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

Association Between Benzodiazepine Use With or Without Opioid Use and All-Cause Mortality in the United States, 1999-2015
Atuobi Nana Yiadom, PharmD, CentraCare Hospital, Paynesville

Background: Benzodiazepines are widely used medications for the management of anxiety and insomnia. It has been reported that about 13% of U.S. adults have used benzodiazepines in the past year, with ambulatory prescriptions of benzodiazepines doubling in the past decade. Additionally, increases in benzodiazepine prescribing and long-term use has been accompanied by falls, cognitive impairment, and life threatening withdrawal. One area of concern has been combined use of benzodiazepines and opioids, which can lead to risk of overdose, suppressed breathing, and death. This study evaluates the association of benzodiazepine use with or without opioid co-prescriptions with long-term all-cause mortality using a large nationally representative data set in the U.S. linked to the National Death Index spanning approximately 15 years of follow-up time (1999-2015).

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.

Study DesignThis study was a retrospective cohort study from 1999 to 2015. Among the eligible participants who were 20 years or older, 43,793 were identified using the National Health and Nutrition Examination Surveys. A total of 5,212 were included in the study who were on either benzodiazepines and opioids, benzodiazepines or opioids, or other comparators such as selective serotonin reuptake inhibitors (SSRIs). There were 38,581 participants excluded from the study who did not participate in face-to-face interviews, had missing data on prescription information or medical conditions, died within one year of follow up, or were not taking SSRIs, benzodiazepines, or opioids. The primary exposure in the study was benzodiazepine and opioid co-prescriptions, with patients taking SSRIs serving as a reference group. SSRIs were chosen as a reference group due to their overlapping indication with benzodiazepines, and diminished morbidity and mortality compared to tricyclic antidepressants and monoamine oxidase inhibitors. The main outcome measure was all-cause mortality from the exposure variable. Cox proportional hazard regression model was used to estimate mortality of participants in the exposure versus reference group, and stratified analyses were performed on follow up time and age (20-65 vs 65 years) of participants. All P values were from 2 sided tests and results were statistically significant at P<0.05.

ResultsThe majority of study participants were women, who accounted for 62% of the study population, and 64% were white with a mean age of 54.8 years. Out of the 5,212 participants, 9% were prescribed both benzodiazepines and opioids, 24% were prescribed benzodiazepines only, 37.5% were prescribed opioids only, and 29.4% were on neither benzodiazepines or opioids, but were on SSRIs. The median time to death was 6.7 years for all participants. Of the 892 deaths that occured in total, 11.3%  occurred  in participants receiving benzodiazepines and opioids, 26.4% occured in benzodiazepines only, 37% in participants on opioids only, and 25.4% of deaths occurred in participants using SSRIs only. A Kaplan-Meier survival curve showed that all-cause mortality was significant in the benzodiazepine and opioid group compared to other groups (χ2=0.41; P<0.001). Participants receiving benzodiazepines both with and without opioids showed increased risk of death when compared with participants taking SSRIs only (co-treatment group: hazard ratio [HR], 1.71 [95% CI 1.34 - 2.19]; benzodiazepines without opioids group: HR, 1.36 [95% CI, 1.13 - 1.64]). A subgroup analysis showed increased risk of mortality in younger participants (20-65 years) on benzodiazepine and opioid co-prescriptions compared to participants 65 years and older. There was increased risk of death in participants with longer follow up who were receiving benzodiazepines only (HR, 2.17 [95% CI 1.59 - 2.98] vs 1.17 [95% CI 0.92 - 1.50]), and similar analysis also showed increased risk of death in participants on benzodiazepine and opioid co-treatment regardless of follow up time.

ConclusionOverall, the results of the study suggest that short or long term co-prescriptions of benzodiazepines and opioids may lead to increased risk of death. In addition, all-cause mortality with benzodiazepine and opioid use together increased in younger participants than in participants older than 65 years.

Key Point: Benzodiazepines and opioids may often be prescribed together and combined use of these   medications can lead to death. Long term use of benzodiazepines and opioids should always be reviewed and targeted interventions are needed to reduce the use of these medications together.



  1. Xu KY, Hartz SM, Borodovsky JT, Bierut LJ, Grucza RA. Association between benzodiazepine use with or without opioid use and all-cause mortality in the United States, 1999-2015. JAMANetwork Open. 2020;3(12). doi:10.1001/jamanetworkopen.2020.28557