Abstract
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. 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. 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. The primary exposure variable was benzodiazepine and opioid coprescriptions. Individuals taking selective serotonin reuptake inhibitors (SSRIs) served as an active comparator reference group. 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. 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. 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.
Highlights
Benzodiazepines are among the most widely used medications worldwide and are prescribed for common problems such as anxiety and insomnia.[1,2,3] Up to 13% of US adults have reported benzodiazepine use in the last year,[4] with ambulatory benzodiazepine prescriptions more than doubling in the last decade.[5]Increasing benzodiazepine prescriptions have clinical relevance amid declining life expectancies and a global epidemic of opioid overdoses
A significant increase in all-cause mortality was associated with benzodiazepine and opioid cotreatment and benzodiazepines without opioids
This study found a significant increase in all-cause mortality associated with benzodiazepine use with or without opioid use in comparison with selective serotonin reuptake inhibitor (SSRI) use
Summary
Benzodiazepines are among the most widely used medications worldwide and are prescribed for common problems such as anxiety and insomnia.[1,2,3] Up to 13% of US adults have reported benzodiazepine use in the last year,[4] with ambulatory benzodiazepine prescriptions more than doubling in the last decade.[5]Increasing benzodiazepine prescriptions have clinical relevance amid declining life expectancies and a global epidemic of opioid overdoses. When benzodiazepines are taken alone, long-term use is associated with falls, cognitive impairment, and life-threatening withdrawal.[1,3] When taken together with opioids, benzodiazepines can further suppress breathing, a common cause of death from opioid overdose.[1,6,7] The danger of benzodiazepine-opioid cotreatment is a timely issue, as 20% to 30% of all benzodiazepine recipients in the US are estimated to have an opioid coprescription[8] and more than 30% of opioid overdose deaths are found to involve benzodiazepines.[9,10,11] Despite a recent plateau in overall opioid use in the US,[8,12,13] benzodiazepine-opioid coprescriptions continue to increase.[2,8,14,15,16] It is tempting to infer elevated mortality risk attributable to benzodiazepines alone or in combination with opioids, but this topic has proven challenging to study. It is not well understood if benzodiazepine use—whether with or without opioids—is associated directly with mortality, as opposed to serving as a marker for unmeasured underlying conditions that are the true factors associated with excess deaths
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