Efficacy of Gut–Brain Neuromodulators in Irritable Bowel Syndrome: An Updated Systematic Review and Meta-Analysis Publisher Pubmed



Khasawneh M^{1, 2} ; Mokhtare M^{3, 4} ; Moayyedi P⁵ ; Black CJ^{1, 2} ; Ford AC^{1, 2} Show Affiliations
Source: The Lancet Gastroenterology and Hepatology Published:2025

Abstract

Background: Gut–brain neuromodulators might be efficacious for irritable bowel syndrome (IBS), but there has been no synthesis of evidence from randomised controlled trials (RCTs) of some drug classes, and whether they have pain-modifying properties in IBS is unclear. We updated a previous systematic review and meta-analysis of RCTs examining these questions. Methods: We searched MEDLINE (from Jan 1, 1946, to Jan 1, 2025), Embase and Embase Classic (from Jan 1, 1947, to Jan 1, 2025), and the Cochrane Central Register of Controlled Trials (from database inception to Jan 1, 2025). Trials recruiting adults with IBS and that compared gut–brain neuromodulators versus placebo over at least 4 weeks of treatment were eligible. Dichotomous symptom data were pooled using a random effects model to obtain a relative risk (RR) of remaining symptomatic after therapy, with a 95% CI. Findings: The search strategy identified 3625 citations. 28 RCTs were eligible containing 2475 patients. Ten RCTs were identified since our previous meta-analysis, containing 1348 patients. The RR of global IBS symptoms not improving with gut–brain neuromodulators versus placebo in 22 RCTs (2222 patients) was 0·77 (95% CI 0·69–0·87). The best evidence in terms of persistence of global IBS symptoms was for tricyclic antidepressants (TCAs) in 11 trials (1144 patients; RR 0·70, 0·62–0·80). The RR of abdominal pain not improving with gut–brain neuromodulators versus placebo in 19 RCTs (1792 patients) was 0·72 (95% CI 0·62–0·83). The best evidence was for TCAs in seven trials (708 patients; RR 0·69, 0·54–0·87), but there was also a benefit of selective serotonin reuptake inhibitors in seven RCTs (324 patients; RR 0·74, 0·56–0·99), and serotonin and norepinephrine reuptake inhibitors in two trials (94 patients; RR 0·22, 0·08–0·59). Adverse events were not significantly more common with gut–brain neuromodulators, although rates of withdrawal due to adverse events were significantly higher. The certainty in the evidence for tricyclic antidepressants for global IBS symptoms was moderate, but it was low to very low for all other endpoints and drug classes studied. Interpretation: Some gut–brain neuromodulators are efficacious in reducing global symptoms and abdominal pain in IBS. The findings support guidelines that recommend use of tricyclic antidepressants for ongoing global symptoms or abdominal pain but also highlight a potential for SSRIs to be modestly effective for abdominal pain. More data for SNRIs, azapirones, and tetracyclic antidepressants in IBS are required. Funding: None. © 2025 Elsevier Ltd