There are several limitations of this study. Firstly, despite use of an active comparator and case-crossover design, we cannot completely exclude the possibility of residual confounding by indication. For instance, benzodiazepines may constitute a proxy for underlying anxiety symptoms that lead to sedative/hypnotic prescriptions, substance use, and overdose, as opposed to directly contributing to poisoning. Unmeasured exposures, such as illicit substances and non-prescribed benzodiazepines, have commonly been found in the opioid user population (37) and warrant further investigation. Secondly, secular time trends in exposure and outcome may introduce confounding into case-crossover designs;(24, 25) we cannot rule out the possibility of unmeasured time-varying factors associated with drug-related poisoning and benzodiazepine exposure. Mitigating this, we made efforts to control for temporal variation and reduce heterogeneity in observation time per person, using calendar-time and time-from event as a covariate and restricting participants to two-year periods of observation bracketing the index event. In addition to an active comparator analysis, we used bidirectional sampling (before and after index poisoning), which has been found to reduce overlap bias resulting from control period selection as a function of event times.(25)
