Prescription opioid use among people with opioid dependence and concurrent benzodiazepine and gabapentinoid exposure: An analysis of overdose and all-cause mortality

Background: Studies investigating mortality risk associated with use of opioid analgesics, benzodiazepines, gabapentinoids, and opioid agonist treatment (OAT) among people with opioid dependence (PWOD) are lacking. This study addresses this gap using a cohort of 37,994 PWOD initiating opioid analgesics between July 2003 and July 2018 in New South Wales, Australia.Methods: Linked administrative records provided data on dispensings, sociodemographics, clinical characteristics, OAT, and mortality. Cox proportional hazards models assessed associations between time-varying measures of individual and concurrent medicine use and OAT with all-cause mortality, accidental opioid overdose, non-drug induced accidents, and non-drug-induced suicide. Opioid analgesic dose effects, expressed as oral morphine equivalents (OMEs) per day, were also examined.Outcomes: During the study period, 3167 individuals died. Compared with no use, all medicines of interest were associated with increased accidental opioid overdose risk; hazard ratios (HR) ranged from 1.33 (95 % CI: 1.05-1.68) for opioid analgesic use to 6.10 (95 % CI: 4.11-9.06) for opioid analgesic, benzodiazepine and gabapentinoid use. Benzodiazepine use was associated with increased non-drug-induced accidents and non-drug-induced suicides. For all-cause mortality, all combinations of benzodiazepines and gabapentinoids with opioid analgesics were associated with increased risk (aHRs ranged from 1.35 to 2.73). For most medicines/medicine combinations, all-cause mortality risk was reduced when in OAT compared to out of OAT. Higher opioid analgesic doses were associated with increased all-cause mortality (e.g., 90-199 mg vs 1-49 mg OME per day: HR 1.90 [95 % CI: 1.52-2.40]).Interpretation: The increased mortality risk associated with benzodiazepines and gabapentinoids among PWOD appear to be reduced when engaged in OAT. A greater focus on encouraging OAT engagement, providing overdose prevention education, and access and coverage of overdose antidotes is necessary to minimise the unintended consequences of medicines use in this population.