Benzodiazepine-opioid cotreatment linked to increased long-term mortality risk

Cotreatment with benzodiazepine and opioids was linked to increased long-term mortality risk, according to results of a retrospective cohort study published in JAMA Network Open.

Researchers noted that targeted interventions are needed to decrease overprescribing.

“When benzodiazepines are taken alone, long-term use is associated with falls, cognitive impairment and life-threatening withdrawal,” Kevin Y. Xu, MD, MPH, of the department of psychiatry at Washington University School of Medicine in Missouri, and colleagues wrote. “When taken together with opioids, benzodiazepines can further suppress breathing, a common cause of death from opioid overdose. The danger of benzodiazepine-opioid cotreatment is thus a timely issue, as 20% to 30% of all benzodiazepine recipients in the U.S. are estimated to have an opioid coprescription and more than 30% of opioid overdose deaths are found to involve benzodiazepines.”

Although opioid use in the U.S. has plateaued in recent years, benzodiazepine-opioid coprescriptions have continued to increase. Xu and colleagues aimed to determine whether benzodiazepine use, with or without opioid use, was linked to increased all-cause mortality compared with the use of low-risk antidepressants. They analyzed data of 5,212 individuals aged 20 years or older who were included in the large, nationally representative National Health and Nutrition Examination Surveys (NHANES), which were conducted between 1999 and 2015. Benzodiazepine and opioid coprescriptions served as the primary exposure variable. The active comparator reference group was comprised of individuals taking selective serotonin reuptake inhibitors. The researchers obtained all-cause mortality by linking NHANES data to the National Death Index. They calculated propensity scores from covariates associated with sociodemographic factors, comorbidities and medication use for more than 1,000 prescription types.

Results showed 101 deaths among those who received cotreatment, 236 deaths among those who received only benzodiazepines and 227 deaths among those who received SSRIs but were taking neither opioids nor benzodiazepines. Propensity score weighting revealed a significant increase in all-cause mortality linked to benzodiazepine and opioid cotreatment (HR = 2.04; 95% CI, 1.65-2.52) and benzodiazepines without opioids (HR = 1.6; 95% CI, 1.33-1.92).

Subgroups analyses demonstrated increased risk for mortality among individuals who received cotreatment who were 65 years or younger but not for those older than 65 years. The researchers observed similar findings for those who received benzodiazepines without opioids.

“Amid very few opioid prescribing guidelines targeting patients receiving sedative hypnotics, benzodiazepine-opioid cotreatment poses a therapeutic dilemma for physicians,” Xu and colleagues wrote. “Concerted efforts by physicians, scientists and policymakers are warranted to decrease overprescribing of these medications, identify patients at elevated risk and ultimately implement targeted interventions.”