Efficacy and Safety of 5-Hydroxytryptamine 3 Receptor Antagonists in Irritable Bowel Syndrome: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Abstract

AimWe assessed the efficacy and safety of 5-hydroxytryptamine (5-HT 3 ) receptor antagonists in adults with non-constipated irritable bowel syndrome (IBS) or diarrhea-predominant IBS (IBS-D). MethodsWe searched PubMed, MEDLINE, EMBASE, and the Cochrane Controlled Trials Register for randomized controlled trials (RCTs) involving adults with non-constipated IBS or IBS-D that compared 5-HT 3 receptor antagonists with placebo or other conventional treatment. Dichotomous symptom data were pooled to obtain the relative risk (RR) and 95% confidence intervals (CIs) for improving global IBS symptoms, abdominal pain and abnormal bowel habits, or stool consistency symptoms after therapy, and adverse events, including constipation. Meta-analysis was performed with Mantel Haenszel method using Revman 5.3 software. ResultsWe included 21 RCTs; 16 were high quality (Jadad score ! 4). The pooled RR of global IBS symptoms improved by 5-HT 3 receptor antagonists versus placebo or mebeverine was 1.56 (95% CI: 1.43-1.71); alosetron, ramosetron, and cilansetron had similar treatment effects. The pooled RR of abdominal pain relieved by 5-HT 3 receptor antagonists versus placebo was 1.33 (95% CI: 1.26-1.39). The pooled RR showed that 5-HT 3 receptor antagonists improved abnormal bowel habits or stool consistency symptoms (RR = 1.63, 95% CI: 1.33, 1.99). The pooled RR of adverse events following 5-HT 3 receptor antagonist treatment was 1.15 (95% CI: 1.08, 1.22). Subgroup analysis indicated that alosetron had a high rate of adverse effects (RR = 1.16, 95% CI: 1.08, 1.25); adverse events following ramosetron treatment were not statistically significantly different. ConclusionsRamosetron, cilansetron, ondansetron, and alosetron are effective for treating non-constipated IBS and IBS-D. Our systematic review found rare serious adverse events.

Mast cells are increased in the small intestinal mucosa of patients with irritable bowel syndrome: A systematic review and meta‐analysis

“…For example, when food particles activate enteroendocrine cells, they release serotonin which can subsequently activate lamina propria mast cells inducing a cascade of events leading to mast cell degranulation and symptoms of pain and stool changes. This mechanism is supported by several studies in which the use of medications that modulate serotonin signaling pathways, such as 5‐HT3 antagonist, resulted in symptom improvement in patients with IBS …”

“…Most patients with IBS report the onset or worsening of symptoms after meals . The list of foods that can induce allergic reactions is dependent on cultural habits and differs from country to country, and the mechanism by which certain food constituents exacerbate IBS symptoms is uncertain but may be mediated via IgE‐dependent pathways and/or serotonin‐mediated reactions . The binding of food allergens to IgE can activate mast cells eliciting the release of inflammatory mediators .…”

“…49 The list of foods that can induce allergic reactions is dependent on cultural habits and differs from country to country, 50 and the mechanism by which certain food constituents exacerbate IBS symptoms is uncertain but may be mediated via IgEdependent pathways and/or serotonin-mediated reactions. 12,51 The binding of food allergens to IgE can activate mast cells eliciting the release of inflammatory mediators. 52 For example, when food particles activate enteroendocrine cells, they release serotonin which can subsequently activate lamina propria mast cells inducing a cascade of events leading to mast cell degranulation and symptoms of pain and stool changes.…”

“…This mechanism is supported by several studies in which the use of medications that modulate serotonin signaling pathways, such as 5-HT3 antagonist, resulted in symptom improvement in patients with IBS. 51,53 Besides food-related IgE and non-IgE mechanisms that activate mast cells, a possible role of the gut microbiota, although not proven, should be acknowledged. Indeed, given the results of this study and our previous systematic review and meta-analysis on the colonic mast cells in IBS, 9 the highest mast cell counts were identified in the ileum and colon, where the concentration of bacteria is higher.…”

Review article: an analysis of safety profiles of treatments for diarrhoea‐predominant irritable bowel syndrome

“…A meta‐analysis of 10 randomised, controlled studies of adults with IBS receiving alosetron (range 0.1‐8 mg twice daily), placebo, or mebeverine for ≥12 weeks noted global improvement of IBS symptoms (n = 3 studies; relative risk 1.58; 95% CI 1.42‐1.75), improvement of abdominal pain and discomfort (n = 8 studies; relative risk 1.24, 95% CI 1.16‐1.33), and improvement of abnormal bowel habits or stool consistency (n = 3 studies; relative risk 1.59; 95% CI 1.04‐2.41) with alosetron . A 2012 clinical study, which did not meet the inclusion criteria for the meta‐analysis, included 705 women with severe IBS‐D and reported that treatment with ≥1 alosetron dose (0.5 mg once daily, or 1 mg once or twice daily) for 12 weeks significantly improved all domains of the Irritable Bowel Syndrome Quality of Life instrument (except sexual relations) compared with placebo ( P < 0.05) . The number needed to treat for alosetron has been estimated at 6 and 8 …”