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Mortality risk during and after opioid substitution treatment: systematic review and meta-analysis of cohort studies.
Open accessAbstract
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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“The monthly rate of overdose among individuals treated with transmucosal buprenorphine or extended-release buprenorphine is 2.72 per 1000 people.4,32”
From Economic Evaluation of Extended-Release Buprenorphine for Persons With Opioid Use Disorder (2023) · cites this paper as [4]
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“Evidence shows that medications for opioid use disorder (MOUD) are a tool that helps reduce opioid-related overdose mortality.2,3,4”
From Economic Evaluation of Extended-Release Buprenorphine for Persons With Opioid Use Disorder (2023) · cites this paper as [4]
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“Overwhelming evidence demonstrates methadone prevents opioid overdose deaths (Larochelle et al., 2018; Sordo et al., 2017).”
BackgroundColledge‐Frisby, S., Peacock, A., Leung, J., Larney, S., Grebely, J., Hickman, M., Cunningham, E. B., Trickey, A., Stone, J., Vickerman, P. T., et al. (2019) · International Journal of Drug Policy · doi:10.1016/j.drugpo.2019.07.030 · Cited by 115
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The opioid crisis and HIV in the USA: deadly synergies
Hodder, S., Feinberg, J., Strathdee, S. A., SHOPTAW, S. J., Altice, F. L., Ortenzio, L., & Beyrer, C. (2021) · The Lancet · doi:10.1016/s0140-6736(21)00391-3 · Cited by 115
Prevalence and treatment of opioid use disorders among primary care patients in six health systems
Lapham, G. T., Boudreau, D. M., Johnson, E. A., Bobb, J. F., Matthews, A. G., McCormack, J., Liu, D., Samet, J. H., Saxon, A. J., Campbell, C. I., et al. (2019) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2019.107732 · Cited by 106
Access to Office-Based Buprenorphine Treatment in Areas With High Rates of Opioid-Related Mortality
Beetham, T., Saloner, B. K., Wakeman, S. E., Gaye, M., & Barnett, M. L. (2019) · Annals of Internal Medicine · doi:10.7326/m18-3457 · Cited by 105
Brothers, S., Viera, A., & Heimer, R. (2021) · Journal of Substance Abuse Treatment · doi:10.1016/j.jsat.2021.108449 · Cited by 104
“Since methadone treatment reduces mortality for people with OUD (Sordo et al., 2017), and unsupervised take-home dosing is positively associated with treatment retention and improvement in quality of life and employment, and does not differ from supervised in-person dosing in illicit opioid use, diversion, or patient…”
BackgroundMcAuley, A., Matheson, C., & Robertson, J. (2021) · International Journal of Drug Policy · doi:10.1016/j.drugpo.2021.103512 · Cited by 104
Barnett, M. L., Lee, D., & Frank, R. G. (2019) · Health Affairs · doi:10.1377/hlthaff.2019.00859 · Cited by 103
The cascade of care for opioid use disorder: a retrospective study in British Columbia, Canada
Piske, M., Zhou, H., Min, J. E., Hongdilokkul, N., Pearce, L. A., Homayra, F., Socias, M. E., McGowan, G., & Nosyk, B. (2020) · Addiction · doi:10.1111/add.14947 · Cited by 104
“Compared with those never on OAT, those currently engaged in OAT were more likely to be under 45 years of age (adjusted odds ratio: 1.75; 95% confidence interval: 1.64,1.89), male (1.72; 1.64,1.82), with concurrent substance use disorders (2.56; 2.44,2.70), HCV (1.22; 1.14,1.33) and either homeless or receiving income…”
BackgroundInfluentialPottie, K. C., Kendall, C., Aubry, T., Magwood, O., Andermann, A. A. J., Salvalaggio, G., Ponka, D., Bloch, G. C., Brcic, V., Agbata, E. N., et al. (2020) · Canadian Medical Association Journal · doi:10.1503/cmaj.190777 · Cited by 116
Eaton, E., Westfall, A. O., McClesky, B., Paddock, C. S., Lane, P. S., Cropsey, K. L., & Lee, R. A. (2020) · Open Forum Infectious Diseases · doi:10.1093/ofid/ofaa074 · Cited by 102
“In cases of opioid use disorders (OUD), our AM providers prescribe medications for OUD (MOUD), which is associated with reduction in illicit opioid use, overdose, death, and retention in treatment [11, 12].”
BackgroundHulme, S., Bright, D. A., & Nielsen, S. (2018) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2018.02.010 · Cited by 104
Association of Medicaid Expansion With Opioid Overdose Mortality in the United States
Kravitz‐Wirtz, N., Davis, C. S., Ponicki, W. R., Rivera‐Aguirre, A., Marshall, B. D. L., Martins, S. S., & Cerdá, M. (2020) · JAMA Network Open · doi:10.1001/jamanetworkopen.2019.19066 · Cited by 102
Impact Of Long-Term Buprenorphine Treatment On Adverse Health Care Outcomes In Medicaid
Samples, H., Williams, A. R., Crystal, S., & Olfson, M. (2020) · Health Affairs · doi:10.1377/hlthaff.2019.01085 · Cited by 100
Methadone in Primary Care — One Small Step for Congress, One Giant Leap for Addiction Treatment
Samet, J. H., Botticelli, M. P., & Bharel, M. (2018) · New England Journal of Medicine · doi:10.1056/nejmp1803982 · Cited by 99
Pharmacological and Behavioral Treatment of Opioid Use Disorder
Sofuoglu, M., DeVito, E. E., & Carroll, K. M. (2018) · Psychiatric Research and Clinical Practice · doi:10.1176/appi.prcp.20180006 · Cited by 102
“1 per 1,000 person-years in and out of methadone treatment, respectively) (32).”
BackgroundMacleod, J., Steer, C. D., Tilling, K. M., Cornish, R., Marsden, J., Millar, T., Strang, J., & Hickman, M. (2019) · PLoS Medicine · doi:10.1371/journal.pmed.1002965 · Cited by 96
“Though mortality rates are highest amongst users not in treatment, deaths during treatment and following the end of treatment are still observed [6,7].”
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“The evaluation of policy efforts to address the current opioid crisis has focused on reducing the risk of overdose and death, that fortunately affect relatively small numbers of people, while treatment trials have focused on abstinence or days of drug use, both salient indicators of disease severity (Gowing et al., 20…”
BackgroundCrotty, K., Freedman, K. I., & Kampman, K. M. (2020) · Journal of Addiction Medicine · doi:10.1097/adm.0000000000000635 · Cited by 95
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Management of Postoperative Pain in Patients Following Spine Surgery: A Narrative Review
Prabhakar, N., Chadwick, A. L., Nwaneshiudu, C. A., Aggarwal, A. K., Salmasi, V., Lii, T. R., & Hah, J. M. (2022) · International Journal of General Medicine · doi:10.2147/ijgm.s292698 · Cited by 108
Editorial: Challenges to Opioid Use Disorders During COVID‐19
Sun, Y., Bao, Y., Kosten, T. R., Strang, J., Shi, J., & Lü, L. (2020) · American Journal on Addictions · doi:10.1111/ajad.13031 · Cited by 93
Harrison, T. K., Kornfeld, H., Aggarwal, A. K., & Lembke, A. (2018) · Anesthesiology Clinics · doi:10.1016/j.anclin.2018.04.002 · Cited by 92
“Patients randomized to placebo withdrawal, compared with methadone or buprenorphine maintenance treatment, are 2 times to 4 times more likely to be dead at a year.(3,8) A Cochrane meta-analysis of oral naltrexone showed no difference compared with”
BackgroundGomes, T., Campbell, T. J., Kitchen, S. A., Garg, R., Bozinoff, N., Men, S., Tadrous, M., Munro, C., Antoniou, T., Werb, D., et al. (2022) · JAMA · doi:10.1001/jama.2022.1271 · Cited by 92
Addressing Racial And Ethnic Disparities In The Use Of Medications For Opioid Use Disorder
Andraka‐Christou, B. (2021) · Health Affairs · doi:10.1377/hlthaff.2020.02261 · Cited by 91
Klimas, J., Hamilton, M.-A., Gorfinkel, L., Adam, A., Cullen, W., & Wood, E. (2021) · Systematic Reviews · doi:10.1186/s13643-021-01764-9 · Cited by 90
“OUD was defined using the diagnostic criteria for OUD as defined in the Diagnostic and Statistical Manual (DSM)-IV, DSM-V, or International Statistical Classification of Diseases and Related Health Problems (ICD)-10 manuals.”
BackgroundInfluentialSnyder, H. R., Kalmin, M. M., Moulin, A. K., Campbell, A., Goodman‐Meza, D., Padwa, H., Clayton, S., Speener, M., SHOPTAW, S. J., & Herring, A. A. (2021) · Annals of Emergency Medicine · doi:10.1016/j.annemergmed.2021.05.024 · Cited by 94
Trends in engagement in the cascade of care for opioid use disorder, Vancouver, Canada, 2006–2016
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“agonist therapy (OAT) with buprenorphine/naloxone or methadone in reducing opioid-related morbidity and mortality (Connery, 2015; Degenhardt et al., 2011; MacArthur et al., 2012; Sordo et al., 2017),”
InfluentialInjectable opioid agonist treatment for opioid use disorder: a national clinical guideline
Fairbairn, N. S., Ross, J. W. G., Trew, M., Meador, K., Turnbull, J., Macdonald, S., Oviedo‐Joekes, E., Foll, B. L., Goyer, M.-È., Perreault, M., et al. (2019) · Canadian Medical Association Journal · doi:10.1503/cmaj.190344 · Cited by 90
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“The first 4 weeks after initiation of methadone treatment and following cessation of buprenorphine or methadone treatment are the periods of greatest mortality risk, and should be the main focus of efforts for the prevention of drug-related deaths (Sordo et al., 2017).”
BackgroundThe Pharmacology of Buprenorphine Microinduction for Opioid Use Disorder
Aquino, J. P. D., Parida, S., & Sofuoglu, M. (2021) · Clinical Drug Investigation · doi:10.1007/s40261-021-01032-7 · Cited by 89
“Further, as the risk of overdose is greater during the start and cessation of opioid pharmacotherapies, this approach may offer a safer way to transition from full opioid agonists to BUP, reducing the mortality associated with OUD [11].”
BackgroundStructural Racism and the Opioid Overdose Epidemic: The Need for Antiracist Public Health Practice
Kunins, H. V. (2020) · Journal of Public Health Management and Practice · doi:10.1097/phh.0000000000001168 · Cited by 90
“A strong body of evidence indicates that the MOUDs methadone and buprenorphine are highly effective first-line treatments of opioid use disorder that reduce the risk of overdose.(17,18) Both medications are tightly regulated, although buprenorphine can be prescribed by outpatient providers of any specialty following a…”
BackgroundClinical Practice Guideline: Opioid Prescribing for Analgesia After Common Otolaryngology Operations
Anne, S., Mims, J. “., Tunkel, D. E., Rosenfeld, R. M., Boisoneau, D. S., Brenner, M. J., Cramer, J. D., Dickerson, D. M., Finestone, S. A., Folbe, A. J., et al. (2021) · Otolaryngology · doi:10.1177/0194599821996297 · Cited by 94
“While data are limited in surgical patients, failure to initiate treatment for OUD increases morbidity and mortality in nonsurgical populations.(84) Evaluation for OUD should be nonjudgmental, and providers should be conscious of potential stigma and implicit bias.”
Background
Metadata
- 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
- Venue
- BMJ
- Publisher
- BMJ
- Published
- 2017-04-26
- Volume
- 357
- Pages
- j1550
- ISSN
- 1756-1833 (ISSN-L)
- 0959-8138
- 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
- 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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