Sept. 05, 2015
Irritable bowel syndrome (IBS) is a multifactorial disorder marked by recurrent abdominal pain or discomfort and altered bowel function. It affects between 10 and 20 percent of people in the developed world, about one-third of whom have IBS associated with diarrhea (IBS-D).
Certain factors that alter gastrointestinal function can contribute to IBS symptoms, including stress, prior gastroenteritis, changes in the gut microbiome, and bile acids and short-chain fatty acids, which may stimulate serotonin (5-HT) release and increase colonic permeability and motility.
Still, the underlying cause of IBS in many cases remains unknown. Michael Camilleri, M.D., of Mayo Clinic in Rochester, Minn., says the ultimate goal "is a better understanding of the mechanisms behind this syndrome so we can foster individualized, specific treatment for IBS patients." So far, that goal remains unrealized.
The only drug currently approved for IBS-D is alosetron, a 5-HT3 antagonist that may relieve abdominal pain and slow colonic and small bowel transit. Alosetron was withdrawn from the market for safety reasons in 2000 and was reintroduced in 2002 with a more restricted indication. Today, incidence rates of adverse events, including ischemic colitis and complications of constipation, are similar to those before the drug was withdrawn.
Non-IBS medications for IBS-D
Given the limited number of drugs marketed specifically for IBS-D, other medications are often used to treat symptoms. They include:
This synthetic mu-opioid agonist decreases intestinal transit while increasing intestinal water and ion absorption. In a small, placebo-controlled study, loperamide improved pain, stool consistency, urgency and overall subjective response, but it must be carefully titrated for individual patients to avoid constipation.
Bile acid binders
Roughly 30 percent of people with IBS-D have diagnosed bile acid malabsorption, and for this subset of patients, bile acid sequestration may relieve the cholerrheic effect of bile acids. Some evidence suggests that certain genetic variants may influence response to the bile sequestrant colesevelam, a medication that may be preferable to cholestyramine.
Tricyclic agents such as amitriptyline and imipramine were initially prescribed to IBS patients with significant depression. Today, they are frequently used to treat patients with severe or refractory IBS symptoms and may have analgesic and neuromodulatory benefits in addition to their psychotropic effects. In one trial, nearly 70 percent of patients receiving 10 mg of amitriptyline experienced a complete loss of IBS symptoms compared with 28 percent of those on placebo.
Of increasing interest in many gastrointestinal disorders, single or combination probiotics have been investigated for IBS-D in several small trials. In these studies, bloating and distension improved but not diarrhea.
Mast cell stabilizers and 5-aminosalicylic acid (5-ASA)
Gastroenteritis precedes IBS-D in about 25 percent of people. Two anti-inflammatory agents have been used for this subset of patients: mast cell stabilizers such as disodium cromoglycate and ketotifen, and 5-ASA, which has shown mixed results for IBS-D in four small trials.
New drugs for IBS-D
Currently under development or in clinical trials, these drugs are more likely than others to play a role in the future management of IBS-D.
Serotonin synthesis inhibitors
LX-1031 is a tryptophan hydroxylase inhibitor that reduces local 5-HT synthesis and 5-hydroxyindoleacetic acid (5-HIAA) excretion. Unlike previous 5-HT inhibitors, LX-1031 does not cross the blood-brain barrier, thereby reducing the risk of depression and central nervous system disorders. A randomized, placebo-controlled phase II clinical trial in 155 patients showed reductions in urinary 5-HIAA and blood 5-HT as well as improvements in pain and stool consistency.
In two placebo-controlled, parallel-group studies of 1,000 patients with IBS-D, this selective 5-HT3 antagonist increased self-reported global assessment of relief of IBS symptoms. Constipation occurred in roughly 5 percent of participants — less than the rate observed with alosetron.
Spherical carbon adsorbent
AST-120 is a preparation consisting of spherical carbon particles that adsorb bacterial toxins, inflammatory mediators and bile acid products and prevent them from entering systemic circulation. In a phase II randomized, controlled eight-week trial of AST-120 in 115 patients, improvements in pain and bloating were short-lived and there was no significant improvement in stool consistency.
Benzodiazepine receptor modulator
The benzodiazepine receptor modulator dextofisopam binds to benzodiazepine receptors in the brain, not the GI tract, without a sedating effect. In animal studies, it exhibited the potential to reduce colonic motility and visceral sensitivity in response to stress. Further studies are needed to determine the mechanism of action, safety and efficacy in humans.
Asimadoline, a kappa-opioid agonist, is being evaluated in clinical trials. So far, it has shown a good safety profile and reduced pain, urgency and stool frequency in IBS-D patients.
In spite of ongoing studies, Dr. Camilleri says several challenges must be met in order to achieve therapeutic advances, including "significant advances in research to understand the pathophysiology and clinical phenotyping of diverse patients with IBS-D, interest and investment by the pharmaceutical companies to develop the next generation of compounds, and greater definition of study endpoints by regulatory agencies to identify a clear path for approval and marketing of those medications."
For more information
Camilleri M. Current and future pharmacological treatments for diarrhea-predominant irritable bowel syndrome. Expert Opinion on Pharmacotherapy. 2013;14:1151.