• Kevin Y Xu, Jacob T Borodovsky, Ned Presnall, Carrie M Mintz, Sarah M Hartz, Laura J Bierut, and Richard A Grucza.
• Department of Psychiatry, Health and Behavior Research Center, Washington University School of Medicine, St. Louis (Xu, Presnall, Mintz, Hartz, Bierut, Grucza); Department of Biomedical Data Science, Center for Technology and Behavioral Health, Geisel School of Medicine, Dartmouth, Hanover, N.H. (Borodovsky); Alvin J. Siteman Cancer Center, Barnes Jewish Hospital and Washington University School of Medicine, St. Louis (Bierut); and Departments of Family and Community Medicine and Health and Outcomes Research, St. Louis University, St. Louis (Grucza).
• Am J Psychiatry. 2021 Jul 1; 178 (7): 651-659.

ObjectivePersons with opioid use disorder who take benzodiazepines are at high risk for overdose. The objective of this study was to evaluate the association of benzodiazepine and Z-drug use with drug-related poisonings among patients receiving buprenorphine maintenance treatment.MethodsA case-crossover study design was used to analyze prescription claims among persons ages 12-64 with opioid use disorder who had buprenorphine prescriptions and had claims data in the IBM MarketScan databases (2006-2016), encompassing 14,213,075 person-days of observation time for 23,036 individuals who experienced drug-related poisoning. The exposures were buprenorphine prescriptions and benzodiazepine or Z-drug prescriptions, standardized as daily diazepam-equivalent milligram doses and separated by pharmacologic properties (short-acting or long-acting benzodiazepines, Z-drugs). The outcome of interest was nonfatal drug-related poisoning. Conditional logistic regression was used to evaluate variation in benzodiazepine or Z-drug and buprenorphine use between poisoning and nonpoisoning days.ResultsBuprenorphine treatment days were associated with a nearly 40% reduction in the risk of poisoning events (odds ratio=0.63, 95% CI=0.60, 0.66) compared with nontreatment days, whereas benzodiazepine or Z-drug treatment days were associated with an 88% increase in the risk of such events (95% CI=1.78, 1.98). In stratified analyses by dose, we observed a 78% (95% CI=1.67, 1.88) and 122% (95% CI=2.03, 2.43) increase in poisonings associated with low-dose and high-dose benzodiazepine or Z-drug treatment days, respectively. High-dose, but not low-dose, benzodiazepine or Z-drug treatment was associated with increased poisonings in combination with buprenorphine cotreatment (odds ratio=1.64, 95% CI=1.39, 1.93), but this was lower than the odds risk associated with benzodiazepine or Z-drug treatment in the absence of buprenorphine (low-dose: odds ratio=1.69, 95% CI=1.60, 1.79; high-dose: odds ratio=2.23, 95% CI=2.04, 2.45).ConclusionsIncreased risk of nonfatal drug-related poisoning is associated with benzodiazepine or Z-drug treatment in patients with opioid use disorder, but this risk is partially mitigated by buprenorphine treatment. Dose reduction of benzodiazepines or Z-drugs while maintaining buprenorphine treatment may provide the advantage of lowering drug-related poisoning risk.

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