(164) Benzodiazepine Drug-Drug-Drug Interactions and Unintentional Traumatic Injury: Pharmacoepidemiologic Screening to Detect Three-Way Drug Interaction Signals

Publication Number: 1209

Background: Benzodiazepines and related drugs (BZDs) are widely used and associated with iatrogenic unintentional traumatic injury (hereafter, injury). Drug interactions involving BZDs are increasingly recognized as a significant contributor to injury. Yet, it remains unknown to what extent drug interaction triads (3DIs) may amplify BZDs’ intrinsic injury risk.

Objectives: To identify potential BZD 3DI signals associated with increased rates of injury.

Methods: We conducted semi-automated high-throughput screening of 2000–2019 administrative data from De-identified Optum’s Clinformatics® Data Mart. Using the self-controlled case series design, we included patients aged ≥16 years who had injury while using a BZD+co-dispensed medication (i.e., base pair). During observation time with continuous base pair use, we identified other co-dispensed medications as candidate interacting precipitants. We compared injury rates during observation time exposed to the base pair with vs. without candidate interacting precipitants using conditional Poisson regression, adjusting for time-varying covariates. We calculated rate ratios (RRs) with 95% confidence intervals (CIs) and accounted for multiple estimation via semi-Bayes shrinkage.

Results: We examined 65,123 BZD triads in adjusted analyses, 79 of which (0.1%) were associated with increased injury rates and thus deemed 3DI signals. All signals involved one of the five most commonly used BZDs—zolpidem, alprazolam, lorazepam, clonazepam, or diazepam. Adjusted RRs for signals ranged from 1.42 (95% CI=1.00–2.02, p = 0.049) for alprazolam+hydrocodone with tizanidine (vs. alprazolam+hydrocodone without tizanidine) to 3.01 (1.53–5.94) for clonazepam+atorvastatin with cefuroxime (vs. clonazepam+atorvastatin without cefuroxime). Most of the identified signals are new and may warrant future etiologic examination.

Conclusions: Using real-world data, we identified 79 BZD 3DI signals, i.e., triads associated with increased rates of injury. These signals may help researchers prioritize future etiologic studies aimed to investigate higher-order BZD interactions.