IBS -- Review and What's New

Amy Foxx-Orenstein, DO, FACG, FACP

Disclosures
In This Article

IBS Treatments

The goal of IBS treatment is to provide relief of symptoms and improve overall well-being.[2] Traditional therapies for IBS can effectively treat single symptoms ( Table 1 ), but their utility may be limited when patients have moderate-to-severe symptoms or when they have multiple symptoms. The multisymptom nature of IBS often leads patients to try numerous treatment methods to achieve a broad spectrum of symptom relief. Additionally, many of these agents are associated with adverse effects that may limit their routine use. Some of these adverse effects mimic IBS symptoms (eg, fiber may cause bloating, tricyclic antidepressants may cause constipation).[2]

Because of their ability to alter serotonin function in the CNS and possibly in the periphery, low-dose tricyclic antidepressants and selective serotonin reuptake inhibitors are sometimes used to treat patients with IBS. They are primarily effective in reducing the pain associated with this disorder and are used at doses well below those used for psychiatric indications such as depression.[2,3] Although evidence suggests that some patients with IBS may benefit from tricyclic antidepressants or selective serotonin reuptake inhibitor therapy, results of clinical studies show significant variability in the response and do not provide overwhelming support for their use, except perhaps in patients with comorbid psychiatric conditions and a lack of response to other therapies.[93,94]

Along with traditional pharmacologic therapies, additional measures such as patient education and behavioral therapy (eg, hypnosis, biofeedback, relaxation, cognitive therapy) are used in treating patients with IBS. Most studies use a combination of these techniques. Biofeedback is one example of a noninvasive, behavioral intervention that may help patients with IBS achieve symptom relief. In this approach, sensors are strategically placed at specific positions on patients, and a computer and video monitor are used to illustrate (via sounds or line graphs) body functions of which patients are normally not aware. This information can be used to help patients recognize and modify (eg, increase, decrease, coordinate) their physiologic responses to various stressful stimuli (eg, stress-related motility).[95,96] The value of biofeedback and other behavioral therapies cannot be discounted in the management strategy for IBS and should be considered in the overall treatment plan.[2] A recently reported systematic review of published trials of psychological treatments for IBS, including biofeedback, found an overall positive outcome for these interventions (odds ratio of treatment effect [50% reduction in symptoms] of 12 [95% CI, 5.56-25.96]); however, this study did not examine the comparative efficacy of one psychological treatment over another.[97] To maximize the likelihood of success with behavioral therapy, these techniques should be administered by a trained professional (eg, physician, physical or occupational therapist, nurse). The scarcity of such trained personnel often limits the utility of these approaches.[95,96]

As discussed previously, increased understanding of the role of serotonin in gut physiology has led to the development of drugs designed to modulate serotonin function in the GI tract. Serotonin affects GI motility, secretion, and visceral sensitivity -- all of which are altered in patients with IBS. Drugs designed to target key serotonin receptors in the GI tract, including 5-HT3 receptor antagonists (eg, alosetron for IBS-D) and 5-HT4 receptor agonists (eg, tegaserod for IBS-C), effectively improve multiple symptoms of IBS. These agents have been tested in large, randomized, placebo-controlled trials and were found to be more effective than placebo in providing global relief of IBS symptoms. Alosetron and tegaserod received grade A recommendations (the highest possible) from the ACG Functional GI Disorders Task Force in its systematic review of treatments for IBS.[2]

Alosetron. Alosetron is a 5-HT3 receptor antagonist originally approved by the US Food and Drug Administration (FDA) in 2000 for the treatment of women with IBS-D. In large, double-blind, placebo-controlled clinical trials, alosetron (1 mg twice daily) was significantly more effective than placebo in improving individual symptoms (eg, bowel urgency, abdominal pain) of IBS-D,[98,99] as well as in global symptom improvement (as measured using the IBS Global Improvement Scale).[100,101] The most frequently reported adverse effects during clinical trials, for alosetron and placebo, respectively, were constipation (29% vs 6%), abdominal pain/discomfort (7% vs 4%), and nausea (6% vs 5%).[102] Constipation generally occurred as single episodes during the first month of treatment and resolved either on its own or after an interruption in treatment.[102] Ischemic colitis and serious complications related to constipation were reported during the clinical trials and during postmarketing surveillance, prompting the withdrawal of the drug from the market less than a year after its introduction. Toward the end of 2002, however, alosetron was reintroduced with a restricted indication for women with severe IBS-D who have not responded to conventional therapy and in whom anatomic and biochemical abnormalities have been excluded.[102] Furthermore, the new prescribing label (revised again in February 2005) includes: (1) a black box warning regarding the risk for serious GI adverse effects, such as ischemic colitis; (2) a new starting dosage (0.5 mg twice daily); and (3) a requirement that physicians and patients subscribe to a risk-management program. The risk-management program was put into place to ensure that physicians and patients are aware of the potential for serious adverse effects and agree to follow steps to maximize the safe use of alosetron.

Recently, the long-term efficacy and safety profile of alosetron (1 mg twice daily) was shown in a 12-month randomized, double-blind, placebo-controlled trial in women with severe IBS-D.[103] In this trial, constipation occurred in 23% of patients taking alosetron and in 5% of those receiving placebo; however, no cases of ischemic colitis or serious constipation were documented.[103] Current clinical trials (phase 2) are aimed specifically at showing the efficacy and safety of alosetron in men with IBS-D.[104]

Tegaserod. Tegaserod is a selective 5-HT4 receptor agonist approved by the FDA for the short-term treatment of women with IBS-C and for men and women younger than 65 years of age with chronic idiopathic constipation. In large, randomized, placebo-controlled clinical trials, tegaserod (6 mg twice daily) provided significantly greater global relief of IBS symptoms, as assessed using the Subject's Global Assessment of Relief, and relief of individual IBS-C symptoms (eg, stool consistency and frequency, abdominal pain and discomfort, bloating).[105,106,107,108] Treatment response was observed within the first week of therapy and continued for the 12-week duration of the trials. Additional studies, in which tegaserod was stopped until symptoms returned and then restarted, indicate that symptoms recur in most patients after tegaserod is withheld, and re-treatment yields response rates similar to those observed during initial treatment.[109,110]

The adverse effects occurring significantly more frequently in tegaserod-treated vs placebo-treated patients, respectively, in IBS clinical trials were headache (15% and 12%) and diarrhea (9% and 4%).[111] In most cases, diarrhea was mild, occurred as a single episode during the first week of therapy, and resolved with continued treatment. Discontinuation of the use of tegaserod as a result of diarrhea was low (1.6% vs 0% for those receiving placebo). Clinically significant diarrhea (resulting in hospital admission, hypovolemia, hypotension, and need for intravenous fluid) occurred in a minority (4 [0.04%] of 10,000) of patients in clinical trials.[111] A long-term, open-label safety study showed that tegaserod was safe and well tolerated in patients receiving 6 mg twice daily for up to 1 year.[112]

The enhanced understanding of putative underlying mechanisms in IBS has led the way for the development of innovative drug classes. Numerous agents are in the drug development pipeline, including newer GI serotonergic agents, alpha2-adrenergic agonists, kappa-opioid receptor agonists, chloride channel openers, 2,3 benzodiazepines, and guanylate cyclase-C agonists. A brief overview of the mechanism of action and potential place in IBS therapy of some of these novel agents appears and is summarized in Table 2 .

Cilansetron is a 5-HT3 receptor antagonist.[113,114,115,116] Similar to alosetron, cilansetron works by inhibiting colonic motility and reducing visceral hypersensitivity. This agent has been shown to be effective (in both male and female patients) in relieving abnormal bowel habits and abdominal pain in patients with IBS-D. Constipation is a common adverse effect. Cases of ischemic colitis have been reported, but all resolved (without complications) within several weeks. This agent received a nonapproval letter from the FDA in April of 2005.

Renzapride is a mixed 5-HT4 receptor agonists/5-HT3 receptor antagonist (benzamide derivative)[117,118,119,120] that works by accelerating colonic transit and reducing visceral hypersensitivity. Preliminary data demonstrate a beneficial effect of renzapride in improving symptoms of abdominal pain/discomfort, stool consistency, and stool frequency in patients with IBS-C; its utility in patients with alternating bowel habits (IBS-A) is less clear, however. In phase 2 clinical trials, diarrhea and headache were frequently reported adverse effects.[117,118,119,120]

Clonidine is an alpha2-adrenergic agonist that works by reducing colonic motor activity and pain sensitivity. In a study conducted in patients with IBS-D, clonidine reduced bowel dysfunction and enhanced the proportion of patients achieving satisfactory relief of IBS, without altering gastrointestinal transit.[121] Commonly reported adverse effects, including somnolence and hypotension, may limit its usefulness on a chronic basis.

Asimadoline[122,123] is a kappa-opioid receptor agonist that exerts anti-nociceptive properties on the gut by reducing colonic sensation without affecting gastrointestinal motility. This agent does not cross the blood-brain barrier and therefore works in a peripheral manner (partially though blockage of gut sodium channels).[124,125] Its efficacy in reducing sensitivity to colonic distension (without altering compliance or tone) has been shown in a preliminary study in patients with IBS-C.[126]

Lubiprostone (a prostaglandin E1 derivative bicyclic fatty acid) acts as a chloride channel opener, increasing intestinal fluid secretion and thereby softening stools, promoting bowel movement, and decreasing bloating and abdominal pain.[127] In phase 3 clinical trials of patients with constipation, the most commonly reported adverse effects were headache, diarrhea, and nausea.[128] A phase 3 clinical trial in patients with IBS-C was initiated in mid-2005.[127]

Dextofisopam is classified as a 2,3 benzodiazepine. Unlike typical benzodiazepines, this agent does not bind to GABA receptors, but rather to 2,3 benzodiazepine receptors.[129,130] Although opioid neurotransmission and altered phosphorylation of proteins that affect signal transmission are among the proposed modes of action, the exact mechanism by which this drug class works continues to be evaluated.[129] The efficacy of dextofisopam in male and female patients with IBS-D or IBS-A was demonstrated in a randomized, placebo-controlled, phase 2b 12-week study. For the primary efficacy endpoint (overall IBS symptom relief), dextofisopam was more effective than placebo for both IBS subtypes. For the secondary endpoints of stool frequency and stool consistency, however, dextofisopam was more effective vs placebo in patients with IBS-D than those with IBS-A.[131,132,133] Abdominal pain occurred more frequently in the dextofisopam treatment groups, whereas headache occurred more often in the placebo groups.[131,132,133]

MD-1100 is an agonist of guanylate cyclase-C, a receptor located on intestinal cell surfaces. In preclinical studies, this compound has been shown to act locally on the intestinal epithelium to enhance secretion and motility and reduce visceral sensation. This agent is in early-stage development for the treatment of patients with IBS-C. Results from a double-blind, randomized, placebo-controlled, single-dose phase 1 study found MD-1100 to be well tolerated. No systemic absorption was detected, and a decrease in stool consistency (as assessed by the Bristol Stool Scale) was noted.[134,135] A multiple, ascending-dose phase 1 study is ongoing, and a phase II study with patients with IBS-C is under way.[135,136]

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