Association Between Benzodiazepine Use With or Without Opioid Use and All-Cause Mortality in the United States, 1999-2015.
paper
Primary
Public
- Authors
- Xu, Kevin Y; Hartz, Sarah M; Borodovsky, Jacob T; Bierut, Laura J; Grucza, Richard A
- Year
- 2020
- Journal
- JAMA network open
- PMID
- 33295972
- DOI
- 10.1001/jamanetworkopen.2020.28557
- PMCID
- PMC7726637
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.
Study Inclusion and Exclusion FlowchartDerivation of the study cohort during follow-up, with 1:1 linkage to the National Death Index. We excluded those who did not participate in mobile examination interviews, were missing medication data or refused to answer, or were missing data on other covariates included in our propensity scores. We also excluded those who died within 1 year of follow-up or were not taking selective serotonin reuptake inhibitors (SSRIs), benzodiazepines, or opioids. NHANES indicates National Health and Nutrition Examination Surveys.
Unadjusted Kaplan-Meier Curves for Survival Probability, With Follow-up in YearsKaplan-Meier curves of survival probability stratified by benzodiazepines (BZDs) plus opioids, BZDs only, opioids only, and neither BZDs nor opioids (active comparator, selective serotonin reuptake inhibitors [SSRIs]). We excluded all participants who died within 1 year of follow-up.
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