Ray WA, Chung CP, Murray KT, et al. - Study hypnotics were not associated with mortality in US Medicare beneficiaries 65 years of age or older without concurrent opioids who initiated treatment with benzodiazepine hypnotics, z-drugs, or low-dose trazodone. With concurrent opioids, The study demonstrated that benzodiazepines and z-drugs were correlated with elevated out-of-hospital and total mortality. These outcomes demonstrate that the dangers of benzodiazepine–opioid coadministration go beyond the documented relationship with overdose death and suggest that in combination with opioids, the z-drugs may be more hazardous than previously thought.

• Researchers designed a retrospective cohort study in the United States including a total of 400,924 Medicare beneficiaries 65 years of age or older without severe illness or evidence of substance use disorder initiating study hypnotic therapy from January 2014 through September 2015.

• The results indicated that individuals without concurrent opioids had 32,388 person-years of current use, 260 (8.0/1,000 person-years) out-of-hospital and 418 (12.9/1,000) total deaths for benzodiazepines; 26,497 person-years,150 (5.7/1,000) out-of-hospital and 227 (8.6/1,000) total deaths for z-drugs; and 16,177 person-years,156 (9.6/1,000) out-of-hospital and 256 (15.8/1,000) total deaths for trazodone.

• For benzodiazepines, out-of-hospital and total mortality (respective HRs: 0.99 [95% confidence interval, 0.81 to 1.22, p = 0.954] and 0.95 [0.82 to 1.14, p = 0.513] and z-drugs (HRs: 0.96 [0.76 to 1.23], p = 0.767 and 0.87 [0.72 to 1.05], p = 0.153) did not differ significantly from that for trazodone.

• The outcomes showed that individuals with concurrent opioids had 4,278 person-years of current use, 90 (21.0/1,000) out-of-hospital and 127 (29.7/1,000) total deaths for benzodiazepines; 3,541 person-years, 40 (11.3/1,000) out-of-hospital and 64 (18.1/1,000) total deaths for z-drugs; and 2,347 person-years, 19 (8.1/1,000) out-of-hospital and 36 (15.3/1,000) total deaths for trazodone.

• It was shown that out-of-hospital and total mortality for benzodiazepines (HRs: 3.02 [1.83 to 4.97], p < 0.001 and 2.21 [1.52 to 3.20], p < 0.001) and z-drugs (HRs: 1.98 [1.14 to 3.44], p = 0.015 and 1.65 [1.09 to 2.49], p = 0.018) were significantly elevated relative to trazodone; observations were similar with exclusion of overdose deaths or restriction to those with cardiovascular causes.

• The composition of the study cohort and potential confounding by unmeasured variables were the limitations.