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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Background
Disparities in Access to Medications for Opioid Use Disorder in the Veterans Health Administration
Finlay, A. K., Harris, A. H. S., Timko, C., Yu, M., Smelson, D. A., Stimmel, M. A., & Binswanger, I. A. (2020) · Journal of Addiction Medicine · doi:10.1097/adm.0000000000000719 · Cited by 61
“Positive outcomes associated with these medications include reduced heroin use, likelihood of repeat overdose, and mortality (Amato et al., 2005; Sordo et al., 2017; Larochelle et al., 2018).”
Background
Model and approach for assessing implementation context and fidelity in the HEALing Communities Study
Knudsen, H. K., Drainoni, M., Gilbert, L., Huerta, T. R., Oser, C. B., Aldrich, A. M., Campbell, A. N. C., Crable, E. L., Garner, B. R., Glasgow, L., et al. (2020) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2020.108330 · Cited by 61
An investigation of an open‐access model for scaling up methadone maintenance treatment
Madden, L. M., Farnum, S. O., Eggert, K. F., Quanbeck, A., Freeman, R. M., Ball, S. A., Schottenfeld, R. S., Shi, J. M., Savage, M. E., & Barry, D. T. (2018) · Addiction · doi:10.1111/add.14198 · Cited by 64
Non-fatal drug overdose after release from prison: A prospective data linkage study
Keen, C., Young, J. T., Borschmann, R., & Kinner, S. A. (2019) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2019.107707 · Cited by 61
Causes of death among people who used illicit opioids in England, 2001–18: a matched cohort study
Lewer, D., Brothers, T. D., van Hest, N., Hickman, M., Holland, A., Padmanathan, P., & Zaninotto, P. (2021) · The Lancet Public Health · doi:10.1016/s2468-2667(21)00254-1 · Cited by 59
Addressing adolescent substance use with a public health prevention framework: the case for harm reduction
Winer, J. M., Yule, A. M., Hadland, S. E., & Bagley, S. M. (2022) · Annals of Medicine · doi:10.1080/07853890.2022.2104922 · Cited by 70
“In adults, treatment with buprenorphine and methadone is associated with reduced all-cause and opioid-related mortality [68,69].”
Background
Comparing Reasons for Starting and Stopping Methadone, Buprenorphine, and Naltrexone Treatment Among a Sample of White Individuals With Opioid Use Disorder
Golan, O. K., Andraka‐Christou, B., Totaram, R., Alamo, J., & Nadig, M. (2019) · Journal of Addiction Medicine · doi:10.1097/adm.0000000000000584 · Cited by 59
“In the United States methadone is only available in highly regulated opioid treatment programs (‘‘methadone clinics’’), whereas buprenorphine and naltrexone may be prescribed and dispensed in physician offices (Sordo et al., 2017).”
Background
One year of methadone maintenance treatment in a fentanyl endemic area: Safety, repeated exposure, retention, and remission
Stone, A. C., Carroll, J. J., Rich, J. D., & Green, T. C. (2020) · Journal of Substance Abuse Treatment · doi:10.1016/j.jsat.2020.108031 · Cited by 58
Opioid use disorder and the brain: a clinical perspective
Herlinger, K., & Lingford-Hughes, A. R. (2021) · Addiction · doi:10.1111/add.15636 · Cited by 69
History of the discovery, development, and FDA-approval of buprenorphine medications for the treatment of opioid use disorder
Heidbreder, C. A., Fudala, P. J., & Greenwald, M. K. (2023) · Drug and Alcohol Dependence Reports · doi:10.1016/j.dadr.2023.100133 · Cited by 59
Self-reported xylazine experiences: A mixed methods study of Reddit subscribers
Spadaro, A., O'Connor, K., Lakamana, S., Sarker, A., Wightman, R. S., Love, J., & Perrone, J. (2023) · Journal of addiction medicine · doi:10.1097/adm.0000000000001216 · Cited by 26
“Among this small sample of people on Reddit, xylazine seems to be an unwanted adulterant, common in the Northeast, with reported adverse effects such as skin wounds and worsening withdrawal from other substances.”
Background
Comparison of opioid use disorder among male veterans and non‐veterans: Disorder rates, socio‐demographics, co‐morbidities, and quality of life
Rhee, T. G., & Rosenheck, R. A. (2019) · American Journal on Addictions · doi:10.1111/ajad.12861 · Cited by 59
Mortality and causes of death among patients with opioid use disorder receiving opioid agonist treatment: a national register study
Bech, A. B., Clausen, T., Waal, H., Benth, J. Š., & Skeie, I. (2019) · BMC Health Services Research · doi:10.1186/s12913-019-4282-z · Cited by 57
Using telehealth to improve buprenorphine access during and after COVID-19: A rapid response initiative in Rhode Island
Clark, S. A., Davis, C. S., Wightman, R., Wunsch, C., Keeler, L. A. J., Reddy, N. G., & Samuels, E. A. (2021) · Journal of Substance Abuse Treatment · doi:10.1016/j.jsat.2021.108283 · Cited by 56
Inpatient Addiction Medicine Consultation Service Impact on Post-discharge Patient Mortality: a Propensity-Matched Analysis
Wilson, J. D., Dunn, S. C. A., Roy, P. J., Joseph, E., Klipp, S., & Liebschutz, J. M. (2022) · Journal of General Internal Medicine · doi:10.1007/s11606-021-07362-8 · Cited by 56
Management of opioid use disorder and associated conditions among hospitalized adults: A Consensus Statement from the Society of Hospital Medicine
Calcaterra, S. L., Martín, M., Bottner, R., Englander, H. L., Weinstein, Z., Weimer, M. B., Lambert, E., & Herzig, S. J. (2022) · Journal of Hospital Medicine · doi:10.1002/jhm.12893 · Cited by 58
Court personnel attitudes towards medication-assisted treatment: A state-wide survey
Andraka‐Christou, B., Gabriel, M. H., Madeira, J. L., & Silverman, R. D. (2019) · Journal of Substance Abuse Treatment · doi:10.1016/j.jsat.2019.06.011 · Cited by 56
Association between mortality rates and medication and residential treatment after in‐patient medically managed opioid withdrawal: a cohort analysis
Walley, A. Y., Lodi, S., Li, Y., Bernson, D., Babakhanlou‐Chase, H., Land, T. G., & Larochelle, M. R. (2020) · Addiction · doi:10.1111/add.14964 · Cited by 56
“Two thirds (20,944) were male, 86% (26311) were less than 45 years old, 81% (24,710) were white, and 23% (6,900) were homeless.”
Experiences of people with opioid use disorder during the COVID-19 pandemic: A qualitative study
Galarneau, L. R., Hilburt, J., O'Neill, Z. R., Buxton, J. A., Scheuermeyer, F. X., Dong, K. A., Kaczorowski, J. A., Orkin, A. M., Barbic, S. P., Bath, M., et al. (2021) · PLoS ONE · doi:10.1371/journal.pone.0255396 · Cited by 55
Substance, use in relation to COVID-19: A scoping review
Kumar, N., Janmohamed, K., Nyhan, K., Martins, S. S., Cerdá, M., Hasin, D. S., Scott, J., Frimpong, A. S., Pates, R. M., Ghandour, L. A., et al. (2021) · Addictive Behaviors · doi:10.1016/j.addbeh.2021.107213 · Cited by 55
“The diversion of resources at the health system level toward the pandemic may also strain MOUD provision, perhaps leading to patient drop out or medication discontinuation (Sun et al., 2020; Sordo et al., 2017).”
Relative effectiveness of medications for opioid-related disorders: A systematic review and network meta-analysis of randomized controlled trials
Lim, J., Farhat, I., Douros, A., & Panagiotoglou, D. (2022) · PLoS ONE · doi:10.1371/journal.pone.0266142 · Cited by 59
“, detoxification, residential services, and behavioural interventions) or no treatment, OMT has lower risk of overdose hospitalizations [8], mortality [9], and frequency of injection drug use and needle sharing [10–12].”
Background
Transitions in care between hospital and community settings for individuals with a substance use disorder: A systematic review
James, H., Morgan, J., Ti, L., & Nolan, S. (2023) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2023.109763 · Cited by 63
Opioid users' willingness to receive prolonged-release buprenorphine depot injections for opioid use disorder
Tompkins, C. N. E., Neale, J., & Strang, J. (2019) · Journal of Substance Abuse Treatment · doi:10.1016/j.jsat.2019.06.007 · Cited by 56
Rise and regional disparities in buprenorphine utilization in the United States
Azar, A. R. P., Cruz‐Mullane, A., Podd, J. C., Lam, W. S., Kaleem, S. H., Lockard, L., Mandel, M. R., Chung, D. Y., Simoyan, O. M., Davis, C. S., et al. (2020) · Pharmacoepidemiology and Drug Safety · doi:10.1002/pds.4984 · Cited by 52
“Systematic reviews have demonstrated a 32-69% reduction in illicit drug use, 20-60% reduction in injection drug use, and 25-86% reduction in sharing injection equipment among individuals receiving MOUD.(1,2) Because federal law limits availability of methadone by to specialized clinics when used for the treatment of O…”
Background
A national model of remote care for assessing and providing opioid agonist treatment during the COVID-19 pandemic: a report
Crowley, D., & Delargy, Í. (2020) · Harm Reduction Journal · doi:10.1186/s12954-020-00394-z · Cited by 54
“Engagement and retention in treatment improve outcomes with disruption in OAT (particularly on release from prison) associated with increased risk of overdose [9].”
BackgroundMethodInfluential
Methadone maintenance treatment among patients exposed to illicit fentanyl in Rhode Island: Safety, dose, retention, and relapse at 6 months
Stone, A. C., Carroll, J. J., Rich, J. D., & Green, T. C. (2018) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2018.07.019 · Cited by 53
Relay: A Peer-Delivered Emergency Department–Based Response to Nonfatal Opioid Overdose
Welch, A. E., Jeffers, A., Allen, B., Paone, D., & Kunins, H. V. (2019) · American Journal of Public Health · doi:10.2105/ajph.2019.305202 · Cited by 53
“How will I get my next week's script?” Reactions of Reddit opioid forum users to changes in treatment access in the early months of the coronavirus pandemic
Krawczyk, N., Bunting, A. M., Frank, D., Arshonsky, J., Gu, Y., Friedman, S. R., & Bragg, M. A. (2021) · International Journal of Drug Policy · doi:10.1016/j.drugpo.2021.103140 · Cited by 52
Implementation of a medical student-run telemedicine program for medications for opioid use disorder during the COVID-19 pandemic
Castillo, M., Conte, B., Hinkes, S., Mathew, M., Na, C. J., Norindr, A., Serota, D. P., Forrest, D. W., Deshpande, A. R., Bartholomew, T. S., et al. (2020) · Harm Reduction Journal · doi:10.1186/s12954-020-00438-4 · Cited by 52
“Despite multiple studies demonstrating the association of MOUD with reduced morbidity and mortality [9, 10], access to MOUD remains limited in the USA, with 96% of states reporting higher rates of opioid use than buprenorphine treatment capacity [11].”
Background
Outcomes of a single-arm implementation trial of extended-release subcutaneous buprenorphine depot injections in people with opioid dependence
Farrell, M., Shahbazi, J., Byrne, M., Grebely, J., Lintzeris, N., Chambers, M. S., Larance, B., Ali, R. L., Nielsen, S., Dunlop, A. J., et al. (2021) · International Journal of Drug Policy · doi:10.1016/j.drugpo.2021.103492 · Cited by 52
“…as multiple other health and social outcomes ( Degenhardt et al., 2019 ) including reducing HIV and HCV incidence ( MacArthur et al., 2012 ; Platt et al., 2017 ), criminal activity ( Gisev et al., 2019 ), overdose ( Sordo et al., 2017 ), and mortality ( Santo et al., 2021 ; Sordo et al., 2017 ).”
Background
Overdose mortality incidence and supervised consumption services in Toronto, Canada: an ecological study and spatial analysis
Rammohan, I., Gaines, T., Scheim, A. I., Bayoumi, A. M., & Werb, D. (2024) · The Lancet Public Health · doi:10.1016/s2468-2667(23)00300-6 · Cited by 58
Cannabinoids for the Neuropsychiatric Symptoms of Dementia: A Systematic Review and Meta-Analysis
Bahji, A., Meyyappan, A. C., & Hawken, E. R. (2019) · The Canadian Journal of Psychiatry · doi:10.1177/0706743719892717 · Cited by 52
“Heterogeneity was quantified using the I(2) statistic and described as low ( 25%), moderate (>25% and 50%), high (>50% and 75%), or substantial ( 75%).(65,69,70) We explored the impact of study characteristics on treatment efficacy and acceptability via subgroup, sensitivity, and meta-regression analyses.”
Method
Toxicology and prescribed medication histories among people experiencing fatal illicit drug overdose in British Columbia, Canada
Crabtree, A., Lostchuck, E., Chong, M., Shapiro, A. M., & Slaunwhite, A. (2020) · Canadian Medical Association Journal · doi:10.1503/cmaj.200191 · Cited by 52
Medication Treatment for Opioid use Disorder and Community Pharmacy: Expanding Care during a National Epidemic and Global Pandemic
Cochran, G., Bruneau, J., Cox, N., & Gordon, A. J. (2020) · Substance Abuse · doi:10.1080/08897077.2020.1787300 · Cited by 52
Medications for opioid use disorder among American Indians and Alaska natives: Availability and use across a national sample
Krawczyk, N., Garrett, B. A., Ahmad, N. J., Patel, E., Solomon, K. T., Stuart, E. A., & Saloner, B. K. (2021) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2021.108512 · Cited by 51
Buprenorphine After Nonfatal Opioid Overdose: Reduced Mortality Risk in Medicare Disability Beneficiaries
Samples, H., Nowels, M., Williams, A. R., Olfson, M., & Crystal, S. (2023) · American Journal of Preventive Medicine · doi:10.1016/j.amepre.2023.01.037 · Cited by 51
Trends in Buprenorphine Initiation and Retention in the United States, 2016-2022
Chua, K., Nguyen, T. D., Zhang, J., Conti, R. M., Lagisetty, P., & Bohnert, A. S. B. (2023) · JAMA · doi:10.1001/jama.2023.1207 · Cited by 51
Bacterial and Fungal Infections in Persons Who Inject Drugs — Western New York, 2017
Hartnett, K. P., Jackson, K. A., Felsen, C. B., McDonald, R., Bardossy, A. C., Gokhale, R. H., Kracalik, I. T., Lucas, T. J., McGovern, O. L., Beneden, C. V., et al. (2019) · MMWR Morbidity and Mortality Weekly Report · doi:10.15585/mmwr.mm6826a2 · Cited by 52
“Opioids, cocaine, and methamphetamine 2 (3)”
Background
Perceptions and preferences for long-acting injectable and implantable medications in comparison to short-acting medications for opioid use disorders
Saunders, E. C., Moore, S. K., Walsh, O., Metcalf, S. A., Budney, A. J., Scherer, E. A., & Marsch, L. A. (2020) · Journal of Substance Abuse Treatment · doi:10.1016/j.jsat.2020.01.009 · Cited by 51
“As both short- and long-acting formulations have been rigorously studied (Mattick et al., 2014; Nielsen et al., 2016; Sordo et al., 2017), the decision for one formulation over another is largely preference sensitive, a choice that depends on patients’ preferences and their individual values…”
BackgroundInfluential
Opioid agonist treatment for people who are dependent on pharmaceutical opioids
Nielsen, S., Tse, W. C., & Larance, B. (2022) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd011117.pub3 · Cited by 50
Prescribing decisions at buprenorphine treatment initiation: Do they matter for treatment discontinuation and adverse opioid-related events?
Meinhofer, A., Williams, A. R., Johnson, P., Schackman, B. R., & Bao, Y. (2019) · Journal of Substance Abuse Treatment · doi:10.1016/j.jsat.2019.07.010 · Cited by 50
“Understanding and overcoming barriers to buprenorphine treatment retention is important as patients who discontinue treatment are at an elevated risk of relapse, overdose, and death [15, 23, 24, 25].”
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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