Association Between Benzodiazepine Use With or Without Opioid Use and All-Cause Mortality in the United States, 1999-2015

Question Is benzodiazepine use, with or without opioid use, an independent risk factor for all-cause mortality or a marker for underlying conditions associated with death? Findings In this cohort study of 5212 individuals from a large, nationally representative data set, it was found that benzodiazepine use, with or without opioid use, was associated with a doubling in all-cause mortality risk in comparison with the use of low-risk antidepressants. These findings persisted even after adjustment for sociodemographic variables and comorbidity burden. Meaning This study suggests that benzodiazepine and opioid cotreatment may confer an increased long-term mortality risk; targeted interventions are needed to decrease overprescribing. This cohort study uses data from the National Health and Nutrition Examination Surveys to evaluate whether benzodiazepine use, with or without opioid use, is associated with increased all-cause mortality relative to the use of low-risk antidepressants. Importance Although overall rates of opioid use have been plateauing, coprescriptions of benzodiazepines and opioids have increased greatly in recent years. It is unknown whether this combination is an independent risk factor for all-cause mortality as opposed to being more frequently used by persons with a baseline elevated risk of death. Objective To evaluate whether benzodiazepine use, with or without opioid use, is associated with increased all-cause mortality relative to the use of low-risk antidepressants. Design, Setting, and Participants This retrospective cohort study used a large, nationally representative US data set (the National Health and Nutrition Examination Surveys [NHANES]) from 1999 to 2015. Eight cycles of NHANES data were used, spanning 37 610 person-years of follow-up time among 5212 individuals. Statistical analysis was performed from August 24, 2019, through May 23, 2020. Exposures The primary exposure variable was benzodiazepine and opioid coprescriptions. Individuals taking selective serotonin reuptake inhibitors (SSRIs) served as an active comparator reference group. Main Outcomes and Measures All-cause mortality was obtained via linkage of NHANES to the National Death Index. Propensity scores were calculated from covariates associated with sociodemographic factors, comorbidities, and medication use for more than 1000 prescription types. Propensity score-weighted mortality hazards were calculated from Cox proportional hazards regression models. Results Of 5212 participants aged 20 years or older (1993 men [38.2%]; mean [SD] age, 54.8 [16.9] years) followed up for a median of 6.7 years (range, 0.2-16.8 years), 101 deaths (33.0 per 1000 person-years) occurred among those receiving cotreatment, 236 deaths (26.5 per 1000 person-years) occurred among those receiving only benzodiazepines, and 227 deaths (20.2 per 1000 person-years) occurred among SSRI recipients taking neither opioids nor benzodiazepines. After propensity score weighting, a significant increase in all-cause mortality was associated with benzodiazepine and opioid cotreatment (hazard ratio, 2.04 [95% CI, 1.65-2.52]) and benzodiazepines without opioids (hazard ratio, 1.60 [95% CI, 1.33-1.92]). Subgroup analyses revealed an increased risk of mortality for individuals receiving cotreatment who were 65 years or younger but not for those older than 65 years; similar findings were observed for those receiving benzodiazepines without opioids. Conclusions and Relevance This study found a significant increase in all-cause mortality associated with benzodiazepine use with or without opioid use in comparison with SSRI use. Benzodiazepine and opioid cotreatment, in particular, was associated with a 2-fold increase in all-cause mortality even after taking into account medical comorbidities and polypharmacy burden.