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

BackgroundPatients 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 findingsData 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.ConclusionsIn 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 mo...

Dispensations of benzodiazepines, z-hypnotics, and gabapentinoids to patients receiving opioid agonist therapy; a prospective cohort study in Norway from 2013 to 2017

“…Our findings were in line with dispensation rates of benzodiazepines, z-hypnotics, and gabapentinoids in the OAT population in the United Kingdom in the period from 1998 to 2014 [9]. Further, the dispensation rates were higher for being dispensed a benzodiazepine or a gabapentinoid and lower for being dispensed a z-hypnotic compared with the OAT population in Sweden in the period 2005 to 2013 [1].…”

“…The proportion of OAT patients who were dispensed benzodiazepines or z-hypnotics varies across countries. In the United Kingdom, the proportion of OAT patients who were dispensed benzodiazepines and z-hypnotics was 42 and 20%, respectively, between 1998 and 2014 [9]. In Sweden, 32% of OAT patients were dispensed a benzodiazepine, and 41% received a z-hypnotic in the period from 2005 to 2012 [1].…”

COVID-19 and the health of people who use drugs: What is and what could be?

“…Here, emergent theories of causation suggest use as a ‘coping strategy’ to manage anxiety, or as an alternative given lack of access to preferred drugs of choice. Shifts to increased benzodiazepine use is an obvious concern given the potential for harm, including through dependence, polysubstance use ( McHugh et al, 2020 , Votaw et al, 2020 ), and increased risk of drug-related morbidity and mortality (particularly among people who are opioid dependent) ( Dasgupta et al, 2016 , Macleod et al, 2019 , McCowan et al, 2009 , Park et al, 2015 ).…”

“…Collectively, these changes may produce a risk environment, especially for overdose, as has been witnessed in various parts of North America ( AMA, 2020 , British Columbia Coroners Service, 2020 , Slavova et al, 2020 ). Fentanyl ( Ciccarone, 2019 , Gomes et al, 2018 ), alcohol ( Tori, Larochelle, & Naimi, 2020 ) and benzodiazepines ( Dasgupta et al, 2016 , Macleod et al, 2019 , McCowan et al, 2009 , Park et al, 2015 ) increase the risk of overdose, particularly when used in combination. The concurrent use of opioids with alcohol and/or benzodiazepines might be particularly problematic in settings where a decreased availability of heroin may lead to reduced tolerance after periods of abstinence, increasing the potential for overdose risk ( Merrall et al, 2010 , Stowe et al, 2020 ).…”

Addressing the context and consequences of substance use, misuse, and dependence: A global imperative

“…The elevated rates were particularly striking for mortality due to avoidable causes like unintentional and intentional injuries. Using 1998–2014 data from a large sample of primary care practices in the UK, John MacLeod and colleagues [10] show that coprescription with benzodiazepines was highly prevalent among patients receiving opioid agonist and partial agonist treatment and that coprescription was strongly associated with drug-related poisonings. This study adds to the relatively thin evidence base [11] about the potential hazards of benzodiazepine coprescription in the setting of opioid agonist treatment [12].…”