Prescription of benzodiazepines, z-drugs, and gabapentinoids and mortality risk in people receiving opioid agonist treatment: Observational study based on the UK Clinical Practice Research Datalink and Office for National Statistics death records

Autoři: John Macleod aff001;  Colin Steer aff001;  Kate Tilling aff001;  Rosie Cornish aff001;  John Marsden aff002;  Tim Millar aff003;  John Strang aff002;  Matthew Hickman aff001
Působiště autorů: Population Health Sciences, Bristol Medical School, Faculty of Health Sciences, University of Bristol, Bristol, United Kingdom aff001;  Addictions Department, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom aff002;  Centre for Mental Health & Safety, School of Health Sciences, University of Manchester, Manchester, United Kingdom aff003
Vyšlo v časopise: Prescription of benzodiazepines, z-drugs, and gabapentinoids and mortality risk in people receiving opioid agonist treatment: Observational study based on the UK Clinical Practice Research Datalink and Office for National Statistics death records. PLoS Med 16(11): e1002965. doi:10.1371/journal.pmed.1002965
Kategorie: Research Article
doi: 10.1371/journal.pmed.1002965



Patients with opioid dependency prescribed opioid agonist treatment (OAT) may also be prescribed sedative drugs. This may increase mortality risk but may also increase treatment duration, with overall benefit. We hypothesised that prescription of benzodiazepines in patients receiving OAT would increase risk of mortality overall, irrespective of any increased treatment duration.

Methods and findings

Data on 12,118 patients aged 15–64 years prescribed OAT between 1998 and 2014 were extracted from the Clinical Practice Research Datalink. Data from the Office for National Statistics on whether patients had died and, if so, their cause of death were available for 7,016 of these patients. We identified episodes of prescription of benzodiazepines, z-drugs, and gabapentinoids and used linear regression and Cox proportional hazards models to assess the associations of co-prescription (prescribed during OAT and up to 12 months post-treatment) and concurrent prescription (prescribed during OAT) with treatment duration and mortality. We examined all-cause mortality (ACM), drug-related poisoning (DRP) mortality, and mortality not attributable to DRP (non-DRP). Models included potential confounding factors. In 36,126 person-years of follow-up there were 657 deaths and 29,540 OAT episodes, of which 42% involved benzodiazepine co-prescription and 29% concurrent prescription (for z-drugs these respective proportions were 20% and 11%, and for gabapentinoids 8% and 5%). Concurrent prescription of benzodiazepines was associated with increased duration of methadone treatment (adjusted mean duration of treatment episode 466 days [95% CI 450 to 483] compared to 286 days [95% CI 275 to 297]). Benzodiazepine co-prescription was associated with increased risk of DRP (adjusted HR 2.96 [95% CI 1.97 to 4.43], p < 0.001), with evidence of a dose–response effect, but showed little evidence of an association with non-DRP (adjusted HR 0.91 [95% CI 0.66 to 1.25], p = 0.549). Co-prescription of z-drugs showed evidence of an association with increased risk of DRP (adjusted HR 2.75 [95% CI 1.57 to 4.83], p < 0.001) but little evidence of an association with non-DRP (adjusted HR 0.79 [95% CI 0.49 to 1.28], p = 0.342). There was no evidence of an association of gabapentinoid co-prescription with DRP (HR 1.54 [95% CI 0.60 to 3.98], p = 0.373) but evidence of an association with increased non-DRP (HR 1.83 [95% CI 1.28 to 2.62], p = 0.001). Concurrent benzodiazepine prescription also increased mortality risk after consideration of duration of OAT (adjusted HR for DRP with benzodiazepine concurrent prescription 3.34 [95% CI 2.14 to 5.20], p < 0.001). The main limitation of this study is the possibility that unmeasured confounding factors led to an association between benzodiazepine prescription and DRP that is not causal.


In this study, co-prescription of benzodiazepine was specifically associated with increased risk of DRP in opioid-dependent individuals. Co-prescription of z-drugs and gabapentinoids was also associated with increased mortality risk; however, for z-drugs there was no evidence for a dose–response effect on DRP, and for gabapentinoids the increased mortality risk was not specific to DRP. Concurrent prescription of benzodiazepine was associated with longer treatment but still increased risk of death overall. Clinicians should be cautious about prescribing benzodiazepines to opioid-dependent individuals.

Klíčová slova:

Death rates – Drug research and development – Drug therapy – Opioids – Poisoning – Primary care – Sedatives – Survival analysis


1. Office for National Statistics. Deaths related to drug poisoning in England and Wales: 2015 registrations. Deaths related to drug poisoning in England and Wales from 1993 onwards, by cause of death, sex, age and substances involved in the death. London: Office for National Statistics; 2016.

2. Amato L, Davoli M, Perucci CA, Ferri M, Faggiano F, Mattick RP. An overview of systematic reviews of the effectiveness of opiate maintenance therapies: available evidence to inform clinical practice and research. J Subst Abuse Treat. 2005;28(4):321–29. doi: 10.1016/j.jsat.2005.02.007 15925266

3. Kimber J, Copeland L, Hickman M, Macleod J, McKenzie J, De Angelis D, et al. Survival and cessation in injecting opiate users, a prospective observational study of outcomes and the effect of opiate substitute treatment. BMJ. 2010;340:c3172 doi: 10.1136/bmj.c3172 20595255

4. MacArthur GJ, Minozzi S, Martin N, Vickerman P, Deren S, Bruneau J, et al. Opiate substitution treatment and HIV transmission in people who inject drugs: systematic review and meta-analysis. BMJ. 2012;345:e5945. doi: 10.1136/bmj.e5945 23038795

5. Platt L, Minozzi S, Reed J, Vickerman P, Hagan H, French C, et al. Needle syringe programmes and opioid substitution therapy for preventing hepatitis C transmission in people who inject drugs. Cochrane Database Syst Rev. 2017;9:CD012021. doi: 10.1002/14651858.CD012021.pub2 28922449

6. Sordo L, Barrio G, Bravo MJ, Indave BI, Degenhardt L, Weissing L, et al. Mortality risk during and after opioid substitution treatment: systematic review and meta-analysis of cohort studies. BMJ. 2017;357:j1550. doi: 10.1136/bmj.j1550 28446428

7. Cornish R, Macleod J, Strang J, Vickerman P, Hickman M. Risk of death during and after opiate substitution treatment in primary care: prospective observational study in UK general practice research database. BMJ. 2010;341:c5475. doi: 10.1136/bmj.c5475 20978062

8. Schuckit MA. Treatment of opioid-use disorders. N Engl J Med. 2016;375:357–68. doi: 10.1056/NEJMra1604339 27464203

9. Lingford-Hughes AR, Welch S, Peters L, Nutt DJ. BAP updated guidelines: evidence-based guidelines for the pharmacological management of substance abuse, harmful use, addiction and comorbidity: recommendations from BAP. J Psychopharmacol. 2012;26(7):899–952. doi: 10.1177/0269881112444324 22628390

10. McCowan C, Kidd B, Fahey T. Factors associated with mortality in Scottish patients receiving methadone in primary care: retrospective cohort study. BMJ. 2009;338:b2225. doi: 10.1136/bmj.b2225 19535400

11. Jones JD, Mogali S, Comer SD. Polydrug abuse: a review of opioid and benzodiazepine combination use. Drug Alcohol Depend. 2012;125:8–18. doi: 10.1016/j.drugalcdep.2012.07.004 22857878

12. Leece P, Cavacuiti C, Macdonald EM, Gomes T, Kahan M, Srivastava A, et al. Predictors of opioid-related death during methadone therapy. J Subst Abuse Treat. 2015;57:30–5. doi: 10.1016/j.jsat.2015.04.008 26014916

13. Bakker A, Streel E. Benzodiazepine maintenance in opiate substitution treatment: good or bad? A retrospective primary care case-note review. J Psychopharmacol. 2017;31(1):62–6. doi: 10.1177/0269881116675508 28072037

14. Herrett E, Gallagher AM, Bhaskaran K, Forbes H, Mathur R, van Staa T, et al. Data resource profile: Clinical Practice Research Datalink (CPRD). Int J Epidemiol. 2015;44(3):827–36. doi: 10.1093/ije/dyv098 26050254

15. Hickman M, Steer C, Tilling K, Lim AG, Marsden J, Millar T, et al. The impact of buprenorphine and methadone on mortality: a primary care cohort study in the United Kingdom. Addiction. 2018;113:1461–76. doi: 10.1111/add.14188 29672985

16. British Medical Association, Royal Pharmaceutical Society. British national formulary. London: Pharmaceutical Press; 2015.

17. Khan NF, Perera R, Harper S, Rose PW. Adaptation and validation of the Charlson Index for Read/OXMIS coded databases. BMC Fam Pract. 2010;11:1. doi: 10.1186/1471-2296-11-1 20051110

18. Office for National Statistics. Statistical bulletin: deaths related to drug poisoning in England and Wales, 2014 registrations; London: Office for National Statistics; 2015 [cited 2015 Nov 12].

19. Pierce M, Bird SM, Hickman M, Marsden J, Dunn G, Jones A, et al. Impact of treatment for opioid dependence on fatal drug-related poisoning: a national cohort study in England. Addiction. 2016;111: 298–308. doi: 10.1111/add.13193 26452239

20. Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine prescribing patterns and deaths from drug overdose among US veterans receiving opioid analgesics: case-cohort study. BMJ. 2015;350:h2698. doi: 10.1136/bmj.h2698 26063215

21. Dasgupta N, Funk MJ, Proescholdbell S, Hirsch A, Ribisl KM, Marshall S. Cohort study of the impact of high-dose opioid analgesics on overdose mortality. Pain Med. 2016;17:85–98. doi: 10.1111/pme.12907 26333030

22. Abrahamsson T, Berge J, Ojehagen A, Hakansson A. Benzodiazepine, z-drug and pregabalin prescriptions and mortality amongst patients in opioid maintenance treatment—a nation-wide register-based open cohort study. Drug Alcohol Depend. 2017;174:58–64. doi: 10.1016/j.drugalcdep.2017.01.013 28315808

23. Gomes T, Juurlink DN, Antoniou T, Mamdani MM, Paterson JM, van den Brink W. Gabapentin, opioids, and the risk of opioid-related death: a population-based nested case–control study. PLoS Med. 2017;14(10):e1002396. doi: 10.1371/journal.pmed.1002396 28972983

24. Gomes T, Greaves S, van den Brink W, Antoniou T, Mamdani MM, Paterson JM, et al. Pregabalin and the risk for opioid-related death: a nested case–control study. Ann Intern Med. 2018;69:732–4. doi: 10.7326/M18-1136

25. Johansen M. Gabapentinoid use in the United States 2002 through 2015. JAMA Intern Med. 2018; 178(2):292–4. doi: 10.1001/jamainternmed.2017.7856 29297045

26. Peckham AM, Fairman KA, Sclar DA. All-cause and drug-related medical events associated with overuse of gabapentin and/or opioid medications: a retrospective cohort analysis of a commercially insured US population. Drug Saf. 2018;41(2):213–28. doi: 10.1007/s40264-017-0595-1 28956286

27. Montastruc F, Loo SY, Renoux C. Trends in first gabapentin and pregabalin prescriptions in primary care in the United Kingdom, 1993–2017. JAMA. 2018;320:2149–51. doi: 10.1001/jama.2018.12358 30480717

28. Office for National Statistics. Number of drug-related deaths involving gabapentin or pregabalin with or without an opioid drug, England and Wales, 2016. London: Office for National Statistics; 2017 [cited 2019 Oct 28].

29. Lyndon A, Audrey S, Wells C, Burnell ES, Ingle S, Hill R, et al. Risk to heroin users of polydrug use of pregabalin or gabapentin. Addiction. 2017;112(9):1580–9. doi: 10.1111/add.13843 28493329

30. Thomas KH, Martin RM, Davies NM, Metcalfe C, Windmeijer F, Gunnell D. Smoking cessation treatment and risk of depression, suicide and self harm in the Clinical Practice Research Datalink: prospective cohort study. BMJ. 2013;347:f5704. doi: 10.1136/bmj.f5704 24124105

31. Elze MC, Gregson J, Baber U, Williamson E, Sartori S, Mehran R, et al. Comparison of propensity score methods and covariate adjustment. Evaluation in 4 cardiovascular studies. J Am Coll Cardiol. 2017;69 (3):345–57. doi: 10.1016/j.jacc.2016.10.060 28104076

32. Sun EC, Dixit A, Humphreys K, Darnall BD, Baker LC, Mackey S. Association between concurrent use of prescription opioids and benzodiazepines and overdose: retrospective analysis. BMJ. 2017;356:j760. doi: 10.1136/bmj.j760 28292769

33. Doran T, Fullwood C, Kontopantelis E, Reeves D. Effect of financial incentives on inequalities in the delivery of primary clinical care in England: analysis of clinical activity indicators for the quality and outcomes framework. Lancet. 2008;372(9640):728–36. doi: 10.1016/S0140-6736(08)61123-X 18701159

Interní lékařství

Článek vyšel v časopise

PLOS Medicine

2019 Číslo 11

Nejčtenější v tomto čísle

Tomuto tématu se dále věnují…

Zapomenuté heslo

Nemáte účet?  Registrujte se

Zapomenuté heslo

Zadejte e-mailovou adresu se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.


Nemáte účet?  Registrujte se