Buprenorphine treatment may reduce benzodiazepine risks for those with opioid use disorder

Benzodiazepine or Z-drug treatment was linked to increased risk for nonfatal drug-related poisoning among patients with opioid use disorder, according to results of a case-crossover analysis published in American Journal of Psychiatry.

However, researchers noted this risk is partially mitigated by buprenorphine treatment.

“Existing observational studies that examined mortality risk associated with benzodiazepine prescriptions among patients with opioid use disorder have produced contradictory results,” Kevin Y. Xu, MD, MPH, of the department of psychiatry at Washington University School of Medicine, and colleagues wrote. “While some findings suggest that benzodiazepines may enhance retention in buprenorphine maintenance treatment, benzodiazepines have also been associated with increases in drug related poisonings, all-cause mortality, nonoverdose deaths, decreased retention in treatment and accidental injury-related emergency department visits. To our knowledge, no studies have specifically examined potential additive or interactive effects between buprenorphine and benzodiazepines.”

The researchers aimed to assess the link between benzodiazepine and Z-drug use with drug-related poisonings among individuals receiving buprenorphine maintenance treatment. They analyzed prescription claims of 23,036 individuals aged 12 to 64 years with opioid use disorder who experienced drug-related poisoning and who had buprenorphine prescriptions and claims data in the IBM MarketScan databases between 2006 and 2016. Buprenorphine prescriptions and benzodiazepine or Z-drug prescriptions, standardized as daily diazepam-equivalent milligram dases and separated according to pharmacologic properties (eg, short- or long-acting benzodiazepines, Z-drugs), served as the exposures. Nonfatal drug-related poisoning served as the outcome of interest. The researchers evaluated variation in benzodiazepine or Z-drug and buprenorphine use between poisoning and nonpoisoning days using conditional logistic regression.

Results showed an association between buprenorphine treatment days and a reduction of nearly 40% in the risk for poisoning events (OR = 0.63; 95% CI, 0.6-0.66) vs. nontreatment days. Benzodiazepine or Z-drug treatment days were linked to an 88% increase in risk for such events (95% CI, 1.78-1.98). Stratified analyses by dose revealed a 78% (95% CI, 1.67-1.88) and 122% (95% CI, 2.03-2.43) increase in poisonings linked to low-dose and high-dose benzodiazepine or Z-drug treatment days, respectively. Further, the researchers noted an association between high-dose, but not low-dose, benzodiazepine or Z-drug treatment and increased poisonings combined with buprenorphine cotreatment (OR = 1.64; 95% CI, 1.39-1.93); however, this was lower than the odds risk linked to benzodiazepine or Z-drug treatment in the absence of buprenorphine, which had an OR of 1.69 (95% CI, 1.6-1.79) for low-dose and 2.23 (95% CI, 2.04-2.45) for high-dose.

“Patients with opioid use disorder who are treated with buprenorphine have double the odds of a drug-related poisoning when benzodiazepines or Z-drugs are coprescribed, with short-acting and high-dose benzodiazepines conferring additional risk,” Xu and colleagues wrote. “Buprenorphine remains protective against overdose in this high-risk population. Our findings contribute to emerging evidence that patients with opioid use disorder who receive buprenorphine may benefit from cessation or dose reduction of benzodiazepines or Z-drugs while remaining on buprenorphine.”