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Risk of death during and after opiate substitution treatment in primary care: prospective observational study in UK General Practice Research Database

BMJ 2010; 341 doi: (Published 26 October 2010) Cite this as: BMJ 2010;341:c5475
  1. Rosie Cornish, statistician1,
  2. John Macleod, professor in clinical epidemiology and primary care1,
  3. John Strang, professor in the psychiatry of the addictions2,
  4. Peter Vickerman, senior lecturer in mathematical modelling13,
  5. Matt Hickman, professor in public health and epidemiology1
  1. 1School of Social and Community Medicine, University of Bristol, Bristol BS8 2PS, UK
  2. 2National Addiction Centre, Institute of Psychiatry, King’s College London, London, UK
  3. 3London School of Hygiene and Tropical Medicine, London
  1. Correspondence to: M Hickman matthew.hickman{at}
  • Accepted 25 August 2010


Objective To investigate the effect of opiate substitution treatment at the beginning and end of treatment and according to duration of treatment.

Design Prospective cohort study.

Setting UK General Practice Research Database

Participants Primary care patients with a diagnosis of substance misuse prescribed methadone or buprenorphine during 1990-2005. 5577 patients with 267 003 prescriptions for opiate substitution treatment followed-up (17 732 years) until one year after the expiry of their last prescription, the date of death before this time had elapsed, or the date of transfer away from the practice.

Main outcome measures Mortality rates and rate ratios comparing periods in and out of treatment adjusted for sex, age, calendar year, and comorbidity; standardised mortality ratios comparing opiate users’ mortality with general population mortality rates.

Results Crude mortality rates were 0.7 per 100 person years on opiate substitution treatment and 1.3 per 100 person years off treatment; standardised mortality ratios were 5.3 (95% confidence interval 4.0 to 6.8) on treatment and 10.9 (9.0 to 13.1) off treatment. Men using opiates had approximately twice the risk of death of women (morality rate ratio 2.0, 1.4 to 2.9). In the first two weeks of opiate substitution treatment the crude mortality rate was 1.7 per 100 person years: 3.1 (1.5 to 6.6) times higher (after adjustment for sex, age group, calendar period, and comorbidity) than the rate during the rest of time on treatment. The crude mortality rate was 4.8 per 100 person years in weeks 1-2 after treatment stopped, 4.3 in weeks 3-4, and 0.95 during the rest of time off treatment: 9 (5.4 to 14.9), 8 (4.7 to 13.7), and 1.9 (1.3 to 2.8) times higher than the baseline risk of mortality during treatment. Opiate substitution treatment has a greater than 85% chance of reducing overall mortality among opiate users if the average duration approaches or exceeds 12 months.

Conclusions Clinicians and patients should be aware of the increased mortality risk at the start of opiate substitution treatment and immediately after stopping treatment. Further research is needed to investigate the effect of average duration of opiate substitution treatment on drug related mortality.


  • This study is based in part on data from the Full Feature General Practice Research Database obtained under licence from the UK Medicines and Healthcare Products Regulatory Agency (MHRA). We acknowledge the help and support of MHRA staff in taking forward our analyses. However, the interpretation and conclusions contained in this study are those of the authors alone.

  • Contributors: MH conceived the study and obtained funding. RC analysed GPRD data and did the main analyses; PV did additional calculations. All authors contributed to interpretation of the findings and writing of the manuscript. MH is the guarantor.

  • Funding: Access to and permission to use the GPRD (protocol 06_058) was funded through the Medical Research Council’s licence agreement with the MHRA. RC was part funded by a grant from the National Institute of Health Research (NIHR) for the Centre for Research on Drugs and Health Behaviour. At the time they did this work, JM and MH were supported by career scientist fellowship awards from the NIHR. PV is supported by an MRC new investigator award.

  • Competing interests: None declared.

  • Data sharing: No additional data available (permission for use of the original data can be sought from the MHRA).

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