Background and rationale
Irritable bowel syndrome (IBS), which affects around 4% of the world population,1 accounts for around 1% of the 285 million consultations per year in primary care in England and Wales,2 which is approximately 2.8 million. Around one-third of these patients meet criteria for IBS with diarrhoea (IBS-D). Symptoms include frequent, loose or watery stools with associated urgency, which can severely limit socialising, travelling and eating out. This results in a reduction in quality of life (QoL) and loss of 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.3 This can often be associated with incontinence, which is socially debilitating, but often under-reported.4 Current over-the-counter treatments for patients with IBS-D such as loperamide reduce bowel frequency, but do not improve abdominal pain5,6 and often lead to constipation. The lack of effective treatments results in frequent referrals to secondary care, and such patients have in the past been a significant proportion of gastroenterology outpatients. A previous meta-analysis showed that the 5-hydroxytryptamine-3 receptor antagonists (5HT3RAs) alosetron and cilansetron benefitted such patients, improving stool consistency, and reducing both frequency and urgency of defaecation.7 However, these drugs had serious side effects, including constipation in 25% of patients and, rarely, ischaemic colitis (1 in 700). Alosetron was initially withdrawn and is now available in the USA, only through a risk evaluation and mitigation strategy and is not available in Europe. Cilansetron never came to market, while ramosetron, another 5HT3RA, is only available in Japan, where it is licensed for IBS-D with several good-quality trials confirming its benefit.8,9
Ondansetron is a potent, highly selective 5HT3RA, which blocks 5HT3 receptors in the gastrointestinal tract. Penetration across the blood–brain barrier is limited, with cerebrospinal fluid (CSF) concentration < 15% of plasma levels so central nervous system (CNS) adverse effects are few. Ondansetron was developed and is currently licenced for use in adults and children for the management of nausea and vomiting induced by cytotoxic chemotherapy and radiotherapy (mediated by local release of serotonin in the gut from enterochromaffin cells), and for the prevention and treatment of postoperative nausea and vomiting. Constipation is an unintended side effect of ondansetron, which was first shown to slow colonic transit 30 years ago.10,11 Ondansetron is widely used and unlike alosetron has not been associated with ischaemic colitis. We previously performed a randomised double-blind, placebo-controlled, crossover pilot study of two 5-week periods of treatment recruiting 120 IBS-D patients randomised to receive either ondansetron [2 mg up to 8 mg three times a day (t.d.s)] followed by placebo, or placebo followed by ondansetron with washout period of 2–3 weeks.12 The primary outcome measure for the study was the difference in average stool consistency in the last 2 weeks of treatment, which showed a highly significant improvement with ondansetron versus placebo. We also showed significant benefits for both urgency and stool frequency, with associated slowing of whole gut transit.12 Despite having limitations, results of this pilot study were very encouraging, supporting our clinical experience of ondansetron’s benefits. Recently a novel formulation of ondansetron (Bekinda) comprising 3 mg immediate release and 9 mg slow-release has been shown in a 12-week randomised, placebo-controlled trial to improve stool consistency, though it was underpowered to show significant benefit for pain. Currently there is lack of understanding as to exactly how it works, nor can we predict the individual dose required for optimum effect, which varies widely.13 One key effect we found, also seen with other 5HT3RAs,14 was a marked reduction in urgency, which may play an important role in improving QoL for patients with IBS-D.15
Potential mechanisms of action of 5HT3 receptor antagonists
Transit
5-HT3 receptor antagonists slow transit,10,11 an effect we found particularly marked in the left colon of IBS-D patients and rectosigmoid region, but the underlying mechanism was unclear.12
Tone and motility
An early colonic barostat study showed a reduction in the postprandial rise in colonic tone with ondansetron in both carcinoid syndrome patients16 and healthy volunteers,17 which would be predicted to slow colonic transit. Previous studies of the impact of 5HT3RAs on human colonic motility18–20 were however paradoxical in showing that the 5HT3RAs tropisetron, alosetron and cilansetron all increased periprandial frequency of colonic contractions, and mean amplitude of contractions in the left colon. We hypothesised that 5HT3RAs increase retrograde sigmoid motility, perhaps enhancing ‘brake’ function,21,22 which would be a novel mode of action.
Proteases
In our pilot study we showed the decrease in urgency associated with ondansetron use correlated directly with the reduction in faecal protease (FP),23 but whether this represents a true causal relationship, or just an epiphenomenon, is unclear. FPs have been shown to be increased in IBS-D and, at least in animal models, cause hypersensitivity to rectal distension via activation of protease-activated receptors type 2 (PAR2).24 We have shown that most FPs are endogenous,23 representing pancreatic enzymes that have escaped degradation by colonic bacteria. We hypothesise that slowing gut transit with ondansetron reduces FP, by allowing time for bacterial degradation, and that this may contribute to the beneficial effects of ondansetron on urgency. Reducing faecal tryptase might improve the anal soreness that is commonly reported by patients with IBS-D.
Bile acids
Bile acids have also been shown to sensitise the rectum,25 and elevated faecal bile acids (FBAs) have been shown by several groups in patients with IBS-D.26 Slowing transit may increase the time for bile acid deconjugation by colonic bacteria, and therefore enhance absorption, but how important this is in reducing rectal sensitivity, compared with the effects on FPs, is unclear.
Genetic factors altering sensitivity to 5HT3RAs
We have shown that individuals vary widely in their responsiveness to ondansetron, explaining why trials using fixed doses of 5HT3RAs result in severe constipation in around one in four patients. Meta-analysis gives a relative risk of constipation of 4.3 (3.3–5.6).7 However, when patients were allowed to dose titrate we found that constipation was rare, occurring in only 9% of patients, most of whom responded to dose reduction and only 2% discontinuing ondansetron because of this.12 However, the required dose of ondansetron ranged from 4 mg on alternate days to 8 mg three times a day (t.d.s.). The reasons for this variation are unclear, but recent evidence suggests that responsiveness to 5HT3RAs might be linked to polymorphisms in the genes controlling 5HT synthesis. Serotonin availability in the rectal mucosa is thought to be determined by the activity of the rate-limiting synthetic enzyme tryptophan hydroxylase-1 (TPH-1), which produces serotonin in enterochromaffin cells. A recent small study showed TPH-1 messenger ribonucleic acid (mRNA) levels in rectal mucosa (and thus presumably serotonin synthesis rate) were approximately doubled in responders to another 5HT3RA, ramosetron, compared with non-responders, and that this was linked to the TPH-1 genotype.27
TPH-1 rs211105 minor allele G was found in 44% of non-responders, but only 4% of responders, indicating that possessing the major allele increases responsiveness to the drug. It was also associated with worse diarrhoea, possibly because of the greater 5HT synthesis.
Objectives
The overall aim was to determine the efficacy and safety of ondansetron in patients with symptoms of IBS-D, in particular evaluating the effect on the characteristic abnormalities of stool consistency, frequency and urgency as well as abdominal pain, satisfactory relief of IBS symptoms, mood and use of rescue medication and to determine the effect of 12 weeks ondansetron over 1 month after discontinuation.
