Ethosuximide and Irritable Bowel Syndrome-Related Abdominal Pain: A Randomized Clinical Trial.

Importance: T-type calcium channels, particularly the Cav3.2 subtype, are involved in pain transduction. Experimental studies and human data suggested that increased T-type channels activity or expression contributes to visceral hypersensitivity in irritable bowel syndrome (IBS), and that their inhibition alleviates pain. Objective: To evaluate the therapeutic potential of ethosuximide, a T-type calcium channel blocker, for IBS-related abdominal pain. Design, Setting, and Participants: This proof-of-concept, multicenter, double-blinded, placebo-controlled randomized clinical trial started in February 2018 and completed in February 2022, with analyses performed between October 2023 and December 2024. Participants were adults meeting Rome IV criteria for IBS, treated in 10 gastroenterology departments in French university hospitals, with abdominal pain intensity rated at least 4 out of 10 during a 7-day run-in period. Interventions: Patients were randomized to receive ethosuximide or placebo daily for 12 weeks. Main Outcomes and Measures: The primary end point was the responder rate, defined as at least 30% reduction in mean abdominal pain intensity associated with a Subject Global Assessment of relief score at least 4 (ie, considerably or completely relieved). Secondary outcomes included safety, IBS symptom severity, and quality of life. Results: Of 161 enrolled patients, 124 were randomized (64 ethosuximide; 60 placebo). The mean (SD) age was 43.7 (14.9) years, 72 (58.1%) were women, the median (IQR) IBS duration was 5.0 (1.4-10.6) years, and the mean (SD) abdominal pain intensity was 6.0 (1.0). In the intent-to-treat analysis, responder rates did not differ significantly between groups (17 of 64 patients [26.6%] for ethosuximide vs 14 of 60 patients [23.3%] for placebo; relative risk, 1.14; 95% CI, 0.61-2.11). Ethosuximide was less well tolerated, with higher discontinuation rates (30 patients [46.9%] vs 13 patients [21.7%]; P = .003) and more adverse events (261 of 463 adverse events reported overall [56.4%] were determined to be caused by ethosuximide; P < .001), most commonly headaches, sleep disturbances, and nausea, compared with placebo. Conclusions and Relevance: In this randomized clinical trial, ethosuximide did not demonstrate efficacy over placebo for the treatment of IBS-related abdominal pain, and was associated with reduced tolerability. These findings do not support the use of ethosuximide for IBS pain management but highlight the need for development of more selective and better-tolerated T-type calcium channel modulators. Trial Registration: ClinicalTrials.gov Identifier: NCT02973542.