Peripherally Acting Therapies for the Treatment of Irritable Bowel Syndrome

Gut-acting therapies are common therapies for irritable bowel syndrome (IBS). Most of these peripheral acting agents are primarily targeted at individual symptoms. The evidence supporting the use of these agents in IBS is largely anecdotal. Serotonergic agents and the chloride channel activator lubiprostone have shown efficacy in treating symptoms of IBS. The clinical evidence supporting the use of these agents is based on data from high-quality clinical trials. The use of serotonergic agents for IBS in the United States is limited to the 5-hydroxytryptamine-3 antagonist alosetron in the treatment of women with severe IBS with diarrhea refractory to traditional therapy.

The irritable bowel syndrome (IBS) is a chronic, relapsing, and variably disabling bowel disorder characterized by the presence of abdominal pain or discomfort in association with altered bowel habits. IBS is further subtyped based on the predominant stool pattern into one of IBS with constipation (IBS-C), IBS with diarrhea (IBS-D), or mixed IBS (IBS-M). Given the nature of symptoms related to IBS, gut-acting therapies have been traditionally used and remain among the most common therapies for this chronic condition. Most of these peripheral acting agents, including fiber supplements, laxatives, antidiarrheals, and antispasmodics, are primarily targeted at individual symptoms. The evidence supporting the use of these agents in IBS is largely anecdotal, based on dated studies of marginal methodological quality because high-quality clinical trials are generally lacking. Serotonergic agents and the chloride channel activator lubiprostone have shown efficacy in global as well as various individual symptoms of IBS. Moreover, the clinical evidence supporting the use of these agents is based on data from high-quality clinical trials. The use of serotonergic agents for IBS in the United States is limited to the 5-hydroxytryptamine-3 (5-HT ₃ ) antagonist alosetron in the treatment of women with severe IBS-D refractory to traditional therapy.

Fiber supplements and laxatives

The use of fiber supplements and laxatives in the treatment of IBS has evolved from the perception of altered gastrointestinal motility as a cause of the abnormal bowel symptoms associated with this heterogeneous condition. Specifically, several clinical observations have reported a decrease in bowel motility and a prolonged transit time in patients with IBS-C compared with controls. Furthermore, given the proven efficacy of fiber supplements and other laxatives in regulating bowel habits and alleviating constipation, clinicians have traditionally turned to these agents to address the bowel symptoms associated with IBS-C and IBS-M. However, the clinical evidence for this practice is based on limited data because high-quality clinical trials assessing these agents in the treatment of IBS are nearly nonexistent.

Dietary fiber supplements represent a heterogeneous group of complex carbohydrates that are resistant to hydrolysis during digestion. These nondigested products result in increased stool bulk and water content, effectively decreasing stool consistency and increasing stool frequency. Of the various commercially available fiber supplements including psyllium, ispaghula husk, bran (wheat and corn), methylcellulose, calcium polycarbophil, and partially hydrolyzed guar gum; psyllium and bran are the best studied in the treatment of IBS. The results of the 6 trials comparing psyllium and ispaghula husk (the husk of psyllium seed) with placebo were pooled, yielding a total of 321 patients with IBS, with 161 in the treatment arm. In this pooled analysis, 52% of patients treated with psyllium had persistent IBS symptoms after treatment compared with 64% of those receiving placebo. Although significant heterogeneity existed amongst the studies, the relative risk (RR) of symptoms not improving with psyllium was 0.78 (95% confidence interval [CI] 0.63–0.96) compared with placebo with a number needed to treat (NNT) of 6 (95% CI 3–50). The investigators noted that limiting this analysis to the 5 higher-quality trials resulted in a loss of this significant difference between psyllium and placebo. The pooled analysis of the 5 trials comparing bran with placebo or a low-fiber diet found no difference in treatment outcomes with bran. Guar gum has been assessed (daily dose of 5–10 g) in 2 open trials involving patients with constipation-predominant and diarrhea-predominant IBS, suggesting short-term benefits in gastrointestinal symptoms as well as in quality-of-life (QOL) measures. The effects of calcium polycarbophil on IBS have been assessed in 2 clinical trials. The first study was a 6-month, placebo-controlled, randomized, double-blind crossover trial in 23 patients with either constipation-predominant IBS or IBS with alternating diarrhea and constipation. Polycarbophil (6 g/d) was preferred over placebo in 71% of patients for treatment of their IBS symptoms. Compared with placebo, polycarbophil was reported to improve ease of bowel movements and relieve symptoms of nausea, pain, and bloating. In the second trial, calcium polycarbophil was given to 26 patients with IBS (14 with IBS-D and 12 with IBS-C). Compared with baseline there was significant improvement in frequency of bowel movement, stool form, and abdominal pain in both IBS subgroups ( P <.05). There are no clinical trials assessing the efficacy of methylcellulose in the treatment of IBS.

The clinical trials assessing fiber supplements have been evaluated collectively in several systematic reviews, with varying conclusions. The American College of Gastroenterology (ACG) Task Force recently reported on their findings from an evidence-based systematic review on the effectiveness of fiber supplements in the management of IBS, concluding that “Psyllium hydrophilic mucilliod (ispaghula husk) is moderately effective and can be given a conditional recommendation (Grade 2C) ( Table 1 ). Wheat bran or corn bran is no more effective than placebo in the relief of global symptoms of IBS and cannot be recommended for routine use (Grade 2C). A single study reported improvement with calcium polycarbophil.” Using dichotomous outcomes for relief of abdominal pain, improvement in global assessment of IBS symptoms, and improvement in symptom scores, a Cochrane review of 11 studies did not find fiber supplements effective in the treatment of IBS. These investigators cautioned that considerable heterogeneity of patients with IBS existed in the included trials and the effectiveness of fiber supplements have not been completely defined in specific IBS subtypes. In an earlier systematic review performed by the ACG Functional Gastrointestinal Disorders Task Force, this panel of experts concluded that bulking agents were not more effective than placebo at relieving the global symptoms of IBS.

Table 1

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