Management of irritable bowel syndrome with diarrhea: focus on eluxadoline

Figures & data

Figure 1. Bristol Stool Form Scale³³.

Table 1. Overview of IBS-D management options, including ACG recommendations³⁴.

Intervention	Number needed to treat (95% CI)	ACG recommendation	ACG strength of evidence	Key points
Dietary and lifestyle modifications
Gluten-free diet	N/A	Weak	Very low	Although up to 72% of patients may benefit when they are aware of the intervention, there is little objective evidence that a gluten-free diet improves symptoms^36–38 If celiac disease is suspected, test for this before commencing a gluten-free diet for IBS
Low-FODMAP diet	5 (3–11)	Weak	Very low	Improves symptoms and quality of life in patients with IBS compared to general dietary advice or a typical Western diet^39–43 While 68–76% of patients may benefit, many studies are limited by incomplete data (e.g. no details of exact foods or combinations of food, missing data on adherence or long-term outcomes)^44–46
Psychological therapies	4 (3.5–5.5)	Weak	Very low	Therapies may include: CBT, relaxation therapy, hypnotherapy, and dynamic psychotherapy^34 Disturbed sleep is more prevalent among patients with IBS compared to the general population. Good sleep quality can improve mood and quality of life, and can decrease abdominal pain symptoms, but does not affect GI symptoms^47–49 CBT is shown to significantly improve GI symptoms^50
Exercise	N/A	Weak	Very low	As well as general health benefits, increased physical activity may improve GI symptoms and quality of life, with long-term benefits^51^,^52
Complementary medicine	N/A	N/A	N/A	Acupuncture may improve stool frequency; a randomized controlled trial showed no significant difference for acupuncture compared to loperamide on stool frequency^53
Over-the-counter medications
Loperamide	N/A	Strong	Very low	Significantly improved stool consistency and urgency in small placebo-controlled clinical trials in IBS^54^,^55 Does not improve abdominal pain and very high doses are associated with serious heart problems, and cases of acute pancreatitis have been reported^56–58 Although abuse potential is low at recommended dosing levels, loperamide may ease withdrawal symptoms in patients with a history of opiate addiction, and very high doses may induce euphoria^59–61
Probiotics	7 (5–12)	Weak	Low	Improve global symptoms, bloating, and flatulence^62 Selected Lactobacillus and Bifidobacterium varieties are thought most effective. There are no safety concerns associated with using these, provided the patient has a normal immune system^34
Peppermint oil	4 (3–6)	Weak	Low	Statistically superior to placebo at improving abdominal pain^63^,^64 Does not improve stool consistency or bloating Similar safety profile to placebo^34 Supplied as enteric-coated capsules and taken orally up to 3 times daily at a dose between 180 and 200 mg^63^,^64
Non FDA-approved prescription medications
Tricyclic antidepressants^a (e.g. amitriptyline, desipramine)	4 (3.5–7)	Strong	High	Improve GI symptoms and mediate central pain as well as relieving depression^34 Very high doses are associated with serious heart problems, including ECG abnormalities, arrhythmias, and hypotension^65
Bile acid sequestrants (e.g. colestyramine)	N/A	N/A	N/A	Up to one-third of patients with IBS-D may have abnormal bile acid malabsorption^22 May improve stool consistency and frequency
Antispasmodics (e.g. dicyclomine)	5 (4–8)	Weak	Very low	May effectively relieve abdominal pain and global symptoms^66^,^67, although they do not generally improve diarrhea symptoms Not associated with particular safety concerns, though tachyphylaxis may occur with long-term use
FDA-approved prescription medications
Alosetron (a selective 5-HT3 receptor antagonist)	7.5 (5–16)	Weak	Low	Indicated for women with severe, disabling, refractory IBS-D, under an FDA risk evaluation and mitigation strategy^67^,^68, due to the risk of severe constipation and ischemic colitis 41–43% of women reported adequate symptom relief in clinical trials^69^,^70
Eluxadoline (a μ-opioid and κ-opioid receptor agonist and δ-opioid receptor antagonist)	12.5 (8–33)	Weak	Moderate	Significantly more eluxadoline-treated patients achieved composite improvement in stool consistency and abdominal pain compared to placebo^71 Contraindicated in patients without a gallbladder, biliary duct obstruction, sphincter of Oddi dysfunction, severe hepatic impairment or alcohol abuse, history of chronic or severe constipation, history of pancreatitis, or structural diseases of the pancreas, including known or suspected pancreatic duct obstruction^71^,^72
Rifaximin (a minimally absorbable antibiotic)	10.5 (8–16)	Weak	Moderate	Significantly more patients reported adequate symptom relief in clinical trials compared to placebo (41 vs. 31%)^73 Rifaximin demonstrated a safety profile in clinical trials similar to placebo^74

Abbreviations. ACG, American College of Gastroenterology; CBT, Cognitive behavioral therapy; CI, Confidence interval; ECG, electrocardiogram; FDA, US Food and Drug Administration; FODMAP, Fermentable oligosaccharides, disaccharides, monosaccharides, and polyols; GI, Gastrointestinal; IBS, Irritable bowel syndrome; IBS-D, Irritable bowel syndrome with diarrhea; N/A, Not available.

^aSelective serotonin reuptake inhibitors also treat depression and improve pain, but can accelerate GI transit (undesirable for IBS-D) [34].

Figure 2. Proportion of responders across multiple symptoms for eluxadoline compared to placebo. *p<.05; **p<.001. Pooled data from Phase 3 trials over weeks 1–26. Response criteria were defined as follows: composite response, improvement of ≥30% in worst abdominal pain score (0–10 scale where 0 = no pain and 10 = worst pain imaginable) vs. baseline and, on the same day, a BSFS score of <5, on ≥50% of treatment days; stool consistency, as for composite response; urgency-free days, no reported urgency episodes; adequate relief, “yes” response to the question: “Over the past week, have you had adequate relief of your irritable bowel syndrome symptoms?” on ≥50% of weeks; abdominal pain, improvement of ≥30%, ≥40%, or ≥50% in worst abdominal pain score vs. baseline, on ≥50% of treatment days. Abbreviations. BSFS, Bristol Stool Form Scale; NS, Not significant.

Table 2. Contraindications of eluxadoline⁷².

Contraindication	Reason
Patients without a gallbladder	Risk of serious pancreatitis and/or sphincter of Oddi spasm
Known or suspected biliary duct obstruction, or sphincter of Oddi disease or dysfunction	Risk of sphincter of Oddi spasm
History of pancreatitis, structural disease of the pancreas, including known or suspected pancreatic duct obstruction	Risk of acute pancreatitis
Alcoholism, alcohol abuse, addiction or dependence, or drink > 3 alcoholic beverages per day^a	Risk of acute pancreatitis
Severe hepatic impairment (Child-Pugh Class C)	Risk of significantly increased eluxadoline plasma concentrations
History of chronic or severe constipation or sequelae from constipation, or known or suspected mechanical gastrointestinal obstruction	Risk of severe complications of bowel obstruction
Pregnancy and breastfeeding	No data available in humans
Known hypersensitivity reaction to eluxadoline	Risk of allergic reaction

^a Eluxadoline may be suitable for patients who have a past history of alcohol-related disorders, provided the risk of relapse is very low and liver disease is absent.

Figure 3. Diagnosis and management flow diagram for IBS-D. Management options should be discussed and selected through shared decision-making with the patient. They often begin with dietary and lifestyle modifications, transitioning to over-the-counter and prescription medications if symptoms do not improve. Abbreviations. BSFS, Bristol Stool Form Scale; CBT, Cognitive behavioral therapy; FODMAP, Fermentable oligosaccharides, disaccharides, monosaccharides, and polyols; IBD, Inflammatory bowel disease; IBS-D, Irritable bowel syndrome with diarrhea; tTG, Tissue transglutaminase.

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