Benzodiazepine Linked to Higher Risk of Overdose in Opioid Use Disorder Treatment


Despite higher risk of adverse effects in patients with opioid use disorder, benzodiazepine does not undo protection benefits of buprenorphine.

Kevin Y. Xu, MD, MPH

Kevin Y. Xu, MD, MPH

Patients undergoing treatment for opioid use disorder (OUD) are at a higher risk for overdose and adverse drug reaction with benzodiazepine use, according to a recent study.

Investigators, led by Kevin Y. Xu, MD, MpH of the Washington University School of Medicine, observed how benzodiazepine subclasses affect overdose risks in OUD patients. They also determined non-fatal drug-related poisoning risk in association with benzodiazepine use.

These findings were presented at the American Psychiatric Association Annual Meeting.

Investigators found benzodiazepine does not reverse OUD treatment benefits of buprenorphine, despite the higher overdose risk.


The team used a case-crossover study design, including 304,676 individuals with OUD between the ages of 12 – 64 prescribed buprenorphine as treatment.

Data was collected from the Truven MarketScan database from January – December 2016.

After exclusion of patients without overdoses or receipt of buprenorphine treatment, the study included 23,036 individuals. Treatment prescriptions were used as the unit of observation of person-days.

Overall, the study encompassed 14,213,075 person-days of observation time, in the year before and after overdose.

Prescriptions of benzodiazepine were standardized as daily diazepam-equivalent milligram doses, separated by short-acting, long-acting, Z drug properties.

The team’s main outcome included non-fatal drug related poisonings, including overdose events.

Xu and team also used a conditional logistic regression to evaluate the variation in benzodiazepine and buprenorphine use between poisoning and non-poisoning days.


The 23,036 participants prescribed buprenorphine had a mean age of 30 years, were 51% male, and had a mean observation time of 600 days.

According to the data, buprenorphine treatment days were associated with a 40% reduction in risk of poisoning (OR 0.63; 95% CI, 0.60 – 0.66), in comparison to non-treatment days.

On the other hand, benzodiazepine treatment days were associated with an 88% increase in risk of poisoning events (95% CI; 1.78 – 1.98).

The team’s stratified analyses by dose showed an increase in poisonings in low-dose benzodiazepine treatment days at 78% (95%Ci, 1.67 – 1.88) and high-dose benzodiazepine treatment at 122% (95% CI, 2.03 – 2.43).

More data show high-dose benzodiazepine treatment resulted in increased poisoning in combination with buprenorphine co-treatment (OR 1.64; 95% CI, 1.39 – 1.93).

However, this treatment risk is lower than the risk investigators found with benzodiazepine without buprenorphine, at both low dose (OR 1.69; 95% CI, 1.60 – 1.79) and high dose (OR 2.23; 95% CI, 2.04 – 2.45).


Investigators concluded with the observation of a clear, dose-dependent pattern involving increased overdose risk with the association of benzodiazepine use in patients with OUD.

The team said both lower dosage and shortened treatment duration may reduce risk in patients who may be affected by benzodiazepine cessation.

They also note that the protection benefits of buprenorphine are not undone by benzodiazepine.

“Benzos do not undo the treatment benefits of buprenorphine,” investigators wrote. “Even though they are associated with increased overdoses, buprenorphine’s protective effect is not eliminated by benzo treatment.

The study, “Benzodiazepine Prescriptions Are Associated With Increased Drug-Related Poisonings in Opioid Maintenance Therapy Patients,” was presented at the American Psychiatric Association.

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