Eluxadoline for Irritable Bowel Syndrome with Diarrhea

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Abstract

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.).

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K Rubinstein, L Handelsman, Andy Ness … (1986)

Two new rating scales for measuring the signs and symptoms of opiate withdrawal are presented. The Subjective Opiate Withdrawal Scale (SOWS) contains 16 symptoms whose intensity the patient rates on a scale of 0 (not at all) to 4 (extremely). The Objective Opiate Withdrawal Scale (OOWS) contains 13 physically observable signs, rated present or absent, based on a timed period of observation of the patient by a rater. Opiate abusers admitted to a detoxification ward had significantly higher scores on the SOWS and OOWS before receiving methadone as compared to after receiving methadone for 2 days. Opiate abusers seeking treatment were challenged either with placebo or with 0.4 mg naloxone. Postchallenge SOWS and OOWS scores were significantly higher than prechallenge scores in the naloxone but not the placebo group. We have demonstrated good interrater reliability for the OOWS and good intrasubject reliability over time for both scales in controls and in patients on a methadone maintenance program. These scales are demonstrated to be valid and reliable indicators of the severity of the opiate withdrawal syndrome over a wide range of common signs and symptoms.

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Opioid receptors in the gastrointestinal tract.

Peter Holzer (2009)

Opium is arguably one of the oldest herbal medicines, being used as analgesic, sedative and antidiarrheal drug for thousands of years. These effects mirror the actions of the endogenous opioid system and are mediated by the principal mu-, kappa- and delta-opioid receptors. In the gut, met-enkephalin, leu-enkephalin, beta-endorphin and dynorphin occur in both neurons and endocrine cells. When released, opioid peptides activate opioid receptors on the enteric circuitry controlling motility and secretion. As a result, inhibition of gastric emptying, increase in sphincter tone, induction of stationary motor patterns and blockade of peristalsis ensue. Together with inhibition of ion and fluid secretion, these effects cause constipation, one of the most frequent and troublesome adverse reactions of opioid analgesic therapy. Although laxatives are most frequently used to ameliorate opioid-induced bowel dysfunction, their efficacy is unsatisfactory. Specific antagonism of peripheral opioid receptors is a more rational approach. This goal is addressed by the use of opioid receptor antagonists with limited absorption such as oral prolonged-release naloxone and opioid receptor antagonists that do not penetrate the blood-brain barrier such as methylnaltrexone and alvimopan. Preliminary evidence indicates that peripherally restricted opioid receptor antagonists may act as prokinetic drugs in their own right.

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Health-related quality of life, work productivity, and health care resource utilization of subjects with irritable bowel syndrome: baseline results from LOGIC (Longitudinal Outcomes Study of Gastrointestinal Symptoms in Canada), a naturalistic study.

R McBurney, Martin Barbeau, Shideh Khorasheh … (2006)

Abdominal pain/discomfort, bloating, and constipation are gastrointestinal dysmotility and sensory symptoms associated with irritable bowel syndrome (IBS). No studies have followed patients with IBS symptoms for 1 year under conditions of routine clinical practice to assess prospectively the impact of treatments on health outcomes. The objective of this ongoing, naturalistic study is to assess the long-term impact of IBS treatments on quality of life (QOL), work productivity, and resource utilization. This report describes the baseline characteristics and patterns of care of the patients enrolled in this study. Patients with physician-diagnosed IBS symptoms were enrolled from 147 physician sites across Canada between May 4, 2004, and March 31, 2005. Clinical data were collected at baseline and at the end of the 12-month follow-up (patients were followed for 1 year between May 4, 2005, and March 31, 2006). Patient-reported outcomes were collected at baseline and at months 1, 2, 6, 9, and 12. Health-related QOL, health status, and work productivity were assessed with the IBS-QOL, a 5-item EuroQol descriptive system, and Work Productivity and Activity Impairment questionnaires, respectively. A resource utilization questionnaire elicited information on physician; visits, treatments, and procedures. Baseline data are reported here. Data were obtained from 1555 patients; 85.1% (1320/1552) were women. Patients had a mean (SD) age of 45.8 (15.0) years and mean (SD) duration of IBS symptoms of 11.4 (11.5) years. Self-reported bowel patterns were predominantly constipation (41.0%, 587/1433) and constipation alternating with diarrhea (39.4%, 564/1433); 60.3% (938/1555) of subjects used > or =3 IBS treatments in the previous 4 weeks. Approximately 50% of all patients reported distress "quite a bit or "extremely" for abdominal pain, gas, bloating, and constipation. The mean overall IBS-QOL score (0-100 scale, with 0 indicating poor QOL) was 66.3; food avoidance (51.8) and health worry (59.3) were the most serious concerns. Patients reported 5.6% work absenteeism, 31.4% presenteeism, and 34.6% overall work productivity loss, equivalent to 13.8 hours lost productivity per 40-hour workweek. The baseline data from this ongoing, prospective, naturalistic study are consistent with previous findings that suggested significant use of health care resources with concomitant low QOL and decreased work productivity in patients with IBS symptoms.