risk Factors for Opioid Overdose
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“Prior research has demonstrated a positive effect of opioid agonist therapy (OAT), such as methadone or buprenorphine, on HIV care outcomes, including improvements in rates of ART initiation and VL suppression [7– 9], as well as in reducing overdose-related mortality [10].”
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Narrowing the treatment gap in managing opioid use disorder
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“Medications for opioid use disorder are FDA-approved as they have been shown to significantly reduce illicit drug use, emergency depart - ment utilization, overdose rates, and improve quality of life [64, 65].”
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“However, despite the strong and ever-growing evidence of the effectiveness of MOUD in saving lives [ 4], reducing overdose risk [5, 6] and improving quality of life among people with opioid use disorder (POUD), treat-ment access, uptake and retention have remained low in the United States [7].”
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“…the use of opioids and other drugs, decreases the transmission of infectious diseases such as human im-munodeﬁciency virus (HIV) and hepatitis, improves social functioning, and reduces psychiatric and somatic comorbidities (Mattick et al. 2009; Ma et al. 2018; Lim et al. 2022; Sordo et al. 2017).”
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“Yet, this is not empirically derived and in the presence of increased risk of opioid-related adverse patient outcomes seen after MOUD discontinuation [18, 19, 48, 49], some have recommended against MOUD discontinuation at any time point [50].”
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“…interventions are effective for opioid use disorder (OUD), though outcomes significantly improve when psychosocial supports are offered in conjunction with medication treatment (Bart, 2012; Mattick et al., 2014; Mayet et al., 2010; Sordo et al., 2017; Veilleux et al., 2010; Weiss & Rao, 2017).”
Background
Predictors and Consequences of Prescription Opioid Use in Women Living With and Without HIV: 20-Year Follow-Up
Cohen, M. H., Benning, L., Weber, K. M., Sharma, A., Plankey, M. W., Kempf, M.-C., Wilson, T. E., Aouizerat, B. E., Milam, J. E., Adimora, A. A., et al. (2022) · Journal of Women s Health · doi:10.1089/jwh.2021.0231 · Cited by 6
“24,25 However, too few programs, insufﬁcient numbers of trained providers, patient co-existing mental illness, and stigmatized treatment limit access to MOUD among many persons with OUD, including people living with HIV.”
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“32,39 Non-treatment OFUS at visit 12 was also analyzed.”
Background
Loss, liberation, and agency: Patient experiences of methadone treatment at opioid treatment programs during the COVID-19 pandemic
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“Medications for opioid use disorder (MOUD) dramatically decrease opioid-involved overdoses [4, 5] and are a powerful tool to curb this public health crisis.”
Background
10-year retention of a comprehensive treatment model of buprenorphine for opioid use disorder
Zheng, W., Cavrak, M., Bowles, H., Deng, Y., Wen, S., Gao, S., Lander, L. R., Berry, J. H., & Winstanley, E. L. (2024) · Journal of Addictive Diseases · doi:10.1080/10550887.2024.2315366 · Cited by 6
Association of buprenorphine retention and subsequent adverse outcomes following non-fatal overdose: An analysis using statewide linked Maryland databases
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Access to Mental Health and Substance Use Treatment in Comprehensive Primary Care Plus
Santos, T. S., Bergman, A., & Smith–McLallen, A. (2024) · JAMA Network Open · doi:10.1001/jamanetworkopen.2024.8519 · Cited by 6
Association Between Cost-Sharing and Buprenorphine Prescription Abandonment
Chua, K., Conti, R. M., Lagisetty, P., Bohnert, A. S. B., Nuliyalu, U., & Nguyen, T. D. (2024) · Journal of General Internal Medicine · doi:10.1007/s11606-024-08819-2 · Cited by 6
“3 Despite this, only a minority of patients with opioid use disorder receive buprenorphine treatment.”
Buprenorphine deaths confirmed by toxicology reveal a low proportion of opioid agonist treatment before death in Finland
Mariottini, C., Häkkinen, M., Kriikku, P., & Ojanperä, I. A. (2024) · International Journal of Legal Medicine · doi:10.1007/s00414-024-03273-5 · Cited by 6
“Previous studies have shown that mortality is highest within 2–4 weeks after OAT cessation [3 , 4].”
Background

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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