Review Article

An Analysis of Safety Profiles of Treatments for Diarrhoea-predominant Irritable Bowel Syndrome

Brian E. Lacy


Aliment Pharmacol Ther. 2018;48(8):817-830. 

In This Article

Abstract and Introduction


Background: Irritable bowel syndrome (IBS) is multifactorial in nature, and a wide range of therapies is available to manage symptoms of this common disorder.

Aim: To provide an overview of the safety of interventions that may be used to manage patients with diarrhoea-predominant IBS (IBS-D).

Methods: Medline and Embase database searches (through 02 May 2018) to identify clinical studies that evaluated treatment safety and/or efficacy in adults with IBS-D.

Results: IBS-D treatments include dietary modification, probiotics, serotonin receptor antagonists, opioid receptor agonists and antagonists, nonsystemic antibiotics, bile acid sequestrants, antidepressants, and complementary and alternative therapies. These treatments vary in administration frequency (eg, daily; short-course therapy) and target various pathophysiologic factors. Safety profiles vary considerably by treatment among IBS-D therapies. The number needed to harm (defined as the number of patients treated to encounter an adverse event) was lowest (worse) for antidepressants (8.5) and highest (best) for probiotics (35), and the number needed to harm (defined as the number of patients who discontinued due to an adverse event) was lowest for tricyclic antidepressants (9) and highest for rifaximin (8971). Notable safety concerns with IBS-D treatments include pancreatitis with eluxadoline, ischaemic colitis and serious complications of constipation with alosetron, and cardiac adverse events with loperamide and tricyclic antidepressants. Treatment decisions need to account for medication risks and adverse events for each patient.

Conclusions: Multiple treatment options are now available for patients with IBS-D. However, the safety profiles of these agents vary widely by number needed to harm value. Providers should consider both safety and efficacy of a specific intervention when determining how best to manage patients' IBS-D symptoms.


Irritable bowel syndrome (IBS) is a functional bowel disorder characterised by abdominal pain and altered bowel habits (constipation, diarrhoea, or alternating constipation and diarrhoea) often coupled with abdominal bloating.[1] The diagnosis of IBS, according to the Rome IV criteria, is based on recurrent abdominal pain at least once weekly in the previous 3 months, with the pain associated with at least two of the following: defecation, alterations in stool frequency, and changes in stool form.[1] IBS is further categorised by its predominant bowel habit, including diarrhoea-predominant IBS (IBS-D; >25% Bristol Stool Scale form types 6 or 7 and <25% Bristol Stool Scale form types 1 or 2), constipation-predominant IBS (>25% Bristol Stool Scale form types 1 or 2 and <25% Bristol Stool Scale form types 6 or 7), or mixed form IBS (>25% Bristol Stool Scale form types 1 or 2 and >25% Bristol Stool Scale form types 6 or 7).[1] IBS, including IBS-D, is associated with reduced quality of life[2,3] and increased healthcare costs.[4,5]

In one study, 76.5% of 179 patients with IBS reported impaired daily activity (ie, ≥5 of 10 domains examined: job/school performance, social activity, physical activity, physical appearance, household activities, sexual activity, leisure activity, travel, eating alone, and eating in groups), with social activity impaired in 80% of patients and job/school performance in 72%.[6] In the United States, IBS is usually managed on an outpatient basis.[7,8] For patients with IBS-D included in a US commercially insured population (2013), mean all-cause annual healthcare costs (eg, diagnostic tests and laboratory or radiology services [50.3%], prescriptions [19.5%], inpatient admissions [13.6%], emergency department visits [8.5%], and outpatient office visits [8.1%]) were estimated at $13 038, an amount $8768 in excess of that of individuals without IBS-D (P < 0.001).[4]

The exact pathophysiology of IBS remains to be elucidated, but it is related in part to alterations in the gut microbiota, changes in gastrointestinal (GI) motility, microscopic inflammation, bile acid malabsorption, and alterations in the enteric nervous system.[9] Given the multifactorial nature of IBS, no gold standard of treatment exists.[9] Available treatments for IBS-D include dietary modification, probiotics, serotonin (5–hydroxytryptamine type 3 [5–HT3]) receptor antagonists (eg, alosetron, ondansetron), opioid receptor agonists and antagonists (eg, loperamide, eluxadoline [Viberzi®, Allergan, Irvine, CA]), nonsystemic antibiotics (eg, rifaximin [Xifaxan®, Salix Pharmaceuticals, Bridgewater, NJ]), bile acid sequestrants (eg, cholestyramine, colesevelam), antidepressants (eg, tricyclic antidepressants, selective serotonin reuptake inhibitors), complementary and alternative medicine (eg, herbal therapies, mind-body interventions [eg, cognitive behavioural therapy, hypnotherapy], and mechanical interventions [eg, yoga, acupuncture]). As no validated treatment algorithm exists for patients with IBS and diarrhoea, many treatments are frequently used to manage symptoms.[10] Ideally, the selection of a therapy should be based on a careful assessment of both efficacy and adverse events (AEs). However, many healthcare providers primarily focus on efficacy. This may occur because efficacy results are reported more widely, and thus are better known, than safety results. As well, many providers tend to focus treatment discussions on benefits of a treatment rather than AEs. However, both types of outcomes are important to discuss and should be given equal weight when evaluating treatment options for a patient. The objective of this article is to provide an overview of the safety of interventions that are used in the management of patients with IBS-D.