Association between opioid analgesic plus benzodiazepine use and death: A case-crossover study

Objective: We aimed to investigate whether concomitant use of benzodiazepines and opioids is associated with an increased risk of death in a population-based case-crossover setting. Methods: We conducted a case-crossover study using the National Sample Cohort database. We introduced a 30-day hazard period before the onset of death and three consecutive previous 30-day control periods with a 30-day washout period. The use of opioids and/or benzodiazepines during the hazard period was compared with that in the three control periods. We performed the conditional logistic regression analysis to estimate the adjusted odds ratios (aORs) and their 95% confidence intervals (CIs). Results: A total of 13,161 individuals who previously used benzodiazepines or opioids and died were included in the study. The risk of death was higher in patients with concomitant use of benzodiazepines and opioids (aOR, 1.86; 95% CI, 1.71-2.02) than in those who used either benzodiazepines or opioids only. In the subgroup analysis among concomitant users, the mortality risks were highest in patients aged less than 20 years (aOR, 3.85; 95% CI, 1.65-8.99), male patients (aOR, 2.20; 95% CI, 1.93-2.51), and patients with renal disease (aOR, 2.42; 95% CI, 1.57-3.74). Conclusion: In this study, concomitant use of benzodiazepines and opioids was associated with a higher risk of death compared with use of a single drug. The risks and benefits of co-prescribing of benzodiazepines and opioids must be weighed carefully.