Association of pharmacotherapy with all-cause mortality among patients with irritable bowel syndrome

BACKGROUND: Irritable bowel syndrome (IBS) is a common disorder associated with high healthcare costs and reduced quality of life. The long-term safety of its pharmacotherapies remains unclear. This study aims to assess the association between long-term pharmacotherapies and all-cause mortality in this population. METHOD: We performed a retrospective cohort study using a nationwide U.S. electronic health record database (January 1, 2005, to January 1, 2023). A 1:1 propensity score-matched cohort included 669,083 adults (aged 18-65) with IBS. Patients were grouped by pharmacotherapy use, with subgroup analyses for IBS with diarrhea (IBS-D) and IBS with constipation (IBS-C). Follow-up started at the time of medication prescription after diagnosis. Exposures included guideline-recommended therapies for IBS, IBS-D, or IBS-C. The primary outcome was all-cause mortality, assessed using Cox proportional hazards models and target trial emulation. RESULTS: Antidepressant use is associated with an increased risk of all-cause mortality (hazard ratio [HR], 1.35; 95% CI, 1.26-1.45; mortality rate, 1.6% vs. 1.0%). This association remains consistent across antidepressant subclasses and demographic subgroups. Antispasmodic use is not linked to increased mortality (HR, 0.95; 95% CI, 0.89-1.00). For IBS-D, cholestyramine/colestipol, eluxadoline, and rifaximin are not associated with mortality. However, diphenoxylate (HR, 1.89; 95% CI, 1.02-3.51) and loperamide (HR, 2.39; 95% CI, 1.48-3.90) show increased mortality risk. For IBS-C, polyethylene glycol-3350 and secretagogues have no significant association with mortality. CONCLUSIONS: These findings raise concerns regarding the safety of antidepressants and mu receptor agonists in IBS treatment and underscore the need for cautious prescribing and further research.