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Abstract
Drug interactions involving benzodiazepines and related drugs (BZDs) are increasingly recognized as a contributor to increased risk of unintentional traumatic injury. Yet, it remains unknown to what extent drug interaction triads (3DIs) may amplify BZDs’ inherent injury risk. We identified BZD 3DI signals associated with increased injury rates by conducting high-throughput pharmacoepidemiologic screening of 2000–2019 Optum’s health insurance data. Using self-controlled case series design, we included patients aged ≥ 16 years with an injury while using a BZD + co-dispensed medication (i.e., base pair). During base pair-exposed observation time, we identified other co-dispensed medications as candidate interacting precipitants. Within each patient, we compared injury rates during time exposed to the drug triad versus to the base pair only 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. Among the 65,123 BZD triads examined, 79 (0.1%) were associated with increased injury rates and considered 3DI signals. Adjusted RRs for signals ranged from 3.01 (95% CI = 1.53–5.94) for clonazepam + atorvastatin with cefuroxime to 1.42 (95% CI = 1.00–2.02, p = 0.049) for alprazolam + hydrocodone with tizanidine. These signals may help researchers prioritize future etiologic studies to investigate higher-order BZD interactions.
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1 University of Pennsylvania, Center for Real-World Effectiveness and Safety of Therapeutics, Center for Clinical Epidemiology and Biostatistics, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972); University of Pennsylvania, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972)
2 University of Pennsylvania, Center for Real-World Effectiveness and Safety of Therapeutics, Center for Clinical Epidemiology and Biostatistics, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972); University of Pennsylvania, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972); Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972); University of Pennsylvania, Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972)
3 University of Pennsylvania, Center for Real-World Effectiveness and Safety of Therapeutics, Center for Clinical Epidemiology and Biostatistics, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972); University of Pennsylvania, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972); University of Pennsylvania, Translational Center of Excellence for Neuroepidemiology and Neurology Outcomes Research, Department of Neurology, Perelman School of Medicine, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972)
4 University of Pennsylvania, Center for Real-World Effectiveness and Safety of Therapeutics, Center for Clinical Epidemiology and Biostatistics, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972); University of Pennsylvania, Department of Psychiatry, Perelman School of Medicine, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972)
5 AthenaHealth, Inc., Watertown, USA (GRID:grid.497101.a)
6 University of Pennsylvania, Center for Real-World Effectiveness and Safety of Therapeutics, Center for Clinical Epidemiology and Biostatistics, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972); University of Pennsylvania, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972); Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972)
7 University of Washington, Department of Pharmacy, School of Pharmacy, Seattle, USA (GRID:grid.34477.33) (ISNI:0000000122986657)
8 University of Pennsylvania, Center for Real-World Effectiveness and Safety of Therapeutics, Center for Clinical Epidemiology and Biostatistics, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972); University of Pennsylvania, Translational Center of Excellence for Neuroepidemiology and Neurology Outcomes Research, Department of Neurology, Perelman School of Medicine, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972); University of Pennsylvania, Department of Neurology, Perelman School of Medicine, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972)