Background Effective and safe treatments are needed for patients who have irritable bowel syndrome (IBS) with diarrhea. We conducted two phase 3 trials to assess the efficacy and safety of eluxadoline, a new oral agent with mixed opioid effects (μ- and κ-opioid receptor agonist and δ-opioid receptor antagonist), in patients with IBS with diarrhea. Methods We randomly assigned 2427 adults who had IBS with diarrhea to eluxadoline (at a dose of 75 mg or 100 mg) or placebo twice daily for 26 weeks (IBS-3002 trial) or 52 weeks (IBS-3001 trial). The primary end point was the proportion of patients who had a composite response of decrease in abdominal pain and improvement in stool consistency on the same day for at least 50% of the days from weeks 1 through 12 and from weeks 1 through 26. Results For weeks 1 through 12, more patients in the eluxadoline groups (75 mg and 100 mg) than in the placebo group reached the primary end point (IBS-3001 trial, 23.9% with the 75-mg dose and 25.1% with the 100-mg dose vs. 17.1% with placebo; P=0.01 and P=0.004, respectively; IBS-3002 trial, 28.9% and 29.6%, respectively, vs. 16.2%; P<0.001 for both comparisons). For weeks 1 through 26, the corresponding rates in IBS-3001 were 23.4% and 29.3% versus 19.0% (P=0.11 and P<0.001, respectively), and the corresponding rates in IBS-3002 were 30.4% and 32.7% versus 20.2% (P=0.001 and P<0.001, respectively). The most common adverse events associated with 75 mg of eluxadoline and 100 mg of eluxadoline, as compared with placebo, were nausea (8.1% and 7.5% vs. 5.1%), constipation (7.4% and 8.6% vs. 2.5%), and abdominal pain (5.8% and 7.2% vs. 4.1%). Pancreatitis developed in 5 (2 in the 75-mg group and 3 in the 100-mg group) of the 1666 patients in the safety population (0.3%). Conclusions Eluxadoline is a new therapeutic agent that reduced symptoms of IBS with diarrhea in men and women, with sustained efficacy over 6 months in patients who received the 100-mg dose twice daily. (Funded by Furiex Pharmaceuticals, an affiliate of Allergan; IBS-3001 and IBS-3002 ClinicalTrials.gov numbers, NCT01553591 and NCT01553747 , respectively.).

In a phase 2 study of the mixed μ-opioid receptor agonist/δ-opioid receptor antagonist eluxadoline vs placebo in patients with IBS-D, patients given eluxadoline were significantly more likely to be clinical responders, based on a composite of improvement in abdominal pain and stool consistency. Further study of eluxadoline is warranted to assess its potential as a treatment for IBS-D.

No abstract

Objectives:Eluxadoline is a mixed μ-opioid receptor (OR) and κ-OR agonist and δ-OR antagonist, approved for the treatment of irritable bowel syndrome with diarrhea (IBS-D). This analysis evaluated the safety and tolerability of eluxadoline 75 and 100 mg twice daily (BID) in one Phase 2 (IBS-2001) and two Phase 3 (IBS-3001 and IBS-3002) studies.Methods:Adults with IBS-D (Rome III criteria) were randomized to placebo or eluxadoline (75 or 100 mg) BID for 12 (IBS-2001), 26 (IBS-3002), or 52 (IBS-3001) weeks. Safety data were pooled. Adverse events (AEs) were assessed, with special focus on opioid-related AEs, including suspected sphincter of Oddi spasm (SOS) events.Results:2,776 patients were included in the enrolled set; the safety set comprised 2,814 patients, based on actual treatments received. The most frequent AEs in the placebo and eluxadoline 75 and 100 mg groups were constipation (2.5, 7.4, and 8.1%, respectively) and nausea (5.0, 8.1, and 7.1%, respectively); discontinuation due to constipation was uncommon (0.3, 1.1, and 1.5%, respectively). Ten SOS events (10/1,839; 0.5%) occurred in eluxadoline-treated patients, manifesting as acute abdominal pain with elevated aminotransferases or lipase, or pancreatitis; all occurred in patients without a gallbladder. Eight of these events occurred with the higher dose of eluxadoline, within 1 week of initiation of therapy, and all resolved with eluxadoline discontinuation. There were five events independently adjudicated as pancreatitis not associated with SOS, three of which were associated with heavy alcohol use.Conclusions:Eluxadoline was well tolerated in Phase 2 and 3 trials, with constipation and nausea the most common AEs. Consistent with the known adverse effects of opioid agonists, clinically apparent SOS events were observed in eluxadoline-treated patients. All occurred in patients without a gallbladder and the majority were observed in patients on the higher dose of eluxadoline, suggesting a possible association.

The sphincter of Oddi (SO) is a smooth muscle valve regulating the flow of biliary and pancreatic secretions into the duodenum, initially described in 1887 by the Italian anatomist, Ruggero Oddi. SO dysfunction (SOD) is a broad term referring to numerous biliary, pancreatic, and hepatic disorders resulting from spasms, strictures, and relaxation of this valve at inappropriate times. This review brings attention to various factors that may increase the risk of SOD, including but not limited to: cholecystectomy, opiates, and alcohol. Lack of proper recognition and treatment of SOD may be associated with clinical events, including pancreatitis and biliary symptoms with hepatic enzyme elevation. Pharmacologic and non-pharmacologic approaches are discussed to help recognize, prevent, and treat SOD. Future studies are needed to assess the treatment benefit of agents such as calcium-channel blockers, glyceryl trinitrate, or tricyclic antidepressants in patients with SOD.