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

Abstract

Background: 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.

Conclusions: 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.

Conflict of interest statement

I have read the journal’s policy and the authors of this manuscript have the following competing interests: In the past three years, JMar declares research grants from the National Institute for Health Research (NIHR; randomised controlled trial of depot naltrexone for OUD, and a randomised controlled trial of acamprosate for alcohol use disorder); and the NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Mental Health Foundation Trust (SLaM; randomised controlled trial of novel cognitive therapy for cocaine use disorder). He has worked part-time as the Senior Academic Advisor for the Alcohol, Drugs, Tobacco and Justice Division, Health and Wellbeing Directorate, PHE and he is a clinical academic consultant for the US National Institute on Drug Abuse, Centre for Clinical Trials Network. JM declares an unrestricted research grant at IoPPN and SLaM from Indivior via Action on Addiction for a completed randomised controlled trial of personalised psychosocial intervention in opioid agonist medication for opioid use disorder and, with MK, unrestricted research grant funding at IoPPN and SLaM from Indivior for a three-year, multi-centre, randomised controlled trial of injectable depot buprenorphine for opioid use disorder (2019-2021). He has received honoraria and travel support from Reckitt-Benckiser (2016; treatment of OUD and PCM Scientific and Martindale for the Improving Outcomes in Treatment of Opioid Dependence conference (2018; contribution and chairing). TM has received research funding from the UK National Treatment Agency for Substance Misuse, Public Health England, the Home Office, and Change Grow Live, a 3rd-sector provider of substance misuse services. He has been a member of the organising committee for conferences supported by unrestricted educational grants from Reckitt Benckiser, Lundbeck, Martindale Pharma, and Britannia Pharmaceuticals Ltd, for which he received no personal remuneration. He is a member of the UK Advisory Council on the Misuse of Drugs. JS 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. JS’s employer (King’s College London) has received, connected to his work, project grant support and/or honoraria and/or consultancy payments from Department of Health, NTA (National Treatment Agency), PHE (Public Health England), Home Office, NICE (National Institute for Health and Clinical Excellence), and EMCDDA (European Monitoring Centre for Drugs and Drug Addiction) as well as research grants from (last 3 years) NIHR (National Institute on Health Research), MRC (Medical Research Council) and Pilgrim Trust. He has also worked with WHO (World Health Organization), UNODC (United Nations Office on Drugs and Crime), EMCDDA, FDA (US Food and Drug Administration) and NIDA (US National Institute on Drug Abuse) and also other international government agencies. JS’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, past 3 years, Martindale, Indivior, MundiPharma, Braeburn/Camurus) and trial medication supply from iGen and Braeburn. JS’s employer (King’s College London) has registered intellectual property on an innovative buccal naloxone with which JS is involved, and JS has been named in a patent registration by a Pharma company as inventor of a potential concentrated naloxone nasal spray. For updated information see http://www.kcl.ac.uk/ioppn/depts/addictions/people/hod.aspx. MH acknowledges support from NIHR Health Protection Research Unit in Evaluation of Interventions and the NIHR School of Public Health Research. MH has received unrelated unrestricted honoraria from Gilead, Abbvie, Jansen and Merck Serono. No other disclosures by the other authors are reported.