Combining benzodiazepines and opioids associated with overdose death risk

About half of the deaths from drug overdose in a cohort of U.S. veterans occurred among current benzodiazepine users concurrently prescribed opioids.


Benzodiazepines were associated with a dose-dependent increased risk of death from drug overdose among veterans receiving opioid analgesics, a study found.

Researchers conducted a case-cohort study at VA facilities from 2004 to 2009 to study the association between benzodiazepine prescribing patterns and the risk of intentional, unintentional, or indeterminate death from drug overdose. The study included 2,400 veterans who died of a drug overdose while receiving opioid analgesics, compared to a random sample of more than 420,000 veterans who received VA medical services and opioid analgesics. Each participant's use of benzodiazepines was classified as none, former, or current. Those not having a prior benzodiazepine prescription were classified as none, those who completed a benzodiazepine prescription during the study period that was not renewed or replaced by another active benzodiazepine prescription were considered former users, and current users had an active benzodiazepine prescription during the study period. The benzodiazepine types studied were alprazolam, chlordiazepoxide, clonazepam, diazepam, lorazepam, temazepam, estazolam, flurazepam, oxazepam, quazepam, and triazolam. Results appeared online June 10 at BMJ.

The researchers reported that 27% (n=112,069) of veterans who received at least 1 opioid analgesic also received benzodiazepines. About half (49%) of the deaths from drug overdose (n=1,185) occurred among current benzodiazepine users concurrently prescribed opioids. Risk of death from drug overdose increased with former benzodiazepine use. For patients with a previous benzodiazepine prescription compared to no prescription, the adjusted hazard ratio (HR) was 2.33 (95% CI, 2.05 to 2.64). For current prescriptions versus no prescription, the adjusted HR was 3.86 (95% CI, 3.49 to 4.26).

Clonazepam was the most commonly prescribed benzodiazepine, and all other benzodiazepines had similar risk except temazepam, which was associated with a decreased risk of death from drug overdose (adjusted HR, 0.63; 95% CI, 0.48 to 0.82); the potential cause of this observation was not able to be addressed in the study. After adjustment, there was no association between benzodiazepine dosing schedule and death from overdose.

Compared with the lowest opioid dose category, higher opioid dose categories were associated with increasingly greater risk of death from overdose for no benzodiazepine receipt, former benzodiazepine receipt, and current benzodiazepine receipt, the authors reported.

Although the observational study prevented researchers from concluding whether benzodiazepine prescribing patterns are the direct cause of death from drug overdose, researchers noted that clinicians should be aware of the increased risk among patients currently receiving benzodiazepines and opioids and that the risk might be higher among those receiving higher doses of either or both drugs.

“This risk might be due to risks inherent to those prescribed benzodiazepines, such as the presence of an anxiety condition and/or to the benzodiazepine itself,” the researchers concluded. “Thus, clinicians should be cautious when prescribing benzodiazepines to this group. Although it is unknown whether patients with comorbid pain and anxiety who use opioids and benzodiazepines would benefit from the same interventions to reduce risk of death from overdose as patients using opioids alone, clinicians might consider including this group in overdose prevention efforts, such as naloxone training for caregivers.”