Ondansetron for the Treatment of IBS With Diarrhea
Ondansetron for the Treatment of IBS With Diarrhea
Background Irritable bowel syndrome with diarrhoea (IBS-D) is particularly debilitating due to urgency and episodic incontinence. Some 5-hydroxytryptamine 3 (5-HT3) receptor antagonists (5-HT3RAs) have proven effective but have serious side effects. Ondansetron, also a 5-HT3RA, has been widely used as an antiemetic with an excellent safety record for over two decades. Our aim was to assess its effectiveness in IBS-D.
Methods 120 patients meeting Rome III criteria for IBS-D entered a randomised, double-blind, placebo-controlled crossover study of 5 weeks of ondansetron 4 mg versus placebo with dose titration allowed, up to two tablets three times daily in the first 3 weeks. Patients completed daily diaries documenting stool consistency using the Bristol Stool Form score. Gut transit was measured in the last week of each treatment. The primary endpoint was average stool consistency in the last 2 weeks of treatment.
Results Ondansetron significantly improved stool consistency (mean difference in stool form between ondansetron and placebo −0.9, 95% CI −1.1 to −0.6, p<0.001). Compared with placebo, patients on ondansetron experienced fewer days with urgency (plt;0.001), lower urgency scores (plt;0.001), reduced frequency of defaecation (p=0.002) and less bloating (p=0.002), although pain scores did not change significantly. IBS symptom severity score fell more with ondansetron than placebo (83±9.8 vs 37±9.7, p=0.001). 65% reported adequate relief with ondansetron but not placebo compared with 14% reporting relief with placebo but not ondansetron, relative risk 4.7, 95% CI 2.6 to 8.5, plt;0.001.
Conclusions Ondansetron relieves some of the most intrusive symptoms of IBS-D, namely loose stools, frequency and urgency.
Irritable bowel syndrome with diarrhoea (IBS-D) affects approximately 3% of the general population and accounts for approximately 20% of gastroenterology outpatient visits in the UK. Since many conditions can cause diarrhoea, such patients typically undergo numerous negative tests. IBS regardless of subtype is also associated with considerable impairment of quality of life. IBS-D is particularly a debilitating form of IBS as it reduces the ability to eat out and socialise because of fear of pain, urgent defaecation and even incontinence. Serotonin (5-hydroxytryptamine (5-HT)) is a major mediator in the gut, signalling via afferent nerves to influence gut motility and secretion. 5-HT3 receptor antagonists (5HT3RAs) block the vagal stimulation induced by 5-HT and were developed as a highly effective treatment for chemotherapy-induced nausea and vomiting, known to be mediated via vagal stimulation by cisplatinum-induced 5-HT release. It was soon discovered that 5HT3RAs also cause constipation. Early studies with ondansetron demonstrated that 16 mg three times a day, the usual dose for chemotherapy-induced emesis, delayed colonic transit in healthy subjects, and reduced the postprandial increase in colonic tone in carcinoid diarrhoea. A small trial using the much lower dose of 4 mg three times a day suggested benefit in IBS and functional dyspepsia. Our aim was to determine whether this inexpensive, safe generic drug would provide similar relief to patients with IBS-D. We also wished to determine the mechanism of action and in particular whether clinical factors or polymorphisms in the SERT genotype could predict those that would respond, as has been suggested for alosetron.
Abstract and Introduction
Abstract
Background Irritable bowel syndrome with diarrhoea (IBS-D) is particularly debilitating due to urgency and episodic incontinence. Some 5-hydroxytryptamine 3 (5-HT3) receptor antagonists (5-HT3RAs) have proven effective but have serious side effects. Ondansetron, also a 5-HT3RA, has been widely used as an antiemetic with an excellent safety record for over two decades. Our aim was to assess its effectiveness in IBS-D.
Methods 120 patients meeting Rome III criteria for IBS-D entered a randomised, double-blind, placebo-controlled crossover study of 5 weeks of ondansetron 4 mg versus placebo with dose titration allowed, up to two tablets three times daily in the first 3 weeks. Patients completed daily diaries documenting stool consistency using the Bristol Stool Form score. Gut transit was measured in the last week of each treatment. The primary endpoint was average stool consistency in the last 2 weeks of treatment.
Results Ondansetron significantly improved stool consistency (mean difference in stool form between ondansetron and placebo −0.9, 95% CI −1.1 to −0.6, p<0.001). Compared with placebo, patients on ondansetron experienced fewer days with urgency (plt;0.001), lower urgency scores (plt;0.001), reduced frequency of defaecation (p=0.002) and less bloating (p=0.002), although pain scores did not change significantly. IBS symptom severity score fell more with ondansetron than placebo (83±9.8 vs 37±9.7, p=0.001). 65% reported adequate relief with ondansetron but not placebo compared with 14% reporting relief with placebo but not ondansetron, relative risk 4.7, 95% CI 2.6 to 8.5, plt;0.001.
Conclusions Ondansetron relieves some of the most intrusive symptoms of IBS-D, namely loose stools, frequency and urgency.
Introduction
Irritable bowel syndrome with diarrhoea (IBS-D) affects approximately 3% of the general population and accounts for approximately 20% of gastroenterology outpatient visits in the UK. Since many conditions can cause diarrhoea, such patients typically undergo numerous negative tests. IBS regardless of subtype is also associated with considerable impairment of quality of life. IBS-D is particularly a debilitating form of IBS as it reduces the ability to eat out and socialise because of fear of pain, urgent defaecation and even incontinence. Serotonin (5-hydroxytryptamine (5-HT)) is a major mediator in the gut, signalling via afferent nerves to influence gut motility and secretion. 5-HT3 receptor antagonists (5HT3RAs) block the vagal stimulation induced by 5-HT and were developed as a highly effective treatment for chemotherapy-induced nausea and vomiting, known to be mediated via vagal stimulation by cisplatinum-induced 5-HT release. It was soon discovered that 5HT3RAs also cause constipation. Early studies with ondansetron demonstrated that 16 mg three times a day, the usual dose for chemotherapy-induced emesis, delayed colonic transit in healthy subjects, and reduced the postprandial increase in colonic tone in carcinoid diarrhoea. A small trial using the much lower dose of 4 mg three times a day suggested benefit in IBS and functional dyspepsia. Our aim was to determine whether this inexpensive, safe generic drug would provide similar relief to patients with IBS-D. We also wished to determine the mechanism of action and in particular whether clinical factors or polymorphisms in the SERT genotype could predict those that would respond, as has been suggested for alosetron.
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