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Cover of The impact of opiate substitution treatment on mortality risk in drug addicts: a natural experiment study

The impact of opiate substitution treatment on mortality risk in drug addicts: a natural experiment study

Health Services and Delivery Research, No. 7.3

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Author Information
Southampton (UK): NIHR Journals Library; .


There was evidence that the treatment period risks varied with the medication, but buprenorphine as an alternative to methadone may not reduce mortality overall due to shorter treatment duration.



Opiate substitution treatment (OST) is the main treatment for people addicted to heroin and other opioid drugs. However, there is limited information on how the delivery of this treatment affects mortality risk.


To investigate the associations of mortality risk with periods during treatment and following cessation of treatment, medication type, co-prescription of other medication and dosing regimens during titration and detoxification. The trends with time of prescribed medication, dose and treatment duration were also explored.


Prospective longitudinal observational study.


UK primary care between 1998 and 2014.


A total of 12,780 patients receiving methadone, buprenorphine or dihydrocodeine.

Main outcome measures:

All-cause mortality relating to 657 deaths and drug-related poisoning relating to 113 deaths.

Data sources:

Clinical Practice Research Datalink with linked information on cause of death from the Office for National Statistics.


For both outcomes, the lowest mortality risk was observed after 4 weeks of treatment and the highest risk was observed in the first 4 weeks following cessation of treatment [e.g. for drug-related poisoning, incidence rate ratio (IRR) 8.15, 95% confidence interval (CI) 5.45 to 12.19]. There was evidence that the treatment period risks varied with OST medication. The largest difference in risk was for the first 4 weeks of treatment for both outcomes, with patients on buprenorphine being at lower risk than those on methadone (e.g. for drug-related poisoning, IRR 0.08, 95% CI 0.01 to 0.48). The co-prescription of benzodiazepines was associated with linearly increasing the risk of drug-related deaths by dose (IRR 2.02, 95% CI 1.66 to 2.47), whereas z-drugs (zolpidem, zopiclone and zaleplon) were associated with increased risk of both all-cause (IRR 1.83, 95% CI 1.59 to 2.12) and drug-related (IRR 3.31, 95% CI 2.45 to 4.47) mortality. There was weak evidence that higher initial and final doses were associated with increased all-cause mortality risk. In the first 4 weeks of treatment, the risk increased by 4% for each 5-mg increment in methadone dose (1-mg increase in buprenorphine) (hazard ratio 1.04, 95% CI 1.00 to 1.09). In the first 4 weeks after treatment ceased, a similar increment in final dose increased the risk by 3% (hazard ratio 1.03, 95% CI 0.99 to 1.07). There were too few deaths to evaluate the effects on drug-related poisoning. The proportion of OST patients receiving buprenorphine increased between 1998 and 2006. Median treatment duration was consistently shorter for buprenorphine than for methadone for each year studied (overall median duration of 48 and 106 days, respectively).


As this was an observational study, the possibility remains of bias from unmeasured factors, which covariate adjustment and inverse probability weighting can eliminate only partially.


Using buprenorphine as an alternative to methadone may not reduce mortality overall despite resulting in lower IRRs from shorter treatment duration. Clinical guidance needs to consider strengthening warnings about the co-prescription of a range of drugs for OST patients.

Future work:

Our analyses need to be replicated using other clinical data sets in the UK and in other countries. New interventions and trials are required to investigate improving the retention of OST patients in primary care.


The National Institute for Health Research Health Services and Delivery Research programme.


About the Series

Health Services and Delivery Research
ISSN (Print): 2050-4349
ISSN (Electronic): 2050-4357

Article history

The research reported in this issue of the journal was funded by the HS&DR programme or one of its preceding programmes as project number 12/136/105. The contractual start date was in September 2013. The final report began editorial review in October 2017 and was accepted for publication in July 2018. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HS&DR editors and production house have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the final report document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

John Marsden acknowledges research grants from the Department of Health and Social Care, the National Institute for Health Research (NIHR) and the NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Mental Health Foundation Trust, and part-time employment as Senior Academic Advisor for the Alcohol, Drugs and Tobacco Division, Health and Wellbeing Directorate, Public Health England. He declares investigator-led educational grant funding from Indivior PLC (administered by Action on Addiction) for a study of adjunctive, personalised psychosocial intervention for non-response to opioid agonist treatment (ARC Trial), and support from NIHR (Health Technology Assessment) for a trial of extended-release naltrexone. He has received honoraria from Merck Serono (Darmstadt, Germany; 2015; clinical oncology medicine); Martindale Pharma (Brentwood, UK; 2017; treatment for opioid use disorder); and Indivior PLC (via PCM Scientific) as co-chairperson and chairperson (2015–18) for the conference on Improving Outcomes in Treatment of Opioid Dependence. Tim Millar has received research funding from the UK National Treatment Agency for Substance Misuse, Public Health England and the Home Office. He has been a member of the organising committee for conferences supported by unrestricted educational grants from Reckitt Benckiser Group plc (Slough, UK), Lundbeck Ltd (Milton Keynes, UK), Martindale Pharma and Britannia Pharmaceuticals Ltd (Reading, UK), for which he received no personal remuneration. He is a member of the UK Advisory Council on the Misuse of Drugs. John Strang is a clinician and researcher and has worked extensively with agencies in the addiction treatment fields and addiction-related charities and with government departments and has contributed to clinical guidelines on treatment types and provision. John Strang’s employer (King’s College London) has received, connected to his work, project grant support and/or honoraria and/or consultancy payments from the Department of Health and Social Care, the National Treatment Agency, Public Health England, the Home Office, the National Institute for Health and Care Excellence and the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), as well as research grants from (2016–18) NIHR, the Medical Research Council and the Pilgrim Trust. He has also worked with the World Health Organization, the United Nations Office on Drugs and Crime, EMCDDA, the US Food and Drug Administration and the US National Institute on Drug Abuse, as well as other international government agencies. John Strang’s employer (King’s College London) has also received, connected to his work, research grant support and/or payment of honoraria, consultancy payments and expenses from pharmaceutical companies [including, for 2016–18, Martindale, Indivior PLC, Mundipharma (Cambridge, UK) and Braeburn/Camurus (Lund, Sweden)] and trial medication supply from iGen and Braeburn. John Strang’s employer (King’s College London) has registered intellectual property on an innovative buccal naloxone with which John Strang has been named in a patent registration for concentrated naloxone nasal spray by Euro-Celtique SA on behalf of Mundipharma Research Limited. For updated information see (accessed 2 October 2018). Matthew Hickman has received unrelated unrestricted honoraria from Gilead Sciences, Inc. (Cambridge, UK), AbbVie (Maidenhead, UK), Janssen Pharmaceuticals (High Wycombe, UK) and Merck Serono. Matthew Hickman is a member of the Public Health Research Research Funding Board.

Last reviewed: October 2017; Accepted: July 2018.

Copyright © Queen’s Printer and Controller of HMSO 2019. This work was produced by Steer et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.
Bookshelf ID: NBK536756PMID: 30702836DOI: 10.3310/hsdr07030


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