LAUSR

BACKGROUND AND AIMS One-third of opioid (OPI) overdose deaths involve concurrent benzodiazepine (BZD) use. Little is known about concurrent opioid and benzodiazepine use (OPI-BZD) most associated with overdose risk. We aimed to examine associations between OPI-BZD dose and duration trajectories, and subsequent OPI or BZD overdose in U.S. Medicare. DESIGN Retrospective cohort study. SETTING US Medicare. PARTICIPANTS Using a 5% national Medicare data sample (2013-2016) of fee-for-service beneficiaries without cancer initiating OPI prescriptions, we identified 37,879 beneficiaries (age ≥65=59.3%, female=71.9%, White=87.6%, having OPI overdose=0.3%). MEASUREMENTS During the 6 months following OPI initiation (i.e., trajectory period), we identified OPI-BZD dose and duration patterns using group-based multi-trajectory models, based on average daily morphine milligram equivalents (MME) for OPIs and diazepam milligram equivalents (DME) for BZDs. To label dose levels in each trajectory, we defined OPI use as very-low-(<25 MME), low-(25-50 MME), moderate-(51-90 MME), high-(91-150 MME), and very-high-(>150 MME) dose. Similarly, we defined BZD use as very-low- (<10 DME), low- (10-20 DME), moderate- (21-40 DME), high- (41-60 DME), and very-high- (>60 DME) dose. Our primary analysis was to estimate the risk of time to first hospital or emergency department visit for OPI overdose within 6 months following the trajectory period using inverse-probability-of-treatment-weighted Cox proportional hazards models. FINDINGS We identified 9 distinct OPI-BZD trajectories: Group (A): Very-low OPI (early discontinuation)-Very-low declining BZD (n=10,598; 28.0% of the cohort); (B): Very-low OPI (early discontinuation)-Very-low stable BZD (n=4,923; 13.0%); (C): Very-low OPI (early discontinuation)-Medium BZD (n=4,997; 13.2%); (D): Low OPI-Low BZD (n=5,083; 13.4%); (E): Low OPI-High BZD (n=3,906; 10.3%); (F): Medium OPI-Low BZD (n=3,948; 10.4%); (G): Very-high OPI-High BZD (n=1,371; 3.6%); (H): Very-high OPI-Very-high BZD (n=957; 2.5%); and (I): Very-high OPI-Low BZD (n=2,096; 5.5%). Compared with Group (A), 5 trajectories (32.3% of the study cohort) were associated with increased 6-month OPI overdose risks: (E) Low OPI-High BZD HR=3.27, 95%CI=1.61-6.63); (F): Medium OPI-Low BZD (HR=4.04, 95%CI=2.06-7.95); (G): Very-high OPI-High BZD (HR=6.98, 95%CI=3.11-15.64); (H): Very-high OPI-Very-high BZD (HR=4.41, 95%CI=1.51-12.85); and (I): Very-high OPI-Low BZD (HR=6.50, 95%CI=3.15-13.42). CONCLUSIONS Patterns of concurrent opioid and benzodiazepine use most associated with overdose risk among fee-for-service US Medicare beneficiaries initiating opioid prescriptions include very-high-dose opioid use (MME>150), high-dose benzodiazepine use (DME>40), or medium-dose opioid with low-dose benzodiazepine use.