Abstract and Introduction
Abstract
Background: Ondansetron may be beneficial in irritable bowel syndrome with diarrhoea (IBS-D).
Aim: To conduct a 12-week parallel group, randomised, double-blind, placebo-controlled trial of ondansetron 4 mg o.d. (titrated up to 8 mg t.d.s.) in 400 IBS-D patients. Primary endpoint: % responders using the Food and Drug Administration (FDA) composite endpoint. Secondary and mechanistic endpoints included stool consistency (Bristol Stool Form Scale) and whole gut transit time (WGTT). After literature review, results were pooled with other placebo-controlled trials in a meta-analysis to estimate relative risks (RR), 95% confidence intervals (CIs) and number needed to treat (NNT).
Results: Eighty patients were randomised. On intention-to-treat analysis, 15/37 (40.5%; 95% CI 24.7%–56.4%) met the primary endpoint on ondansetron versus 12/43 (27.9%; 95% CI 14.5%–41.3%) on placebo (p = 0.19). Ondansetron improved stool consistency compared with placebo (adjusted mean difference − 0.7; 95% CI −1.0 to−0.3, p < 0.001). Ondansetron increased WGTT between baseline and week 12 (mean (SD) difference 3.8 (9.1) hours, versus placebo −2.2 (10.3) hours, p = 0.01). Meta-analysis of 327 patients from this, and two similar trials, demonstrated ondansetron was superior to placebo for the FDA composite endpoint (RR of symptoms not responding = 0.86; 95% CI 0.75–0.98, NNT = 9) and stool response (RR = 0.65; 95% CI 0.52–0.82, NNT = 5), but not abdominal pain response (RR = 0.95; 95% CI 0.74–1.20).
Conclusions: Although small numbers meant the primary endpoint was not met in this trial, when pooled with other similar trials meta-analysis suggests ondansetron improves stool consistency and reduces days with loose stool and urgency.
Trial Registration: – http://www.isrctn.com/ISRCTN17508514
Introduction
Irritable bowel syndrome (IBS), which affects 3%–5% of the population,[1] accounts for 2.5% of the 340 million consultations per year in primary care in England and Wales,[2,3] or approximately 8.5 million consultations per year. Patients with IBS report abdominal pain and erratic bowel habit with around one-third meeting criteria for IBS with diarrhoea (IBS-D).[4] Symptoms of IBS-D include frequent loose or watery stools with associated urgency, which if associated with incontinence,[5] can severely limit socialising, travelling and eating out and markedly reduce quality of life and work productivity. When patients with IBS are asked to rank symptoms in order of importance, erratic bowel habit is rated first, followed by abdominal pain and for those with diarrhoea, urgency.[4] Current treatments for patients with IBS-D, such as loperamide, reduce bowel frequency, but often lead to constipation.[6,7]
A previous meta-analysis showed that the 5-hydroxytryptamine-3 receptor antagonists (5-HT3RAs) alosetron and cilansetron benefited IBS-D patients,[8] improving stool consistency, and reducing both frequency and urgency of defaecation. However, these drugs have serious side effects, including potentially severe constipation in 25% and ischaemic colitis in 0.14% of patients.[9] Alosetron was initially withdrawn and is now only available in the United States with its use restricted to women with severe IBS-D. Cilansetron never came to market, while ramosetron, another 5-HT3RA is only available in Asia, despite confirmed efficacy.[10,11] Ondansetron is a 5-HT3RA that, despite 30 years of widespread use for nausea, has never been associated with ischaemic colitis. Generic ondansetron is inexpensive but is currently only licensed for the management of nausea and vomiting induced by cytotoxic chemotherapy, radiotherapy or following anaesthesia. However, a pilot randomised, placebo-controlled cross-over trial showed that 5 weeks of ondansetron was effective in improving both diarrhoea and urgency in IBS-D.[12] More recently, a bimodal release formulation, BekindaR, delivering 3 mg of immediate-release and 9 mg delayed-release ondansetron, has been shown to improve stool consistency, but not abdominal pain, in 127 IBS-D patients.[13] Our pilot cross-over study showed the decrease in urgency with ondansetron correlated directly with the reduction in faecal protease,[14] but whether this is important for its effectiveness remains unclear.
The primary aim of the current study was to evaluate the efficacy of ondansetron in IBS-D in a 12-week, multi-centre, parallel group, randomised, placebo-controlled trial. Secondary aims were to assess potential mechanisms of benefit including slowing transit, reducing faecal proteases, and altering rectal sensitivity, which may help design studies of future novel agents for this common condition. Difficulties in recruitment meant we were underpowered. However, since the methodology was similar, we were able to combine the current results with those of two previous studies and perform a meta-analysis, which confirmed ondansetron's effectiveness.
Aliment Pharmacol Ther. 2023;57(11):1258-1271. © 2023 Blackwell Publishing
