The prevalence of Americans affected by irritable bowel syndrome (IBS) is estimated to be around 35 million by the American Gastroenterological Association (AGA). ¹ IBS is a bowel disorder characterized by abdominal pain and abnormal bowel patterns, in the absence of any particular reason. ² IBS is often diagnosed based on patient symptoms using the Manning or Rome III criteria. Per the Rome III criteria, an IBS diagnosis requires patients to have 3 months of symptoms with at least 3 days of abdominal pain or discomfort per month with at least two of the following features: symptom improvement with defecation, onset associated with a change in the frequency of the stool, and/or onset associated with a change in the form or appearance of the stool. ² Based on the principal bowel pattern, IBS is further categorized into diarrhea-predominant (IBS-D), constipation-predominant (IBS-C), or mixed (IBS-M) if bowel habits fluctuate between diarrhea and constipation. Patients with IBS-D often report their altered bowel habits (e.g. increased loose stool frequency and urgency) have a large impact on daily life leading to a decreased quality of life. ³ Additionally, IBS can result in bloating, fecal incontinence, and reduced productivity. ^1,3 The pathophysiology of IBS-D is unknown, but thought to be multifactorial, in that it involves a variety of body systems and activities, including visceral hypersensitivity, genetics, environment, motility, dietary intolerance, microbiology of the gut, and the overall mind-gut axis. ^2,3

Several drug therapies are used for symptom relief in the treatment of IBS-D including: anti-diarrheals, antispasmodics, 5-HT3 receptor antagonists, and tricyclic antidepressants (TCAs). Anti-diarrheals such as loperamide work by stimulating opioid receptors to delay intestinal transit and strengthen the rectal sphincter tone. ³ Loperamide helps with acute episodes and prevention; however, it does not assist in relieving the pain or bloating associated with IBS-D. Antispasmodics (i.e. hyoscyamine, dicyclomine), competitively inhibit muscarinic receptors, yielding a constipating effect and may also alleviate some of the pain associated with IBS-D. Alosetron is the only 5-HT3-receptor antagonist FDA approved for the treatment of IBS-D. It exerts its effects through regulation of visceral pain and slowing colonic and intestinal transit. ^3,4 Alosetron is approved only in women due to a lack of clinical evidence demonstrating efficacy in men. After a brief period of time on the market, alosetron was withdrawn due to severe adverse events associated with its use (e.g. constipation and ischemic colitis). It was later reapproved in women with severe IBS-D symptoms not relieved by conventional therapies who are enrolled in a prescribing program. ³ TCAs (e.g. amitriptyline and desipramine) have shown some benefit in relieving the overall symptoms of IBS-D. These agents seem to lessen the patient's perception of visceral pain, alter gastrointestinal (GI) transit time, and help to treat any underlying emotional struggles that may be associated with the condition. ³

Unfortunately, many patients require multiple agents for symptom relief and despite treatment, some patients still continue to struggle with debilitating symptoms. A recent survey conducted by the AGA found that less than 40% of patients taking prescription medications for the treatment of IBS-D were "very satisfied" with their treatment. ⁷ This emphasizes the clear need for new options in the treatment of IBS-D. In 2015, Xifaxan ^© (rifaximin) and Viberzi

^© (eluxadoline) were FDA approved for the treatment of adults with IBS-D. ⁵ Unlike many of the current treatment options, these agents more directly target the proposed physiologic mechanisms thought to cause IBS-D. Additional treatment options under investigation for IBS-D include: ramosetron, disodium cromoglycate (DSCG) and fecal microbiota. ³

Rifaximin is a non-absorbable oral antibiotic that covers both gram negative and gram-positive bacteria. In addition to reducing bacteria, rifaximin also alters the bacterial composition of the gut. As discussed, one theory of the etiology of IBS-D is the alteration of the microbiome of the gut; therefore, rifaximin is thought to alleviate this imbalance. The recommended treatment dose of rifaximin for IBS-D is 550 mg three times daily for 14 days. ⁶ Clinical trials have demonstrated that a two-week course of rifaximin can help to improve symptoms such as rectal urgency, abdominal pain and bloating, and stool consistency for an average of 10 weeks. Rifaximin can be repeated up to two times in patients who experience a recurrence of symptoms. The most common adverse effects of therapy are nausea, headache, peripheral edema, dizziness, and fatigue. ^3,6

Rifaximin's efficacy in treating adults with IBS-D was evaluated in 3 randomized, multi-center, double-blind, placebo-controlled trials; TARGET-1, 2, and 3. The TARGET-1 and TARGET-2 trials were identical in design and evaluated the efficacy of a 14-day course of rifaximin treatment. The TARGET-3 trial evaluated re-treatment with rifaximin in patients who experienced symptom recurrence after an initial course of rifaximin therapy. ⁵        

The TARGET-1 and TARGET-2 trials included a total of 1,258 adults with IBS-D. Participants were randomly assigned to receive either rifaximin 550 mg or placebo by mouth three times daily for two weeks; participants were then followed for 10 weeks after treatment. The primary endpoint was the number of patients to achieve adequate symptom relief for at least two of four weeks during the month following a 14-day treatment course with rifaximin 550 mg by mouth three times daily. ⁷ The number of patients achieving the primary endpoint was significantly higher in those who received rifaximin, as compared to placebo in each trial (TARGET-1: 40.8% rifaximin vs. 31.2% placebo, p=0.01; TARGET-2: 40.6% rifaximin vs. 32.2% placebo, p=0.03). There were no significant differences found between the safety profiles of rifaximin and placebo and no deaths were reported. ⁷

The TARGET-3 trial included a total of 2,579 adults with IBS-D. All patients received open-label treatment with rifaximin 550 mg by mouth three times daily for two weeks. Patients were assessed for response to treatment after 4 weeks of no treatment therapy. Patients identified as responders were then followed for IBS symptoms (i.e. abdominal pain or mushy/watery stools) for up to 20 treatment-free weeks. ⁷ Patients whose IBS symptoms returned, were randomized to the double-blind, placebo-controlled repeat treatment phase. The primary endpoint was the proportion of patients responding to re-treatment with rifaximin. Response was defined as an improvement in abdominal pain and stool consistency.The number of patients to achieve adequate symptom relief was significantly higher in those who received rifaximin as compared to placebo (38 % vs 31% respectively; p<0.05). ⁷ A total of 1,074 patients responded to initial treatment of rifaximin; 636 patients relapsed and were randomized to the repeat treatment phase. Thirty-six of 308 (11.7%) patients randomized to the placebo cohort and 56 of 328 (17.1%) patients randomized to the rifaximin cohort responded to the first repeat treatment and did not have recurrence of signs and symptoms through the treatment-free follow-up period. To date, overall data results from this study have not been published.

Eluxadoline is a peripherally acting mixed mu-opioid receptor agonist, delta opioid receptor antagonist, and kappa opioid receptor agonist. It acts locally on mu-opioid receptors in the gastrointestinal tract, which slows gastrointestinal (GI) motility and reduces visceral sensations and secretions. ⁸ This leads to a reduction of abdominal pain and diarrhea associated with IBS-D. Eluxadoline is a controlled substance (CIV) due to its mechanism of action and subsequent potential for abuse. Eluxadoline is indicated for the treatment of adults with IBS-D; however, there are several populations where eluxadoline use is contraindicated.

⁸ These populations include: patients with known or suspected biliary duct obstruction, patients with sphincter of Oddi disease or dysfunction, patients who abuse alcohol (consume > 3 alcoholic drinks per day), patients with a history of pancreatitis, patients with severe hepatic impairment, or patients with a history of chronic or severe constipation. The recommended dose for most patients is 100 mg by mouth twice daily with food. Dose reduction to 75 mg by mouth twice daily is recommended in those patients who do not have a gallbladder, are unable to tolerate the 100 mg dose, are concomitantly taking an OATP1B1 inhibitor (e.g. gemfibrozil, ritonavir, rifampin) or have mild to moderate hepatic impairment. The most common adverse effects of therapy are constipation, nausea, abdominal pain, and upper respiratory infection. ⁸

The safety and efficacy of eluxadoline in the treatment of IBS-D was evaluated in two randomized, multi-center, double-blind, placebo-controlled, parallel-group studies, IBS-3001 and IBS-3002. ⁹ The primary endpoint was the number of patients who achieved an overall response to therapy of decreased abdominal pain and improved stool consistency on the same day, for ≥ 50% of the days, during weeks 1-12 and 1-26. The decrease in abdominal pain and improvement in stool consistency were defined as ≥ 30% reduction from the patient's baseline average score of worst abdominal pain and a stool-consistency score of <5 on the Bristol Stool Form Scale, respectively. Symptoms were reported daily by patients using an electronic diary. ⁹

Overall, a total of 2,425 adults were evaluated, with 1,280 in IBS-3001 trial and 1,145 in IBS-3002 trial. Both studies began with a 26-week double blind, placebo-controlled period in which participants were randomized to receive either oral eluxadoline 75 or 100 mg twice daily or placebo twice daily. During this period, participants were also allowed to utilize the anti-diarrheal loperamide, as needed. The IBS-3001 study followed the initial 26-week period with an additional 26-weeks of double-blind treatment for safety assessment plus another 2 weeks of follow-up after completion of treatment. ⁹ The IBS-3002 study followed the initial 26-week period with 4 weeks of single-blinded placebo withdrawal to evaluate rebound symptoms. The number of patients to achieve the overall response endpoint at 12 weeks was significantly higher in those who received either dose of eluxadoline, as compared to placebo. In the IBS-3001 trial, the endpoint was achieved by 23.9% of patients who received 75 mg of eluxadoline and 25.1% of those who received 100 mg of eluxadoline, as compared to 17.1% who received placebo (p=0.01 for comparison of 75 mg dose with placebo; p=0.004 for comparison of 100 mg dose with placebo). ⁹ In IBS-3002, the same endpoint was achieved by 28.9% of those who received 75 mg of eluxadoline and 29.6% of those who received 100 mg of eluxadoline, as compared to 16.2% who received placebo (p<0.001 for both comparisons). At 26 weeks, the number of patients who achieved the primary endpoint was significantly higher than placebo in patients who received the 100 mg dose of eluxadoline in both studies (p<0.001 in both studies); the difference between patients who received the 75 mg dose of eluxadoline and placebo was significant only in the IBS-3002 study (IBS-3001: p=0.11; IBS-3002: p=0.001) ⁹. In addition, patients who received either dosage of eluxadoline reported greater reductions in stool frequency and urgency, as well as greater improvements in quality of life, as compared to placebo.