Drug-related death rates associated with prescribed and illicit benzodiazepine exposure among people receiving opioid-agonist treatment in Scotland, 2015 to 2020

BACKGROUND: Opioid agonist treatment (OAT) reduces mortality among individuals with opioid dependence. Benzodiazepine co-prescribing with OAT has previously been associated with increased rates of drug-related death (DRD). In Scotland, rising DRD rates have coincided with increasing detection of illicit benzodiazepines at post-mortem. We quantified DRD rates associated with prescribed and baseline self-reported illicit benzodiazepine exposure among OAT recipients. METHODS: We conducted a retrospective cohort study using linked prescribing, specialist drug treatment, and mortality records for individuals prescribed OAT in Scotland, 2015-2020. DRD rates were compared during periods with and without prescribed benzodiazepine exposure. Analyses were stratified by OAT status (on treatment and up to 24 months off treatment) and incorporated baseline self-reported illicit benzodiazepine use. Multiple imputation was used to address missing baseline data. RESULTS: Among 40,753 individuals prescribed OAT, 40% were prescribed benzodiazepines during follow-up. There were 3159 DRDs over 189,202 person-years of follow-up. Prescribed benzodiazepine exposure was not associated with increased DRD rates overall (adjusted incidence rate ratio (aIRR) 1.13, 95% confidence intervals (CI) 0.95 to 1.35) and was not associated with increased rates during periods on OAT (aIRR 0.89, 95% CI 0.77 to 1.02). However, prescribed benzodiazepine exposure was associated with higher DRD rates during periods off OAT (aIRR 1.55, 95% CI 1.15 to 2.07), compared to no prescribed exposure. Self-reported illicit benzodiazepine use at baseline was associated with increased DRD rates overall (aIRR 1.60, 95% CI 1.29 to 1.99), with similar associations during periods on and off OAT. Findings were consistent in complete-case and multiply imputed analyses. CONCLUSIONS: Among people receiving OAT, prescribed benzodiazepines were associated with elevated DRD rates primarily during periods off treatment, whereas illicit benzodiazepine use was associated with increased DRD rates both on and off OAT. These findings highlight the importance of addressing illicit benzodiazepine use and supporting retention in OAT.