# Ethosuximide and Irritable Bowel Syndrome–Related Abdominal Pain: A Randomized Clinical Trial

## TL;DR

A clinical trial found that ethosuximide, a drug that blocks calcium channels, was not effective for treating abdominal pain in people with irritable bowel syndrome and caused more side effects than a placebo.

## Contribution

This study is the first to evaluate ethosuximide's efficacy and safety in IBS-related pain in humans.

## Key findings

- Ethosuximide did not significantly improve abdominal pain compared to placebo.
- Ethosuximide had higher discontinuation rates and more adverse events than placebo.
- The results suggest that T-type calcium channel blockers may need to be more selective to be effective for IBS pain.

## Abstract

What is the therapeutic efficacy of ethosuximide, a Cav3.2 blocker which has demonstrated analgesic activity in animal models of irritable bowel syndrome (IBS), in patients with IBS-related abdominal pain?

In this randomized clinical trial in 124 patients assessing ethosuximide to improve IBS-related abdominal pain, intention-to-treat analysis showed no significant difference in responder rates between ethosuximide and placebo. Ethosuximide had limited tolerability, with higher discontinuation rates, and induced more adverse events compared with placebo.

These findings suggest ethosuximide is not recommended as treatment for IBS-related abdominal pain.

This randomized clinical trial examines the therapeutic potential of ethosuximide, a T-type calcium channel blocker, for irritable bowel syndrome–related abdominal pain.

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.

To evaluate the therapeutic potential of ethosuximide, a T-type calcium channel blocker, for IBS-related abdominal pain.

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.

Patients were randomized to receive ethosuximide or placebo daily for 12 weeks.

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.

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.

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.

ClinicalTrials.gov Identifier: NCT02973542