Management Options for Irritable Bowel Syndrome

Abstract

Irritable bowel syndrome (IBS) is associated with diverse pathophysiological mechanisms. These include increased abnormal colonic motility or transit, intestinal or colorectal sensation, increased colonic bile acid concentration, superficial colonic mucosal inflammation, as well as epithelial barrier dysfunction, neurohormonal upregulation and activation of secretory processes in the epithelial layer. Novel approaches to treatment include lifestyle modification, changes in diet, probiotics and pharmacotherapy directed to the motility, sensation and intraluminal milieu of patients with IBS. Despite recent advances, there is a need for developing new treatments to relieve pain in IBS without deleterious central or other adverse effects.

Introduction

Irritable bowel syndrome (IBS) pain, diarrhea or constipation result from one or more pathophysiological mechanisms in each individual patient. IBS treatment typically addresses the predominant symptom experienced by the patient and targets the pathophysiology, such as accelerated transit or visceral hypersensitivity. There are still no effective disease-modifying treatments;¹ however, research that has demonstrated and validated biomarkers based on the pathophysiology of IBS provides opportunities to direct effective treatments to correct those mechanisms, such as abnormalities of colonic transit or increased colonic concentrations of bile acids.^2,3 Novel therapeutic approaches that have targeted these abnormalities in single-center, randomized, controlled trials (RCTs) using biomarker endpoints have correctly predicted therapeutic efficacy based on symptom-based endpoints in phase 2B or 3 multicenter RCTs.³

Visceral pain is a hallmark of IBS. Pain is transmitted to conscious perception in the brain via a three neuron chain, as with somatic pain; the main pathways are vagal, thoracolumbar and lumbosacral afferents that have both pro- and anti-nociceptive ion channels and receptors.⁴ There are several relevant neurotransmitters on the afferents conveying sensory signals to the central nervous system, including serotonin (5-HT) and neurokinins, as well as ion channels including transient receptor potential (TRP) channels that mediate activation of afferent nerves and detect thermal and chemical stimuli that produce acute or persistent pain.⁵

This article addresses the current approaches to treatment of IBS, including lifestyle modifications, changes in diet, alternative and herbal therapies, probiotics and pharmacotherapy (Figure 1)⁶ directed to the motility, sensation and intraluminal milieu of patients with IBS. There are recent, national societal guidelines for the management of IBS based on the available literature and systematic reviews and meta-analyses.^7-10 With recently introduced medications, trials have used Food and Drug Administration (FDA)-recommended endpoints to judge efficacy. The level of evidence is weaker for more traditional therapies that were previously approved based on smaller, lower quality RCTs that involved heterogeneous patients or unvalidated endpoints.¹¹ For each intervention discussed, the mechanisms, efficacy and safety (where available) are summarized.

Figure 1. Pharmacotherapy in Irritable Bowel Syndrome.

From J Clin Med⁶with permission. Note: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

^aCl = chloride; GC-C = guanylate cyclase C; NHE = sodium/hydrogen exchanger; TSPO = translocator protein

General Lifestyle Measures

Dietary Modifications

Many patients believe their IBS symptoms are due to food sensitivity.¹²

Mechanisms:

Food generates symptoms in patients with IBS,¹³ and four potential explanations are: prominent contractile¹⁴ and sensory¹⁵ responses of the colon to the ingestion of food (“gastrocolonic response”); alterations in the microbiome (which may occur quite rapidly after a change in diet);¹⁶ insoluble dietary fiber may exacerbate IBS symptoms;¹⁷ and dietary antigens may alter intestinal epithelial barrier.¹⁸ These putative mechanisms provide rationale for dietary modifications.

Efficacy:

The quality of published trials of dietary interventions in IBS is generally weak. A systematic review recommended that more evidence is needed.¹⁹ Specific diets, including low fructose, oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) diet, are discussed below.

Elimination Diets

A sham-diet, RCT of 150 patients assessed a diet based on avoidance of foods to which patients had 3-fold elevated IgG antibody titers over background.²⁰ Symptoms were substantially improved at 12 weeks. The results of the study showed that the number needed to treat (NNT) was 9 and reintroducting eliminated foods resulted in substantial worsening of symptoms. It is unclear whether the diet’s efficacy differed according to stool pattern. On the other hand, double-blind rechallenge to the dietary triggers resulted in reproducible symptoms in only ~25% of patients.²¹

Increased Dietary Fiber

Efficacy:

In the largest trial of the use of fiber in 275 patients with IBS (all subtypes) in the primary care setting, patients were randomized to 12 weeks of treatment with soluble fiber (psyllium), insoluble bran fiber, or placebo.²² Whereas bran was of no benefit, there was reduction in IBS symptom severity score (IBS-SSS) with psyllium over placebo at 12 weeks, and greater proportion of responders (>2 weeks’ adequate relief per month) with an NNT for psyllium of 4. Adverse event rates (overall) were not significantly more prevalent in either of the fiber groups compared to placebo.

In a systematic review and meta-analysis²³ that included 906 patients in 14 RCTs (most of low methodological quality), there was only modest improvement of symptoms with fiber in IBS (NNT of 10), and the beneficial effect was limited to psyllium (which was tested in 499 patients in 7 studies) with an NNT of 7. The effect of bran was not significant. The rates of adverse events with psyllium, bran and placebo were not significantly different.

In contrast to weak benefits in IBS, mixed soluble and insoluble fiber and psyllium were equally efficacious in improving constipation in patients with chronic constipation.²⁴

Mechanism:

The mechanism of benefit with psyllium is uncertain and is unlikely to relate to stool bulking alone, since bran has similar effects.²⁵ On the other hand, increased production of short chain fatty acids, such as butyrate, with psyllium treatment may have anti-inflammatory effects on the colonic mucosa²⁶ or alter the intestinal microbiota,²⁷ which may conceivably contribute to reported benefits of psyllium.

Low FODMAP Diet

Mechanism:

FODMAPs are present in many commonly consumed foods (such as stone fruits and legumes), lactose-containing foods, and artificial sweeteners. As these chemical substances are poorly absorbed, they may induce osmotic effects (and fluid secretion) or fermentation (and distension) in the intestine,^28,29 leading to increased colonic sensitivity from the distension.³⁰ Sugar alcohols can induce dose-dependent symptoms of flatulence, abdominal discomfort, and laxative effects when consumed by both healthy volunteers and patients with IBS.³¹ A low FODMAP diet may lead to reduction in bacterial abundance³² and lower proportions of certain bacteria including Bifidobacteria.³³ However, it is unclear whether the restriction of FODMAPs leads to long-term effects on the gut microbiota.

Efficacy:

The clinical benefits of a low FODMAPs diet remain indeterminate. For example, a crossover, RCT comparing a diet low in FODMAPs with a typical Australian diet in 30 patients with IBS of all subtypes,³⁴ reported reduced global IBS symptoms, bloating, and pain while on the low FODMAP diet, with greater benefit in those with diarrhea-predominant IBS (IBS-D). Conversely, a larger parallel-group RCT of 67 IBS patients showed no difference in efficacy between low FODMAPs diet and conventional dietary recommendations,³⁵ with both diets showing benefit relative to baseline.

Several meta-analyses suggest efficacy of low FODMAPs diet;^36,37 however, analysis identified risk of bias, primarily due to lack of proper blinding and choice of control.³⁸ Despite the weak evidence, the National Institute of Health and Care Excellence of the United Kingdom recommended, as a first line treatment, the use of low FODMAPs diet for patients with IBS in primary care.³⁹ The IBS dietary algorithm from the British Dietetic Association was simplified to first-line healthy eating (provided by any healthcare professional) and second-line low FODMAP dietary advice.⁴⁰

Gluten-free Diet

In the absence of markers of celiac disease, there is evidence that a subgroup of patients with IBS may benefit from use of gluten-free diet (GFD).

Mechanism:

The mechanism of the effect of gluten in IBS is unclear; gluten-containing diet affects small bowel epithelial mRNA expression of barrier protein and higher small bowel mucosal permeability in patients with IBS-D compared to GFD.⁴¹ There is also evidence that there are differences in expression of immune markers on gluten sensitivity without celiac disease in those who present with symptoms mimicking IBS-D, and increased expression of tolllike receptor 2 and reduced T-regulatory cell marker FOXP3 relative to controls and patients with celiac disease.⁴² In view of the fact that wheat contains high levels of fructans in addition to gluten, a trial examined the combination of low FODMAPs diet and GFD,⁴³ and showed no additive effect of the GFD, suggesting that reduction in fructans may partly explain the effectiveness of a GFD in IBS.

Efficacy:

Two RCTs demonstrate that response to a GFD is greater in patients who are HLA-DQ2 or –DQ8 positive.^41,44 A third RCT showed similar improvement in IBS symptoms severity score; in addition, patients who were HLA-DQ2/8-positive had a greater reduction in depression score and increase in vitality score on the GFD, whereas patients who were HLA-DQ2 negative had improved bloating scores.⁴⁵

Exercise

A few studies examined exercise as an approach to reduce symptoms in IBS. In a Swedish trial, initially over 12 weeks⁴⁶ and, subsequently, with median follow-up of 5.2 (range: 3.8-6.2) years,⁴⁷ 20 to 60 minutes of moderate to vigorous physical activity (most commonly walking, aerobics and cycling) on 3 to 5 days per week was associated with significant improvement in symptom scores (IBS-SSS and psychological symptoms) over those in the control arm. It is unclear whether the effect of exercise differs according to IBS subtype.

Other movement-based, self-regulatory behavioral treatments have been shown to be beneficial for IBS patients, with yoga tending to reduce severity of IBS and somatic symptoms, and walking improving overall GI symptoms, negative affect, and anxiety.⁴⁸

Alternative and Herbal Therapies

Prebiotics and Probiotics

Prebiotics include food ingredients such as fructo-oligosaccharides or inulin that remain undigested in the human gastrointestinal system and can promote the growth or activity of gut bacteria. In contrast, probiotics are live or attenuated micro-organisms that can affect the composition of the intestinal microorganisms. Probiotics may have anti-inflammatory and anti-nociceptive properties.^49-52

Two trials of prebiotics in IBS were reported in the last three years. A RCT of 12 weeks duration compared 6g partially hydrolyzed guar gum, a prebiotic fiber, to placebo in 121 patients with IBS of all subtypes⁵³ and demonstrated significant improvement in bloating; however, there was no benefit on global symptoms, abdominal pain, or quality of life. A second study tested the prebiotic, inulin (900mg), in children with IBS, and none of the 6 symptoms of IBS tested improved, in contrast to significant improvements with the synbiotic [5×10⁹ colony forming units (CFU) of B. lactis B94 and 900 mg inulin] and the probiotic (5×10⁹ CFU B. lactis B94) tested over 4 weeks.⁵⁴

In a meta-analysis published in 2014, 35 trials of probiotics, involving 3452 patients with IBS⁵⁵ showed that probiotics have a beneficial overall effect in IBS (NNT of 7) with the greatest impact on abdominal pain, bloating, and flatulence, but not on bowel urgency or bowel function. Mild adverse events were significantly more common with probiotics compared to placebo.

More recent meta-analyses of probiotics suggest benefit in IBS patients for overall symptoms treated with B. infantis (5 RCTs),⁵⁶ S. cerevisiae CNCM I-3856 (2 trials),⁵⁷ single probiotics at relatively lower dosage of organisms (<10¹⁰ CFU/day) and shorter duration (<8weeks).⁵⁸ A meta-analysis of 15 trials that included 1793 patients showed improvement of general symptoms (7 trials), and of pain, distension, bloating, and flatulence each in 2 to 3 trials.⁵⁹ With most trials of probiotics, few were of high methodological quality, and combining data from different probiotic species, strains, or combinations may not be valid.⁶⁰

Other Herbal Therapies

The efficacy of other herbal therapies in IBS is unclear. Iberogast (STW-5) is a mixture of diverse extracts of flower, leaves, fruit, root, and herbs⁶¹ with antispasmodic effects on gastrointestinal smooth muscle⁶² through diverse mechanisms,⁶³ and secretory effect on diverse chloride channels.⁶⁴ In a RCT of 208 patients with IBS,⁶⁵ there was improvement in global symptoms and abdominal pain scores with STW-5 compared to placebo.

The benefits of Chinese herbal medicines in IBS are inconsistent.^66-68

MEDICATIONS FOR PAIN (Table 1)

Table 1. Summary of Current Pharmacological Treatments for IBS.

Mode of Action	Therapy	Efficacy	Quality of data	Adverse events	Limitations of data
Smooth muscle relaxation	Antispasmodic drugs	+/−	Low	Dry mouth, dizziness, and blurred vision	No high quality trials, heterogeneity between studies, possible publication bias, and only a small number of RCTsc assessing each individual antispasmodic
	Peppermint oil	+	Moderate	No increase in AEsa	Heterogeneity between studies
Secretagogues	Lubiprostone	+	Moderate	Nausea commoner vs. placebo	Only a modest benefit over placebo in published RCTsc
	Linaclotide	+	High	Diarrhea commoner vs. placebo	None
	Plecanatide	+	High	Diarrhea commoner vs. placebo	None
	Tenapanor	+/−	Moderate	Diarrhea commoner vs. placebo	Awaiting phase 2B/3 trials
Neuromodulators	Antidepressants	+	Moderate	Dry mouth and drowsiness	Few high quality trials, heterogeneity between studies, possible publication bias, and some atypical trials included
	Neurokinin NK2 antagonist	Promising in phase 2B RCTc	Moderate	No increase in AEsa	Awaiting phase 3 trials
	Histamine H1 antagonist	Promising in single center trial	Low	No increase in AEsa	Awaiting phase 2B trials
	TSPOd inhibitor	+/−	Low	Modest efficacy in a single proof of concept trial	Awaiting phase 2B trials
Opioids	Loperamide	+/−	Low	Limited data	Few RCTsc, with a small number of participants, not all of whom had IBSb
	Eluxadoline	+	High	Serious AEsa: acute pancreatitis and sphincter of Oddi spasm. Nausea and headache common vs. placebo	Only a modest benefit over placebo in published RCTsc. No benefit over placebo in terms of abdominal pain
e5-HT3 receptor antagonists		+	High	Serious AEa with alosetron: ischemic colitis; Constipation commoner vs. placebo.	Fewer RCTsc of ramosetron and ondansetron. Ondansetron may have no benefit over placebo for abdominal pain.
e5-HT4 receptor agonists		+/−	high	Diarrhea, cramping, and cardiovascular AEsa with “old generation” drugs in this class	Data available for tegaserod and mosapride, not for “new generation” drugs in this class: prucalopride, naronapride, velusetrag, YKP10811
Bile acid sequestrants		?	Low	Limited data	No published RCT sc
Rifaximin		+	Moderate	No increase in AEsa	Only a modest benefit over placebo in published RCTsc

^aAEs=adverse events

^bIBS=irritable bowel syndrome

^cRCTs=randomized, controlled trials

^dTSPO=translocator protein

^e5-HT=serotonin

Antispasmodic Drugs

Mechanism:

Antispasmodics inhibit the action of acetylcholine at muscarinic or tachykinin NK2 receptors, or block calcium channels on gastrointestinal smooth muscle, and alter gastrointestinal transit, contributing to relief of pain and disturbances in bowel habit.

Efficacy:

Systematic reviews documented weak evidence for the benefit of some antispasmodics for abdominal pain and global symptom relief,⁶⁹ and significant improvement in abdominal pain in 7 of 9 studies, bowel symptoms in 2 of 9, and global symptom severity in 4 of 9 studies was reported.⁷⁰

In a meta-analysis of 22 separate RCTs involving 1778 patients and 12 different antispasmodic drugs,⁷¹ antispasmodics were more effective than placebo, with an NNT of 5 overall, and slightly lower NNTs with hyoscine 3.5 (426 patients enrolled in 3 trials), otilonium 4.5 (435 patients enrolled in 4 trials,), cimetropium 3 (158 patients enrolled in 3 trials), and pinaverium 3 (188 patients enrolled in 3 trials), but confidence in these estimates is reduced because of significant heterogeneity, methodological weaknesses, possible publication bias and insufficient information on efficacy according to IBS subtype. In addition, most of the drugs studied are not approved by the Food and Drug Administration for the treatment of IBS in the United States, and promising data for those medications are reviewed elsewhere.⁶

Safety:

Antispasmodics cause more side effects than placebo, with the most common being dry mouth, dizziness, blurred vision, and constipation.

Peppermint Oil

Mechanism:

The major constituent of peppermint oil is menthol, which inhibits smooth muscle contractility in the gastrointestinal tract by blocking calcium influx.^72,73 Menthol also induces analgesia by activating the temperature sensing ion channel, transient receptor potential cation channel subfamily M member 8 (TRPM8),⁷⁴ which has anti-nociceptive properties in visceral afferents.

Efficacy:

Peppermint oil was more effective than placebo in a meta-analysis of four trials including 392 IBS patients with IBS (NNT of 2.5).⁷¹ The same methodological issues described for anti-spasmodics apply, and the estimate of efficacy (NNT) is likely inaccurate.

In a later meta-analysis of five RCTs of peppermint oil including 197 patients on active treatment and 195 on placebo, peppermint oil resulted in global improvement of IBS symptoms (5 studies) and abdominal pain (5 studies).⁷⁵

A novel formulation with sustained release in the small intestine⁷⁶ was tested in a 4-week trial in 72 patients with IBS-D or IBS-mixed (IBS-M), and there was no superiority over placebo for total IBS symptom score, though both treatment arms showed improvement from baseline.

Safety:

Peppermint oil can cause symptoms of gastroesophageal reflux, xerostomia, belching, a peppermint taste in the mouth, and a peppermint smell.

Antidepressants

Mechanism:

The rationale for using antidepressants in IBS includes: the co-existence of psychological disorders in IBS;⁷⁷ evidence that depression modifies the central nervous system response to painful stimuli;⁷⁸ the benefits of antidepressants in chronic painful disorders;^79,80 and correction of altered intestinal transit. Thus, tricyclic antidepressants (TCAs) prolong orocecal and intestinal transit times, whereas selective serotonin re-uptake inhibitors (SSRIs) decrease orocecal transit time.⁸¹ Based on this, TCAs are used in IBS-D and SSRIs are preferred in constipation-predominant IBS (IBS-C).

The mechanism of action of antidepressants in IBS is multifactorial, and may include reduced activation of pain centers in the anterior cingulate cortex and central pain processing,⁸² and peripheral mechanisms that have an effect on pain sensation such as colonic compliance and visceral afferent function.

Efficacy:

An updated systematic review and meta-analysis⁸³ including 17 separate trials of antidepressants found overall beneficial effects of antidepressants on IBS symptoms (NNT of 4). However, low level of trial quality, inconsistencies of trial endpoints, questionable generalizability, uncharacteristic response levels of the placebo arm (14%)⁸⁴ or the antidepressant (63%),⁸⁵ and evidence of heterogeneity between studies and possible publication bias raise questions on the accuracy of the reported NNT.

In general, TCAs appear to have greater efficacy with an NNT of 4. In the meta-analysis, no heterogeneity was seen between the 11 studies that included TCAs compared with SSRIs, which also had an NNT of 4, but with significant heterogeneity among 7 trials. Seven RCTs reported benefit for abdominal pain, but there was substantial heterogeneity between studies. Effectiveness according to IBS subtype has been studied in only two RCTs.^84,85 Three trials of antidepressants in IBS have showed no correlation between improvement in IBS symptoms and depression scores,^86-88 and a fourth trial of a TCA showed greater benefit in non-depressed individuals.⁸⁹

There are three open-label trials of the effects of duloxetine, a serotonin- and norepinephrine-reuptake inhibitor, that has shown efficacy in the treatment of IBS, such as in IBS-SSS (symptom severity), pain, bowel dysfunction, and quality of life.^90-92 The SNRI class of medications is used in the treatment of pain; however, double-blind, placebo-controlled, randomized clinical trials for the relief of IBS, pain and the associated co-morbid depressive or generalized anxiety disorders are required.

Safety:

Side effects were significantly more common with TCAs; the most frequent side effects were drowsiness and dry mouth. Long-term use of some classes of psychotropic drugs for nonpsychiatric indications may be linked with dementia, based on population studies,^93,94 although a cause and effect relationship has not been proven.

Drugs Acting on Opioid Receptors

Mechanism:

Opioid receptor agonists slow gut and colonic transit, increase fluid absorption, and reduce the sensation of pain.⁹⁵

Efficacy:

Loperamide and diphenoxylate, μ-opioid agonists, are anti-diarrheal agents that have been in use for the treatment of chronic functional diarrhea for many years,⁹⁶ based on limited evidence from small studies conducted around 30 years ago. One small trial of 21 patients with IBS-D, showed loperamide improved stool consistency, pain, as well as urgency.⁹⁷ A second trial⁹⁸ of 60 patients with either functional diarrhea or IBS-D confirmed reduction in stool frequency, improved consistency, as well as number of days with pain. A third trial⁹⁹ of loperamide in unselected IBS patients showed improvement in stool frequency and consistency, and overall pain intensity, but was associated with increased abdominal pain during the night. Loperamide is the most useful agent for diarrhea or urgency.⁹

Eluxadoline is a novel κ- and μ-opioid receptor agonist and δ-opioid receptor antagonist. Based on 3 trials with ~3000 patients with IBS treated over 12 weeks, it was efficacious in the relief of diarrhea or the composite endpoint of diarrhea and pain.^100,101 The recommended dose is 100 mg bid, unless not tolerated or if there is hepatic impairment, then the 75 mg bid dose should be used.

Safety:

Adverse events with eluxadoline are mainly nausea and headache. Rare cases of pancreatitis and sphincter of Oddi spasm have been reported. In accordance with FDA recommendation, eluxadoline should not be prescribed to patients with a history of biliary obstruction, cholecystectomy, pancreatitis, severe hepatic impairment, or severe constipation, or to those who consume more than three alcoholic drinks per day.

Off-Label Approaches for Visceral Pain

Histamine H₁ receptor antagonist, ebastine

This drug is not approved in the U.S.

Mechanism:

Mast cells and their mediators, in particular, histamine, serotonin and proteases, contribute to the pathogenesis of IBS.¹⁰² Histamine released by colonic biopsies from patients with IBS can sensitize (via H₁ histamine receptors) the TRPV1 on neurons in dorsal root ganglia (on afferent pathways) and on human submucosal neurons in rectal biopsies.¹⁰³

Ebastine, a non-sedating antagonist of H₁ receptors, has been shown to reduce visceral hypersensitivity, overall IBS symptoms, and abdominal pain in patients with IBS.¹⁰³

Gamma-aminobutyric acid (GABA)ergic agents

GABAergic agents are α2δ ligands that reduce the release of many excitatory neurotransmitters involved in pain mechanisms including glutamate, noradrenaline, substance P, and calcitonin gene-related peptide (CGRP). Three studies assessed the effects of gabapentin and pregabalin on rectal and colonic sensation and compliance in IBS-D patients or healthy controls, and overall they suggest that these agents reduce senation without significantly affecting compliance. This suggests an effect exclusively on sensory mechanisms.^104-106

A preliminary report of a randomized, controlled, 12-week clinical trial of pregabalin (dose escalation regimen to a maximum of 225 mg bid conducted at Mayo Clinic, Rochester, Minnesota in 85 patients with IBS showed lower average pain scores during weeks 9-12 and lower mean symptom severity scores with pregabalin compared with placebo.¹⁰⁷

Future Approaches to Pain Relief in IBS

A new generation of peripherally active visceral analgesics,¹⁰⁸ including opioid agents with no risk of respiratory depression or addiction potential, is being developed; these medications are eagerly awaited to address the significant unmet need of pain in IBS.

MEDICATIONS FOR DIARRHEA (Table 1)

Opioid agents and antidepressants (TCAs and SNRIs) may relieve diarrhea in addition to their effects on pain.

5-HT₃ Receptor Antagonists

Mechanism:

Ninety percent of the total body serotonin (5-HT) is within intestinal enterochromaffin cells.^109,110 5-HT is also a transmitter in the brain, and there are several different classes of 5-HT receptors in the brain and gut. Patients with IBS-D have increased and those with IBS-C have reduced postprandial 5-HT levels.¹¹¹ 5-HT₃ receptor antagonists such as alosetron¹¹² retard colonic transit. 5-HT₃ receptors are also important mediators of visceral pain.¹¹³

Efficacy:

Alosetron is an effective agent based on the results of several meta-analyses of high quality, large RCTs which have all shown consistent results.^114,115 In these studies, alosetron has an NNT of 8 for relief of abdominal pain, and an NNT of 4 for improvement in global symptoms. Alosetron is approved for use in women with severe IBS-D in the United States, but is regulated by an FDA prescribing program.

Ramosetron is efficacious and licensed for use in both male and female patients with IBS-D in Japan.^116,117

In a crossover clinical trial¹¹⁸ in patients with IBS-D (n=122), ondansetron had significant effects on stool consistency, urgency, and frequency, and bloating, but no significant beneficial effect on pain.

Safety:

As a drug class, 5-HT₃ antagonists can cause constipation butthis is usually manageable by adjusting the dose. Alosetron, unlike other drugs in this class, is associated with ischemic colitis (~1:800 treated patients).¹¹⁹

Bile Acid Sequestrants

Approximately 25% of patients with IBS-D have evidence of bile acid malabsorption (BAM).^120,121 Although no RCTs of BA sequestrants in IBS have been reported, a Mayo Clinic open-label trial of colesevelam, 1875 mg twice daily for 10 days,¹²² in patients with IBS-D and increased fecal bile acid excretion demonstrated reduction in stool consistency and frequency. Another open-label study of colestipol, 1g b.i.d. for 8 weeks,¹²³ showed improvements in IBS symptom severity scores, stool frequency, and adequate relief of symptoms in patients with IBS-D and BAM [a selenium-75-homocholic acid taurine (⁷⁵SeHCAT) retention <20%].

Antibiotics

Rifaximin is a non-absorbable antibiotic that has shown improved global symptoms and bloating in IBS in two phase III RCTs.^124,125 These trials included more than 1,200 patients with non-constipated IBS. Rifaximin, 550 mg TID for 2 weeks was associated with higher rates of adequate relief of global IBS symptoms and bloating (NNT of 9-12.5). The effect on symptoms lasted up to 10 weeks post-treatment. The NNT of 10 was confirmed for global symptoms and bloating in a meta-analysis of five RCTs of rifaximin,¹²⁶ including 1803 patients. However, stool consistency, frequency of bowel movements, and urgency were not improved.

With repeat courses of rifaximin separated by 10 weeks, 550mg t.i.d. daily for 2 weeks in each course, there was significant benefit for urgency, bloating and combined abdominal pain and stool consistency with each of 2 repeat treatment courses compared to placebo. Rifaximin is approved for IBS-D patients with up to two repeat treatments in case of symptom recurrence. It is worth noting that rifaximin¹²⁷ accelerated ascending colon emptying and overall colonic transit at 48 hours in IBS-D, although it had no effects on intestinal mucosal permeability, stool microbiome, or stool bile acids. The acceleration of colonic transit would seem deleterious for patients with IBS-D; on the other hand, it may explain the reported improvement in IBS-C (bloating, constipation, and straining) with combined neomycin plus rifaximin compared to neomycin with placebo.¹²⁸

Importantly, there is no evidence of adverse effects with rifaximin compared to placebo, and no increased risk of Clostridium difficile.

MEDICATIONS FOR CONSTIPATION (Table 1)

Intestinal Secretagogues

Chloride channel-related

Lubiprostone is a prostaglandin derivative that acts on chloride channels on the apical membrane of the intestinal enterocyte to induce chloride secretion, which is then followed by the passive movement of sodium ions and water into the lumen. As a result, stools become looser and gastrointestinal transit is accelerated.¹²⁹ The drug is approved at a dose of 8 μg twice daily for women with IBS-C¹³⁰ and 24 μg bid for men and women with chronic constipation.^131,132 There are general improvements in abdominal pain scores that parallel the improved straining and stool consistency. Nausea is the most common side effect, experienced by 8% of patients, but it is generally relatively mild and self-limited.¹³³

Linaclotide is a minimally absorbed guanylate cyclase C receptor (GC-C) agonist that causes secretion of chloride and bicarbonate into the intestinal lumen via the cystic fibrosis transmembrane regulator (CFTR). This results in parallel and sodium and water secretion. The activation of CFTR results from increase in intracellular cyclic guanosine monophosphate (cGMP), which has also been shown to affect sensory afferent neurons, leading to inhibition of pain. In clinical trials conducted in patients with IBS-C (as well as others in chronic constipation), linaclotide relieved constipation and significantly improved abdominal discomfort and bloating.^134-136 Three dose levels are approved: 72, 145, and 290 mcg per day: 72 mcg and 145 mcg doses are for chronic idiopathic constipation, and the 290 mcg dose for IBS-C (men and women). Dose can be titrated to observe benefit and reduce the risk of diarrhea, which may occur in up to 20% of patients administered the highest dose.

Plecanatide is a peptide analog of uroguanylin, which is an endogenous GC-C agonist¹³⁷ released into the intestine from goblet cells. Plecanatide, 3 or 6mg per day, is also efficacious in treating chronic idiopathic constipation¹³⁸ and IBS-C¹³⁹, including relief of worst abdominal pain. Plecanatide, 3 mg dose, is now FDA approved for both indications. It is reported to be associated with lower risk of diarrhea than linaclotide, although the availability of 3 doses of linaclotide provides opportunity to titrate its dose to avoid diarrhea.

5-HT₄ Receptor Agonists

As a class, 5-HT₄ receptor agonists have demonstrated efficacy in patients with IBS-C. Tegaserod (available in come countries, but not in the U.S.) is an effective treatment for IBS-C, relieving overall and multiple individual IBS-C symptoms (abdominal pain/discomfort, bloating, and constipation) in placebo-controlled as well as open-label trials.¹⁴⁰ Repeat treatments with tegaserod are effective, and tegaserod is associated with improvements in quality of life and work productivity.¹⁴⁰

Adverse effects associated with tegaserod are diarrhea, cramping, and rare cardiovascular events, with the latter attributed to off-target effects on other 5-HT receptors (e.g. 5-HT2A and 2B antagonist). However, in a matched cohort study conducted within a large U.S. health insurance database involving 52,229 patients, there was no increased risk of cardiovascular ischemic events.¹⁴¹

Mosapride (approved in some countries, but not in the U.S.) improved symptoms in patients with IBS-C in a pilot study (n=10).¹⁴² However, a 12-month study in a larger cohort (n=69 patients) showed no significant improvements in overall or specific IBS symptoms (pain, bloating, stool frequency or consistency), or quality of life with mosapride over placebo.¹⁴³

Cognitive Behavioral Therapy and Hypnotherapy

Where available, cognitive behavioral therapy (CBT) and hypnotherapy may be used in the management of patients with IBS. Recent systematic reviews show psychological interventions are efficacious including long-term benefits, and that the gains are not dependent on the number of sessions. Indeed, CBT and hypnosis appear efficacious in minimal-contact formats, as well as various technologies (e.g., internet, telephone, smartphone apps), self-help interventions and engaging trained nonprofessional mental health providers to deliver interventions.¹⁴⁴

Conclusions

At the present time, the treatment of IBS remains focused on treating the patient’s most troublesome symptom. These treatments are quite efficacious for bowel dysfunction, though the treatment of pain without use of opioids or centrally acting agents is suboptimal. Hence, lifestyle interventions including diet, cognitive behavioral therapy and hypnotherapy (the latter not discussed here) should be considered to relieve symptoms in a holistic approach to the patient’s symptoms. Pharmacotherapies have not been shown to alter the long-term or natural history of the disorder. There is still considerable unmet need; new treatments that target some of the important actionable biomarkers of IBS, as well as the ability to conduct high quality, randomized, controlled trials augur well for the development of treatments that will impact patients’ symptoms and hopefully the natural history of IBS in the future. In particular, the new generation of peripherally active visceral analgesics, including opioid agents with no risk of respiratory depression or addiction potential, is eagerly awaited to address the significant unmet need of pain in IBS.

Abbreviations:

IBS

irritable bowel syndrome

RCTs

randomized, controlled trials

5-HT

serotonin

TRP

transient receptor potential

FDA

Food and Drug Administration

FODMAPs

fructose, oligosaccharides, disaccharides, monosaccharides and polyols

NNT

number needed to treat

IBS-SSS

IBS symptom severity score

IBS-D

diarrhea-predominant IBS

GFD

gluten-free diet

CFU

colony forming units

STW-5

iberogast

TRPM8

transient receptor potential cation channel subfamily M member 8

IBS-M

IBS-mixed

TCAs

tricyclic antidepressants (TCAs)

SSRIs

selective serotonin re-uptake inhibitors

IBS-C

constipation-predominant IBS

GABA

amma-aminobutyric acid

CGRP

calcitonin gene-related peptide

BAM

bile acid malabsorption

⁷⁵SeHCAT

selenium-75-homocholic acid taurine

GC-C

guanylate cyclase C

CFTR

cystic fibrosis transmembrane regulator

cGMP

cyclic guanosine monophosphate

CBT

cognitive behavioral therapy