Prescription of Benzodiazepines, Z-Drugs, and Gabapentinoids and Mortality Risk in People Receiving Opioid Agonist Treatment

1. Co-prescription of benzodiazepines and z-drugs with opioid agonists was associated with a significantly increased risk of drug-related poisoning in opioid-dependent individuals.

Evidence Rating Level: 2 (Good)

Opioid agonist treatment (OAT) is common and effective for individuals with opioid dependence. Concurrent medications, particularly sedatives, prescribed alongside OAT may increase risk of adverse events and mortality despite their benefits. The objective of this cohort study was to examine the association between prescription of concurrent sedatives and treatment retention, and whether concurrent sedative prescription was associated with overall benefit or harm in opioid-dependent individuals on OAT (buprenorphine or methadone). Using data from a United Kingdom database of 12,118 adult primary care patients prescribed OAT between 1998 and 2014, the use of benzodiazepines, z-drugs (zaleplon, zolpidem, and zopiclone), and gabapentinoids concurrently with opioid agonists buprenorphine or methadone and associations with all-cause mortality, drug-related poisoning (DRP), and non-DRP were examined. Over 36,126 person-years of follow-up, 657 deaths and 29,540 OAT episodes were reported, of which 42% were co-prescribed benzodiazepines, 20% co-prescribed z-drugs, and 8% co-prescribed gabapentinoids. Concurrent benzodiazepine use was associated with increased methadone treatment duration (466 [95% CI 450 to 483] vs. 286 [275 to 297] days). There was also a dose-dependent response in benzodiazepine normal dose (adjusted HR 2.51, 95% CI 1.57 to 4.01, p<0.001) and high dose (4.57, 95% CI 2.46 to 8.47, p<0.001). Co-prescription was associated with increased risk of DRP (adjusted HR 2.96 (95% CI 1.97 to 4.43)), though not with non-DRP. Z-drug co-prescription was also associated with increased risk of DRP, while gabapentinoid drugs showed a significant association with non-DRP. The findings of this study highlight the importance of clinical judgment in the treatment of opioid-dependent individuals, such that concurrent use of benzodiazepines, z-drugs, and gabapentinoids increase risk of mortality irrespective of treatment stage.

Click to read the study in PLOS Medicine

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