Diarrhea-Predominant Irritable Bowel Syndrome: Therapeutic Options

Irritable bowel syndrome (IBS) is a common disorder that affects approximately 11% of the world’s population.

This functional bowel disorder is defined by the presence of recurrent abdominal pain associated with defecation or a change in bowel habits. A positive diagnosis of IBS is made based on symptom history using Rome IV Criteria, with minimal need for diagnostic testing.

Based on these criteria, IBS patients can be grouped into one of four subtypes: constipation-predominant IBS, diarrhea-predominant IBS (IBS-D), mixed IBS, where stool patterns vary from constipation to diarrhea, or IBS. Not qualified. IBS-D accounts for approximately one-third of all cases. In addition to the cardinal symptoms of IBS-D, which include diarrhea and abdominal pain, there are many other symptoms, including fecal urgency and bloating.

Patients with IBS report a significant impact on their work productivity, time management, and participation in social activities due to their symptoms. IBS is also associated with comorbid conditions such as anxiety, stress, and depression.

The pathogenesis of IBS is believed to be multifactorial, involving visceral hypersensitivity, abnormal intestinal motility, and dysregulation of the gut-brain axis, among other factors. Newer potential etiological factors include gut microflora dysbiosis and small intestinal bacterial overgrowth (SIBO), which can also cause abdominal pain or discomfort, bloating, flatulence, and loose stools.

Antibiotic treatment has been shown to relieve symptoms associated with SBID, as well as IBS, including abdominal pain, bloating, and diarrhea. SBID is often diagnosed using exhaled hydrogen testing, for which there is currently a lack of standardization in both the substrates used and test preparation and performance, leading to variability in the reported incidence of the condition.

Currently, treatment options are limited for patients with IBS-D, and the heterogeneous nature of this condition presents a challenge in managing the wide range of symptoms observed. Recently published guidelines from the Canadian Association of Gastroenterology (ACG) highlight that patients with IBS may benefit from an individualized, multi-pronged approach, including dietary modifications and psychological and pharmacological therapies.

The objective of this review is to describe available and future treatment options for IBS-D in Canada, with special attention to eluxadoline and rifaximin, two recent additions to the IBS-D armamentarium.

Treating IBS-D symptoms involves lifestyle and diet modifications, over-the-counter therapies, and prescription medications. There is no standard treatment protocol for IBS-D. Many treatment regimens are associated with inadequate control of IBS symptoms, which may lead to treatment change, discontinuation, or use of concomitant therapies.

Lifestyle modifications that can improve IBS symptoms include exercise, reducing stress, and solving sleep problems. Dietary modifications include soluble fiber supplementation as well as restriction of fermentable oligosaccharides, disaccharides, monosaccharides and polyols (OFDMP).

A meta-analysis found that a low OFDMP diet was associated with a reduction in global IBS symptoms compared to a control diet. However, due to the fact that details of a low OFDMP diet are readily available on the Internet, most of these trials were classified as unblinded. In the two studies that were considered to have adequate levels of blinding, the low OFDMP diet showed no benefit versus an alternative diet.

> Psychological Therapies. IBS-D is associated with a high disease burden and low quality of life, which can be addressed with psychological interventions. Referral to psychological treatment may be recommended as part of a multidisciplinary approach to managing IBS symptoms. Evidence suggests that psychological therapies, particularly cognitive behavioral therapies and hypnotherapy, may be effective in treating IBS symptoms.

>  Non-prescription therapies. Over-the-counter therapies for the treatment of IBS-D include loperamide, probiotics, and peppermint oil. Loperamide reduces colonic transit, urgency and consistency of stool in patients with IBS. However, the overall quality of evidence for the use of loperamide in the treatment of IBS is "very low." The ACG guidelines also suggest that, although loperamide is an effective antidiarrheal, there is insufficient evidence to recommend it for relief of overall IBS symptoms.

Probiotics are live microorganisms that can provide health benefits. Probiotics appear effective in reducing global IBS symptom scores or abdominal pain, bloating and flatulence scores, although the quality of evidence is also considered ’low’, particularly due to significant heterogeneity between studies and use of probiotics. different probiotics between studies.

Peppermint oil is a relatively low-cost intervention that has demonstrated consistently favorable results in improving IBS symptoms, and the ACG guidelines conditionally suggest offering peppermint oil as a treatment option.

Several prescription therapies are used off-label for the treatment of IBS-D, including bile acid sequestrants and tricyclic antidepressants. Bile acid diarrhea can occur in up to one-third of IBS-D patients and bile acid sequestrants have been reported to improve stool consistency.

Tricyclic antidepressants are also used off-label to treat IBS-D symptoms, and a recent meta-analysis showed that they can slow intestinal transit, improve overall IBS symptoms, and reduce pain. The ACG guidelines recommend offering tricyclic antidepressants at low doses to improve IBS symptoms.

Antispasmodics are used off-label in the treatment of IBS based on the theory that smooth muscle spasms in the intestine may contribute to IBS symptoms, particularly abdominal pain or cramps. The effects of individual agents are difficult to interpret given the small number of studies completed because of the large number of antispasmodics available.

Recently, two new treatment options have entered the market for the treatment of IBS-D in Canada. Eluxadoline is a new µ- and κ-opioid receptor agonist and δ-opioid receptor antagonist administered orally twice daily at a dose of 100 mg. The ACG has made a conditional suggestion in favor of eluxadoline for the treatment of IBS-D symptoms.

Rifaximin is a minimally absorbed broad-spectrum antibiotic derived from rifamycin administered orally three times daily at a dose of 550 mg for a total of 14 days. The recently updated ACG guidelines make no recommendations (either for or against) offering a course of rifaximin therapy to patients with IBS-D.

Phase 2 and 3 trials

A phase 2 trial enrolled 807 patients who met the Rome III criteria for IBS-D and were randomized to receive placebo or eluxadoline 5, 25, 100, or 200 mg twice daily for 12 weeks. A significantly higher proportion of patients treated with eluxadoline 25 mg or 200 mg met primary composite response criteria at week 4 and week 12 compared to placebo. After 12 weeks, patients receiving eluxadoline 100 mg or 200 mg had greater improvements in stool frequency, urgency, IBS global symptom scores, IBS severity scores, adequate relief, and quality of life scores.

Two randomized, double-blind, placebo-controlled phase 3 trials included 2428 patients with IBS-D who met Rome III criteria to receive placebo or eluxadoline 75 or 100 mg twice daily. The primary efficacy endpoint of both trials was a simultaneous improvement in both abdominal pain and stool consistency, assessed at 12 and 26 weeks of treatment. The data demonstrated that a significantly higher proportion of patients in the eluxadoline group were composite responders compared to the placebo group. Improvements in symptoms were evident in the first week of treatment in patients receiving eluxadoline and were maintained throughout the 26-week treatment period.

A significantly higher proportion of patients receiving either dose of eluxadoline responded for stool consistency at week 12. Eluxadoline was also effective in terms of number of days without urgency, frequency and bloating, with a significant reduction in these results compared to placebo. A greater proportion of patients receiving eluxadoline responded to overall IBS symptoms and a significantly greater proportion of patients responded adequately to relief in both phase 3 clinical trials. Eluxadoline demonstrated efficacy from the first week of treatment and a sustained response up to 6 months .

The efficacy and safety of eluxadoline was evaluated in a phase 4 trial in patients with IBS-D who reported inadequate symptom control with prior loperamide. A significantly higher proportion of eluxadoline patients achieved the primary composite responder endpoint compared to placebo.

Eluxadoline was well tolerated in clinical trials. The most common adverse events (AEs) were constipation, abdominal pain, and nausea. Pancreatitis was the most frequently reported serious AE (SAE) among eluxadoline-treated patients; however, the overall incidence was low (0.4% of eluxadoline-treated patients).

Ten events consistent with sphincter of Oddi spasm were reported in patients receiving eluxadoline, and seven events of pancreatitis, all of which were defined as mild, and all patients discontinued treatment. No cases of sphincter of Oddi spasm or pancreatitis were reported in the phase 4 trial. Eluxadoline is contraindicated in patients without a gallbladder, or in those who consume >3 alcoholic drinks per day. Patients should avoid excessive alcohol consumption while taking eluxadoline.

Eluxadoline has been reported to interact with cyclosporine, strong CYP inhibitors, and medications that cause constipation. The incidence of potentially abuse-related AEs (i.e., dizziness, fatigue, anxiety, etc.) was similar between the placebo group, eluxadoline 75 mg and eluxadoline 100 mg treatment groups, and using the Subjective Opioid Withdrawal Scale , there was minimal evidence of withdrawal symptoms and no significant difference between the treatment groups in terms of withdrawal scores.

Phase 2 and 3 trials

In a phase 2 clinical trial, 87 patients who met the Rome I criteria for IBS were enrolled and randomly assigned to receive rifaximin 400 mg three times a day or placebo for 10 days and were followed for 10 weeks after treatment. Rifaximin resulted in greater improvements in IBS symptoms compared to placebo during the 10-week follow-up.

In 2 double-blind, placebo-controlled phase 5 trials, 1260 patients with IBS without constipation were randomly assigned to rifaximin 550 mg or placebo three times a day for 2 weeks, and were followed for 10 weeks thereafter.

Pooled data from the two studies demonstrated that significantly more patients in the rifaximin group had adequate relief of global IBS symptoms during the first 4 weeks after treatment and maintained this relief for 2 to 12 weeks after treatment. Additionally, significantly more patients in the rifaximin group had adequate bloating relief, abdominal pain response, and stool consistency response.

To investigate the need for retreatment with rifaximin for long-term response, a 51-week randomized, placebo-controlled, phase 3 study enrolled patients with IBS without constipation. Patients who initially responded and subsequently experienced a relapse of IBS-D symptoms entered the double-blind treatment phase.

Patients were randomized to receive two repeat treatment cycles with rifaximin 550 mg or placebo three times daily for 14 days and were followed for 4 weeks after each treatment, with a 6-week treatment-free observation phase between treatment rounds. treatment. The percentage of responders during the double-blind treatment phase was significantly higher with rifaximin than with placebo. The proportions of abdominal pain responders, recurrence prevention responders, and durable responders were also significantly higher with rifaximin treatment than with placebo.

Rates of AEs observed during clinical trials were low overall and were similar between the rifaximin and placebo groups. The most common AEs with rifaximin treatment included headache, upper respiratory tract infection, and nausea. The incidences of drug-related AEs, SAEs, and infection-related AEs were similar between the placebo group and the rifaximin group in the combined phase 2 and phase 3 clinical trial. Rifaximin demonstrates minimal drug interactions and only known which interacts significantly with cyclosporine.

Rifaximin is administered orally three times daily at a dose of 550 mg for a total of 14 days, with up to two retreatments for patients who experience recurrence of symptoms. Treatment with rifaximin has not shown any association with clinically relevant antibiotic resistance.

While data indicate that rifaximin is effective in patients with IBS-D and mixed IBS, the mechanism of action of its benefits is largely unknown and warrants further investigation. Although short courses of rifaximin have been shown not to cause antibiotic resistance, rifamycins are important for the treatment of serious infections, and using an antibiotic to treat a common disorder without understanding its mechanism of action is raising concerns.

IBS is a prevalent gastrointestinal disorder, which significantly affects the quality of life of patients. The heterogeneous presentation and multifactorial pathogenesis of IBS-D require an individualized approach to the treatment of IBS-D symptoms. Eluxadoline and rifaximin are two novel treatments for adults with IBS-D that show efficacy and safety.