Effects of 5-Hydroxytryptamine (Serotonin) Type 3 Antagonists on Symptom Relief and Constipation in Nonconstipated Irritable Bowel Syndrome: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

doi:10.1016/j.cgh.2007.12.015

Clinical Gastroenterology and Hepatology

Volume 6, Issue 5, May 2008, Pages 545-555

https://doi.org/10.1016/j.cgh.2007.12.015 Get rights and content

Background & Aims: We performed a systematic review and meta-analyses to estimate treatment efficacy and constipation rate of 5-hydroxytryptamine (serotonin) (5-HT₃) antagonists in patients with nonconstipated (NC) or diarrhea-predominant (D)–irritable bowel syndrome (IBS). Methods: Two reviewers independently searched MEDLINE, EMBASE, and Web of Science (January 1, 1966 to December 15, 2006) for randomized controlled trials of 5-HT₃ antagonists in IBS reporting clinical end points of the IBS symptom complex and safety parameters. Study characteristics, markers of methodologic quality, and outcomes for the intention-to-treat population for each randomized controlled trial were extracted independently. Results: We found 14 eligible randomized controlled trials of alosetron (n = 3024) or cilansetron (n = 1116) versus placebo (n = 3043) or mebeverine (n = 304). Random-effects meta-analyses found 5-HT₃ antagonists more effective than the comparators in achieving global improvement in IBS symptoms (pooled relative risk, 1.60; 95% confidence interval [CI], 1.49–1.72; I² = 0%) and relief of abdominal pain and discomfort (pooled relative risk, 1.30; 95% CI, 1.22–1.39; I² = 22%). Benefit was apparent for both agents, in patients of either sex. These agents were more likely to cause constipation (pooled relative risk, 4.28; 95% CI, 3.28–5.60, I² = 65%); there was less constipation with 5-HT₃ antagonists in D-IBS patients than in mixed populations (NC-IBS and D-IBS; relative risk ratio, 0.65; 95% CI, 0.41–0.99). Nine patients (0.2%) using 5-HT₃ antagonists had possible ischemic colitis versus none in control groups. Conclusions: 5-HT₃ antagonists significantly improve symptoms of NC-IBS or D-IBS in men and women. There is an increased risk of constipation with 5-HT₃ antagonists, although the risk is lower in those with D-IBS.

Section snippets

Methods

The present meta-analysis was performed and reported according to the standards of the quality of reporting of meta-analysis (QUOROM) statement.²⁸

Flow of Study Retrieval

Figure 1 describes the study identification and selection process. Reasons for exclusion included the type of study (review, animal study, basic research, and review and analysis of already included trials and postmarketing data), the study end points (pharmacodynamic end points, quality of life, patient satisfaction, and patient adherence to therapy), duplicate publication (eg, of other end points such as quality of life) of studies that already were included, and the indication (functional

Main Findings

This systematic review of large randomized controlled trials indicates that 5-HT₃ antagonists, as a class, significantly improve abdominal pain and discomfort and global IBS symptoms in patients with NC-IBS or D-IBS. Treatment response was consistent across a range of studies performed in different countries with an estimated pooled RR of 1.60 [1.49–1.72], a number needed to treat of 4.2, and a risk difference of 0.22 [0.18–0.25] for the improvement of global IBS symptoms, and an estimated

Conclusions

This systematic review and meta-analysis found that 5-HT₃ antagonists improve abdominal pain and discomfort, and global IBS symptoms in men and women with NC-IBS and D-IBS. This evidence is consistent across agents within this class and across a broad range of participants in clinical trials. Constipation is a common but usually mild to moderate side effect of treatment with 5-HT₃ antagonists. The risk for constipation is lower in patients with a predominance of diarrhea and this emphasizes the

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: Dr Andresen served as a consultant for Solvay, the manufacturer of cilansetron, from 2004 to 2005 and was employed in the medical department of the German affiliate of GlaxoSmithKline, the manufacturer of alosetron, from 2000 to 2001. Dr Camilleri received research support in 2006 to 2007 for a single-center pharmacodynamic study with a drug that was not in the 5-HT₃ antagonist class from GlaxoSmithKline, the manufacturer of alosetron, and served as a consultant in 2006, receiving annually less than the federal threshold for a significant financial conflict of interest. Dr Keller served as a consultant for GlaxoSmithKline from 2000 to 2001. Dr Layer served as a consultant for GlaxoSmithKline from 2000 to 2001 and for Solvay from 2004 to 2005. Dr Andresen is supported by the Gustav und Catharina Schuerfeld Foundation, Hamburg, Germany. Dr Camilleri is funded in part by grants RO1- DK54681 and K24-DK02638 from the National Institutes of Health.

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Original article—alimentary tractEffects of 5-Hydroxytryptamine (Serotonin) Type 3 Antagonists on Symptom Relief and Constipation in Nonconstipated Irritable Bowel Syndrome: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Section snippets

Methods

Flow of Study Retrieval

Main Findings

Conclusions

Gastroenterology

Gastroenterology

Gastroenterology

Am J Gastroenterol

Am J Gastroenterol

Am J Gastroenterol

Clin Gastroenterol Hepatol

Am J Gastroenterol

Am J Gastroenterol

Lancet

Lancet

Clin Gastroenterol Hepatol

Am J Gastroenterol

Irritable bowel syndrome in the general population

BMJ

U.S. householder survey of functional gastrointestinal disordersPrevalence, sociodemography, and health impact

Dig Dis Sci

Functional bowel disorders and functional abdominal pain

Gut

The effects of granisetron, ICS 205-930 and ondansetron on the visceral pain reflex induced by duodenal distension

Br J Pharmacol

Differences between 5-HT3 receptor antagonists in modulation of visceral hypersensitivity

Br J Pharmacol

Central modulation of rectal distension-induced blood pressure changes by alosetron, a 5-HT3 receptor antagonist

Dig Dis Sci

The 5-HT(3) receptor antagonist alosetron inhibits the colorectal distention induced depressor response and spinal c-fos expression in the anaesthetised rat

Gut

Effect of alosetron on responses to colonic distension in patients with irritable bowel syndrome

Aliment Pharmacol Ther

Effects of 5-HT(3) antagonism on postprandial gastric volume and symptoms in humans

Aliment Pharmacol Ther

Alosetron, a 5-HT3 receptor antagonist, delays colonic transit in patients with irritable bowel syndrome and healthy volunteers

Aliment Pharmacol Ther

Original article—alimentary tract
Effects of 5-Hydroxytryptamine (Serotonin) Type 3 Antagonists on Symptom Relief and Constipation in Nonconstipated Irritable Bowel Syndrome: A Systematic Review and Meta-Analysis of Randomized Controlled Trials