By: Benedette Cuffari, B.S. of Toxicology Candidate 2016

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Affecting 10%-15% of the population in Western countries, irritable bowel syndrome (IBS) is most often categorized by altered bowel habits involving chronic or recurrent diarrhea or constipation.¹ IBS patients with chronic diarrhea, sometimes referred to as IBS-D, exhibit abdominal pain and/or discomfort in addition to loose or watery stools. Current treatment options for IBS-D are limited and include antispasmodics, antidepressants, antidiarrheal agents, and alosteron.² IBS-D can be quite disabling for some patients, and the current treatment options are not effective for everyone. Recently, the FDA has approved two new therapies, eluxadoline (Viberzi®) and rifaximin (Xifaxan®), to treat IBS-D in adult men and women.¹

The gastrointestinal tract contains μ, δ, and κ opioid receptors, which all play a key role in regulating gastrointestinal motility, secretion, and visceral sensation.² Eluxadoline interacts with these opioid receptors in two ways to treat acute diarrhea. As a m-opioid receptor agonist, eluxadoline slows gastrointestinal transit, and as a d-opioid receptor antagonist, this drug acts as an analgesic agent, alleviating some of the abdominal pain that often accompanies diarrhea in IBS-D.² The FDA has evaluated several phases of trials testing the efficacy of eluxadoline in both in vitro and in vivo studies. In vitro showed that eluxadoline reduces intestinal contractility and inhibits neurogenically mediated secretion, while in vivo studies showed a reduction in gastrointestinal transit and fecal output in stressed and nonstressed mice.²

      In a pair of phase III, randomized, double-blind, placebo controlled studies, patients receiving eluxadoline reported experiencing a greater relief of their IBS symptoms than placebo patients. These studies involved a combined total of 2,427 patients who were randomized to receive a twice-daily treatment with either eluxadoline at 75 or 100 mg, or the placebo, for a duration of 12 weeks in one study and 26 weeks in the other.³ 29% of patients taking 100 mg of eluxadoline b.i.d. during the trials reported that more than 75% of their days were urgency free, compared to 12% of patients on placebo.³ 43.2% of patients taking 100 mg of eluxadoline also experienced a 40%-50% mean reduction in daily abdominal pain scores, compared with 34.8% of the control patients.³

Some recent studies have also suggested that patients with IBS may have an alteration in their gastrointestinal flora, particularly bacterial overgrowth in the small intestine. Small intestinal bacterial overgrowth (SIBO) can cause excessive gas production and intestinal malabsorption that can result in diarrhea, bloating, abdominal pain, and/or constipation.⁴ Rifaximin has gastrointestinal-specific antibiotic effects that prevent SIBO. This effect against SIBO prevents the mucosal inflammation,  impaired intestinal barrier function, and visceral hyperalgesia in response to chronic stress that is often associated with IBS-D.⁵ Compared to other antibiotics that relieve the symptoms of SIBO, such as neomycin and β-lactams, rifaximin showed efficacy with fewer side effects.⁶ Rifaximin is a particularly desirable treatment option for bacterial IBS-D because of its lengthy residence time in the colon and its minimal systemic absorption.

The study of rifaximin for IBS-D was conducted in two double-blind, placebo-controlled, parallel trials designated as TARGET1 and TARGET 2, in which 600 IBS-D patients took either a 550 mg dose of rifaximin or a placebo three times a day for two weeks.⁷ Patients were followed for 10 weeks after the 2-week study period, during which time 40.7% of patients receiving rifaximin experienced relief of global IBS symptoms, compared to 31.7% of placebo patients claiming similar relief.⁷

One of the biggest problems in treating IBS-D is the lack of understanding of the exact pathology of this disease. As scientists continue to persevere toward understanding the complexity of this debilitating illness, more treatment options are emerging in order to improve the quality of life of these patients. The approval of eluxadoline and rifaximin will hopefully provide more patients with a promising future in maintaining a healthy and comfortable life with IBS-D.

 

SOURCES:

1. U.S. Food and Drug Administration. FDA approves two therapies to treat IBS-D. U.S. Food and Drug Administration Web Site. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm448328.htm. Published 27 May 2015. Last updated 28 May 2015. Accessed 4 August 2015.
2. Dove LS, Lembo A, Randall CW, et al. Eluxadoline benefits patients with irritable bowel syndrome with diarrhea in a phase 2 study. Gastroenterology. 2013; 145(2):329-38.e1. doi: 10.1053/j.gastro.2013.04.006.
3. Jancin B. Eluxadoline scores in phase III trial for IBS. GI & Hepatology News. 2014; 8(7):17. https://m.gastro.org/journals-publications/gi-hepatology-news/GI_-_Hepatology_News_-_July_2014.pdf.
4. Saadi M, and McCallum RW. Rifaximin in irritable bowel syndrome: rationale, evidence and clinical use. Ther Adv Chronic Dis. 2013; 4(2): 71-5. doi: 10.1177/2040622312472008
5. Xu D, Gao J, Gillilland M 3rd, et al. Rifaximin alters intestinal bacteria and prevents stress-induced gut inflammation and visceral hyperalgesia in rats. Gastroenterology. 2014; 146(2):484-96. doi: 10.1053/j.gastro.2013.10.026.
6. Basseri RJ, Weitsman S, Barlow GM, Pimental M. antibiotics for the treatment of irritable bowel syndrome. Gastroenterol Hepatol. 2011; 7(7):455-93.
7. Pimentel M, Lembo A, Chey WD, et al. Rifaximin therapy for irritable bowel syndrome without constipation. N Engl J Med. 2011; 364(1):22-32.  doi: 10.1056/NEJMoa1004409.

Published by Rho Chi Post