Do certain pharmacotherapies for IBS increase the risk of mortality?

Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder characterized by abdominal pain associated with altered bowel habits. It affects 10%–15% of the population worldwide and can present as diarrhea-predominant (IBS-D), constipation-predominant (IBS-C) or a mixed pattern (IBS-M). Several medications have been approved by Health Canada and/or the U.S. Food and Drug Administration for the treatment of IBS. These include lubiprostone (not marketed in Canada), tenapanor, linaclotide and plecanatide for IBS-C, and rifaximin, eluxadoline and alosetron (not marketed in Canada) for IBS-D. However, many patients are prescribed other medication classes off-label, including tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), antispasmodics and bile acid sequestrants to treat various symptoms of IBS. The long-term safety of these pharmacotherapies remains unclear. To examine this issue, U.S. and U.K. researchers assessed the association between long-term IBS pharmacotherapies and all-cause mortality. Their retrospective cohort study used a nationwide U.S. electronic health record database from 2005–2023. The 1:1 propensity score matched cohort included 669,083 adults (age 18–65 years) with IBS. Patients were grouped by pharmacotherapy use, with subgroup analyses for IBS-D and IBS-C. Exposures included guideline-recommended therapies for IBS, IBS-D or IBS-C. Follow-up started at the time of medication prescription after diagnosis. The primary outcome was all-cause mortality, assessed using Cox proportional hazards models and target trial emulation.Key results:Of the 669,083 patients with IBS who met the inclusion criteria, antidepressants were the most commonly used medications (52.3%), followed by antispasmodics (22.1%). Antidepressant use was associated with an increased risk of all-cause mortality compared with controls (hazard ratio [HR], 1.35; 95% CI, 1.26–1.45; mortality rate, 1.6% vs. 1.0%). This association was consistent across antidepressant subclasses (SSRIs, SNRIs, TCAs, mirtazapine) and subgroups stratified by sex, age, body mass index and ethnicity.Antispasmodic (i.e., hyoscyamine and dicyclomine) use was not linked to increased mortality (HR, 0.95; 95% CI, 0.89–1.00). For IBS-D, cholestyramine/colestipol, eluxadoline and rifaximin were not associated with mortality. For IBS-D, the mu receptor agonists diphenoxylate/atropine (HR, 1.89; 95% CI, 1.02–3.51) and loperamide (HR, 2.39; 95% CI, 1.48–3.90) showed increased mortality risk. For IBS-C, polyethylene glycol-3350 and secretagogues (i.e., tenapanor, plecanatide, lubiprostone, linaclotide) had no significant association with mortality.The investigators conclude that their findings raise concerns regarding the safety of antidepressants in IBS and mu receptor agonists in IBS-D. Cautious prescribing of these agents is recommended. In addition, further research into the long-term safety of IBS medications is needed.Reference:Mehravar S, Yeo SH, Pimentel M, et al. Association of pharmacotherapy with all-cause mortality among patients with irritable bowel syndrome. Communications Medicine 2026;6:176. (accessed April 29, 2026).

Do certain pharmacotherapies for IBS increase the risk of mortality?

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