New Therapies in Irritable Bowel Syndrome: What Works and When

Orla Craig

Disclosures

Curr Opin Gastroenterol. 2018;34(1):50-56. 

In This Article

Irritable Bowel Syndrome With Diarrhoea

The serotonin receptor has also been targeted for drug development in IBS-D. Alosetron, a 5-HT3 antagonist that was introduced in the 1990s has been found to be effective in the treatment of IBS-D.[65] However, it was withdrawn from the market because of safety concerns, namely an association with serious constipation and rarely ischaemic colitis.[66] In response to patient outcry, it was later reintroduced and is available in the United States under a risk management programme.[67]

Ramosetron is a highly selective 5-HT3 antagonist that has a similar chemical structure to Alosetron but is not known to be associated with ischaemic colitis.[68] Three randomized controlled trials conducted in an Asian population have shown that it improves abdominal pain, bloating and diarrhoeal symptoms in men with IBS-D.[69–71] It is currently licenced in South-East Asia for management of IBS-D in men. More recently, a similar benefit has been demonstrated in women.[72] Interestingly it appears that a lower dose is effective in women.[73]

Ondansetron is a 5-HT antagonist that is widely used to treat chemotherapy-induced nausea. It was shown to reduce colonic transit over 20 years ago.[74] Although its affinity for the 5-HT receptor is much less than that of the more recently developed Ramosetron and its half-life is shorter,[75] it offers the advantages of being inexpensive and widely available. Furthermore, in 25 years of clinical use, it has not been shown to be associated with ischaemic colitis.[76] A small randomized controlled trial has shown that ondansetron relieves loose stools, frequency and urgency in IBS-D but had minimal effect on abdominal pain.[77] Those with severe diarrhoea responded less well.

Rifaximin is a gut-specific, minimally absorbed antibiotic that is associated with a low risk of bacterial resistance.[78] The results of two phase-3 studies (Target 1 and Target 2)[79] in patients with nonconstipated diarrhoea, showed that treatment with Rifaximin at a dose of 550 mg three times daily for 14 days provides better relief of symptoms of IBS than does placebo. This response was durable for up to 10 weeks after completion of therapy. The therapeutic gain over placebo is 8–9%, with an NNT of approximately 10. It is approved by the FDA for the treatment of nonconstipated IBS but is not licenced in Europe. The TARGET-3 trial[80] explored the efficacy of Rifaximin retreatment in patients with IBS-D who had received open-label Rifaximin for 14 days. Sixty-five per cent of patients with IBS who responded to Rifaxamin relapsed within 18 weeks. Those who relapsed were rerandomized to up to two further 2-week courses, 10 weeks apart versus placebo. There was a significant increase in responders with Rifaximin treatment compared with the placebo after the first and second treatment phases. Retreatment up to two times has been approved by the FDA on the basis of this study.

Eluxadoline is a mixed μ-opioid receptor agonist and [delta]-receptor antagonist with low-systemic absorption and bioavailability. Animal studies suggest, it reduces visceral hypersensitivity without complete inhibition of gastrointestinal motility.[81] Two large phase-3 trials,[82] demonstrated that Eluxadoline (75 and 100 mg twice daily) was effective in simultaneously relieving the symptoms of abdominal pain and diarrhoea of IBS and was generally well tolerated. It has also recently been shown to be effective in patients with IBS-D who have previously been treated with Loperamide.[83**] Across these trials, a response was seen in 23–29% of the treatment groups compared with 12–19% of the placebo groups. It has been approved for the treatment of IBS-D both in Europe and the United States. μ-Opioid receptor agonism, however, has the potential to cause Sphincter of Oddi spasm. The pooled safety and tolerability data from the phase 2 and 3 trials[84] found Sphincter of Oddi spasm to be a rare occurrence. Where it did occur , it tended to be in those without a gallbladder. It was also noted that Eluxadoline increased the risk of pancreatitis in those with heavy alcohol use and it is contraindicated in this patient group. Postmarketing surveillance identified a number of cases of severe pancreatitis including two deaths.[85**] Both deaths and most cases of pancreatitis occurred in patients without a gallbladder. Therefore, Eluxadoline is contraindicated in those who have undergone a prior cholecystectomy.

Bile acids accelerate colonic transit, reduce stool consistency and increase stool frequency.[86] It has recently been demonstrated that 20–30% of patients with IBS-D have evidence of bile acid malabsorption.[87] Wherever available,[75]SeHCAT scanning or serum C4 levels should be considered to identify bile acid malabsorption in those with treatment-resistant IBS-D. Where not available, a therapeutic trial of a bile acid sequestrant may be worthwhile. Although there are no large randomized controlled trials of bile acid-binding drugs in IBD-D, small pilot and open-label studies suggest that they are of benefit in improving stool form and consistency in this patient group.[88,89]

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