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Management Options for Irritable Bowel Syndrome

  • Michael Camilleri
    Correspondence
    Correspondence: Address to Michael Camilleri, MD, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905.
    Affiliations
    Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.) Program and Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
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      Abstract

      Irritable bowel syndrome (IBS) is associated with diverse pathophysiologic mechanisms. These mechanisms include increased abnormal colonic motility or transit, intestinal or colorectal sensation, increased colonic bile acid concentration, and superficial colonic mucosal inflammation, as well as epithelial barrier dysfunction, neurohormonal up-regulation, 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 development of new treatments to relieve pain in IBS without deleterious central or other adverse effects.

      Abbreviations and Acronyms:

      CFU (colony-forming units), FDA (Food and Drug Administration), FODMAPs (fructose, oligosaccharides, disaccharides, monosaccharides, and polyols), GFD (gluten-free diet), 5-HT (5-hydroxytryptamine (serotonin)), IBS (irritable bowel syndrome), IBS-C (constipation-predominant IBS), IBS-D (diarrhea-predominant IBS), IBS-SSS (IBS symptom severity score), NNT (number needed to treat), RCT (randomized controlled trial), SNRI (serotonin-norepinephrine reuptake inhibitor), SSRI (selective serotonin reuptake inhibitor), TCA (tricyclic antidepressant), TRP (transient receptor potential)
      CME Activity
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      Learning Objectives: On completion of this article, you should be able to (1) select lifestyle and dietary interventions for patients with irritable bowel syndrome, (2) select medications proven to be efficacious and approved for the treatment of constipation-predominant irritable bowel syndrome, and (3) select efficacious, but off-label, medications for treatment of other symptoms of irritable bowel syndrome, such as diarrhea and pain.
      Disclosures: As a provider accredited by ACCME, Mayo Clinic College of Medicine and Science (Mayo School of Continuous Professional Development) must ensure balance, independence, objectivity, and scientific rigor in its educational activities. Course Director(s), Planning Committee members, Faculty, and all others who are in a position to control the content of this educational activity are required to disclose all relevant financial relationships with any commercial interest related to the subject matter of the educational activity. Safeguards against commercial bias have been put in place. Faculty also will disclose any off-label and/or investigational use of pharmaceuticals or instruments discussed in their presentation. Disclosure of this information will be published in course materials so that those participants in the activity may formulate their own judgments regarding the presentation. In their editorial and administrative roles, Karl A. Nath, MBChB, Terry L. Jopke, Kimberly D. Sankey, and Jenna M. Pederson, have control of the content of this program but have no relevant financial relationship(s) with industry.
      Dr Camilleri has received research funding regarding this topic from Novartis AG, Allergan, and Entera Health, Inc. He has done consulting regarding this topic (with the fee going to his employer, Mayo Clinic) for Elobix AB, Shire, and Takeda Pharmaceutical Company Limited.
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      Irritable bowel syndrome (IBS) pain, diarrhea, or constipation result from one or more pathophysiologic mechanisms in each individual patient. The treatment of IBS 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
      • Ford A.C.
      • Forman D.
      • Bailey A.G.
      • Axon A.T.
      • Moayyedi P.
      Irritable bowel syndrome: a 10-yr natural history of symptoms and factors that influence consultation behavior.
      ; 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.
      • Camilleri M.
      • Shin A.
      • Busciglio I.
      • et al.
      Validating biomarkers of treatable mechanisms in irritable bowel syndrome.
      • Camilleri M.
      Review article: biomarkers and personalised therapy in functional lower gastrointestinal disorders.
      Novel therapeutic approaches that have targeted these abnormalities in single-center, randomized controlled trials (RCTs) using biomarker end points have correctly predicted therapeutic efficacy based on symptom-based end points in phase 2B or 3 multicenter RCTs.
      • Camilleri M.
      Review article: biomarkers and personalised therapy in functional lower gastrointestinal disorders.
      Visceral pain is a hallmark of IBS. Pain is transmitted to conscious perception in the brain via a 3-neuron chain, as with somatic pain; the main pathways are vagal, thoracolumbar, and lumbosacral afferents that have both pronociceptive and antinociceptive ion channels and receptors.
      • Brierley S.M.
      • Linden D.R.
      Neuroplasticity and dysfunction after gastrointestinal inflammation.
      There are several relevant neurotransmitters on the afferents conveying sensory signals to the central nervous system, including serotonin (5-hydroxytryptamine [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.
      • Julius D.
      TRP channels and pain.
      This article addresses the current approaches to treatment of IBS, including lifestyle modifications, changes in diet, alternative and herbal therapies, probiotics, and pharmacotherapy (Figure)
      • Camilleri M.
      • Ford A.C.
      Invited Review: Pharmacotherapy for irritable bowel syndrome.
      directed to the motility, sensation, and intraluminal milieu of patients with IBS. There are recent national society guidelines for the management of IBS based on the available literature and systematic reviews and meta-analyses.
      American College of Gastroenterology Task Force on Irritable Bowel Syndrome
      An evidence-based position statement on the management of irritable bowel syndrome.
      • Chang L.
      • Lembo A.
      • Sultan S.
      American Gastroenterological Association Institute Technical Review on the pharmacological management of irritable bowel syndrome.
      • Ford A.C.
      • Moayyedi P.
      • Lacy B.E.
      • et al.
      Task Force on the Management of Functional Bowel Disorders
      American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation.
      • Spiller R.
      • Aziz Q.
      • Creed F.E.A.
      • et al.
      Clinical Services Committee of the British Society of Gastroenterology
      Guidelines on the irritable bowel syndrome: mechanisms and practical management.
      With recently introduced medications, trials have used US Food and Drug Administration (FDA)–recommended end points to judge efficacy. The level of evidence is weaker for more traditional therapies that were previously approved on the basis of smaller, lower-quality RCTs that involved heterogeneous patients or unvalidated end points.
      • Camilleri M.
      American College of Gastroenterology monograph on the management of irritable bowel syndrome.
      For each intervention discussed, the mechanisms, efficacy, and safety (when available) are summarized.
      Figure thumbnail gr1
      FigurePharmacotherapy in irritable bowel syndrome. Cl = chloride; GC-C = guanylate cyclase C; 5-HT = 5-hydroxytryptamine (serotonin); NHE = sodium/hydrogen exchanger; NK2 = neurokinin 2; TSPO = translocator protein.
      From J Clin Med,
      • Camilleri M.
      • Ford A.C.
      Invited Review: Pharmacotherapy for irritable bowel syndrome.
      with 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]).

      General Lifestyle Measures

       Dietary Modifications

      Many patients believe that their IBS symptoms are due to food sensitivity.
      • Böhn L.
      • Störsrud S.
      • Törnblom H.
      • Bengtsson U.
      • Simrén M.
      Self-reported food-related gastrointestinal symptoms in IBS are common and associated with more severe symptoms and reduced quality of life.

       Mechanisms

      Food generates symptoms in patients with IBS,
      • Ragnarsson G.
      • Bodemar G.
      Pain is temporally related to eating but not to defaecation in the irritable bowel syndrome (IBS): patients' description of diarrhea, constipation and symptom variation during a prospective 6-week study.
      and 4 potential explanations are (1) prominent contractile
      • Sullivan M.A.
      • Cohen S.
      • Snape Jr., W.J.
      Colonic myoelectrical activity in irritable-bowel syndrome: effect of eating and anticholinergics.
      and sensory
      • Simrén M.
      • Abrahamsson H.
      • Björnsson E.S.
      An exaggerated sensory component of the gastrocolonic response in patients with irritable bowel syndrome.
      responses of the colon to the ingestion of food (“gastrocolonic response”); (2) alterations in the microbiome (which may occur quite rapidly after a change in diet)
      • David L.A.
      • Maurice C.F.
      • Carmody R.N.
      • et al.
      Diet rapidly and reproducibly alters the human gut microbiome.
      ; (3) insoluble dietary fiber may exacerbate IBS symptoms
      • Francis C.Y.
      • Whorwell P.J.
      Bran and irritable bowel syndrome: time for reappraisal.
      ; and (4) dietary antigens may alter the intestinal epithelial barrier.
      • Fritscher-Ravens A.
      • Schuppan D.
      • Ellrichmann M.
      • et al.
      Confocal endomicroscopy shows food-associated changes in the intestinal mucosa of patients with irritable bowel syndrome.
      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.
      • Moayyedi P.
      • Quigley E.M.
      • Lacy B.E.
      • et al.
      The effect of dietary intervention on irritable bowel syndrome: a systematic review.
      Specific diets, including a diet low in fructose, oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs), are discussed subsequently.

       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.
      • Atkinson W.
      • Sheldon T.A.
      • Shaath N.
      • Whorwell P.J.
      Food elimination based on IgG antibodies in irritable bowel syndrome: a randomised controlled trial.
      Symptoms were substantially improved at 12 weeks. The results of the study revealed that the number needed to treat (NNT) was 9, and reintroducing eliminated foods resulted in substantial worsening of symptoms. It is unclear whether the diet's efficacy differed according to stool pattern. Conversely, double-blind rechallenge to the dietary triggers resulted in reproducible symptoms in only approximately 25% of patients.
      • Young E.
      • Stoneham M.D.
      • Petruckevitch A.
      • Barton J.
      • Rona R.
      A population study of food intolerance.

       Increased Dietary Fiber

       Efficacy

      In the largest trial of the use of fiber in patients with IBS (all subtypes) in the primary care setting, 275 patients were randomized to 12 weeks of treatment with soluble fiber (psyllium), insoluble bran fiber, or placebo.
      • Bijkerk C.J.
      • de Wit N.J.
      • Muris J.W.
      • Whorwell P.J.
      • Knottnerus J.A.
      • Hoes A.W.
      Soluble or insoluble fibre in irritable bowel syndrome in primary care? Randomised placebo controlled trial.
      Whereas bran was of no benefit, there was reduction in IBS symptom severity score (IBS-SSS) with psyllium over placebo at 12 weeks and a 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 with placebo.
      In a systematic review and meta-analysis
      • Moayyedi P.
      • Quigley E.M.
      • Lacy B.E.
      • et al.
      The effect of fiber supplementation on irritable bowel syndrome: a systematic review and meta-analysis.
      that included 906 patients with IBS in 14 RCTs (most of low methodological quality), there was only modest improvement of symptoms with fiber (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.
      • Erdogan A.
      • Rao S.S.
      • Thiruvaiyaru D.
      • et al.
      Randomised clinical trial: mixed soluble/insoluble fibre vs. psyllium for chronic constipation.

       Mechanism

      The mechanism of benefit with psyllium is uncertain and is unlikely to relate to stool bulking alone because bran has similar effects.
      • Tomlin J.
      • Read N.W.
      Laxative properties of indigestible plastic particles.
      Conversely, increased production of short-chain fatty acids, such as butyrate, with psyllium treatment may have anti-inflammatory effects on the colonic mucosa
      • Zimmerman M.A.
      • Singh N.
      • Martin P.M.
      • et al.
      Butyrate suppresses colonic inflammation through HDAC1-dependent Fas upregulation and Fas-mediated apoptosis of T cells.
      or alter the intestinal microbiota,
      • Lee S.M.
      • Han H.W.
      • Yim S.Y.
      Beneficial effects of soy milk and fiber on high cholesterol diet-induced alteration of gut microbiota and inflammatory gene expression in rats.
      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. Because these chemical substances are poorly absorbed, they may induce osmotic effects (and fluid secretion) or fermentation (and distention) in the intestine,
      • Shepherd S.J.
      • Parker F.C.
      • Muir J.G.
      • Gibson P.R.
      Dietary triggers of abdominal symptoms in patients with irritable bowel syndrome: randomized placebo-controlled evidence.
      • Undseth R.
      • Berstad A.
      • Kløw N.E.
      • Arnljot K.
      • Moi K.S.
      • Valeur J.
      Abnormal accumulation of intestinal fluid following ingestion of an unabsorbable carbohydrate in patients with irritable bowel syndrome: an MRI study.
      leading to increased colonic sensitivity from the distention.
      • Major G.
      • Pritchard S.
      • Murray K.
      • et al.
      Colon hypersensitivity to distension, rather than excessive gas production, produces carbohydrate-related symptoms in individuals with irritable bowel syndrome.
      Sugar alcohols can induce dose-dependent symptoms of flatulence, abdominal discomfort, and laxative effects when consumed by both healthy volunteers and patients with IBS.
      • Lenhart A.
      • Chey W.D.
      A systematic review of the effects of polyols on gastrointestinal health and irritable bowel syndrome.
      A low FODMAP diet may lead to reduction in bacterial abundance
      • Halmos E.P.
      • Christophersen C.T.
      • Bird A.R.
      • Shepherd S.J.
      • Gibson P.R.
      • Muir J.G.
      Diets that differ in their FODMAP content alter the colonic luminal microenvironment.
      and lower proportions of certain bacteria including Bifidobacterium.
      • Staudacher H.M.
      • Lomer M.C.
      • Anderson J.L.
      • et al.
      Fermentable carbohydrate restriction reduces luminal bifidobacteria and gastrointestinal symptoms in patients with irritable bowel syndrome.
      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
      • Halmos E.P.
      • Power V.A.
      • Shepherd S.J.
      • Gibson P.R.
      • Muir J.G.
      A diet low in FODMAPs reduces symptoms of irritable bowel syndrome.
      reported reduced global IBS symptoms, bloating, and pain with the low FODMAP diet, with greater benefit in those with diarrhea-predominant IBS (IBS-D). Conversely, a larger parallel-group RCT of 67 patients with IBS found no difference in efficacy between a low FODMAPs diet and conventional dietary recommendations,
      • Böhn L.
      • Störsrud S.
      • Liljebo T.
      • et al.
      Diet low in FODMAPs reduces symptoms of irritable bowel syndrome as well as traditional dietary advice: a randomized controlled trial.
      with both diets producing benefit relative to baseline.
      Several meta-analyses suggest efficacy of a low FODMAPs diet
      • Varjú P.
      • Farkas N.
      • Hegyi P.
      • et al.
      Low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet improves symptoms in adults suffering from irritable bowel syndrome (IBS) compared to standard IBS diet: a meta-analysis of clinical studies.
      • Altobelli E.
      • Del Negro V.
      • Angeletti P.M.
      • Latella G.
      Low-FODMAP diet improves irritable bowel syndrome symptoms: a meta-analysis.
      ; however, analysis identified risk of bias, primarily due to lack of proper blinding and choice of control.
      • Krogsgaard L.R.
      • Lyngesen M.
      • Bytzer P.
      Systematic review: quality of trials on the symptomatic effects of the low FODMAP diet for irritable bowel syndrome.
      Despite the weak evidence, the National Institute for Health and Care Excellence of the United Kingdom recommended as a first-line treatment the use of a low FODMAPs diet for patients with IBS in primary care.
      Diagnosis and management of irritable bowel syndrome in adults in primary care: summary of NICE guidance [correction].
      The IBS dietary algorithm from the British Dietetic Association was simplified to first-line healthy eating (provided by any health care professional) and second-line low FODMAP dietary advice.
      • McKenzie Y.A.
      • Bowyer R.K.
      • Leach H.
      • et al.
      IBS Dietetic Guideline Review Group on behalf of Gastroenterology Specialist Group of the British Dietetic Association
      British Dietetic Association systematic review and evidence-based practice guidelines for the dietary management of irritable bowel syndrome in adults (2016 update).

       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 a gluten-free diet (GFD).

       Mechanism

      The mechanism of the effect of gluten in IBS is unclear; a gluten-containing diet affects small bowel epithelial messenger RNA expression of barrier protein and higher small bowel mucosal permeability in patients with IBS-D compared with a GFD.
      • Vazquez Roque M.I.
      • Camilleri M.
      • Smyrk T.
      • et al.
      A controlled trial of gluten-free diet in patients with irritable bowel syndrome-diarrhea: effects on bowel frequency and intestinal function.
      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 toll-like receptor 2 and reduced regulatory T-cell marker FOXP3 relative to controls and patients with celiac disease.
      • Sapone A.
      • Lammers K.M.
      • Casolaro V.
      • et al.
      Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity.
      Because wheat contains high levels of fructans in addition to gluten, a trial examined the combination of a low FODMAPs diet and a GFD
      • Biesiekierski J.R.
      • Peters S.L.
      • Newnham E.D.
      • Rosella O.
      • Muir J.G.
      • Gibson P.R.
      No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates.
      and found no additive effect of the GFD, suggesting that reduction in fructans may partly explain the effectiveness of a GFD in IBS.

       Efficacy

      Two RCTs reported that response to a GFD is greater in patients who are HLA-DQ2– or HLA-DQ8–positive.
      • Vazquez Roque M.I.
      • Camilleri M.
      • Smyrk T.
      • et al.
      A controlled trial of gluten-free diet in patients with irritable bowel syndrome-diarrhea: effects on bowel frequency and intestinal function.
      • Wahnschaffe U.
      • Schulzke J.D.
      • Zeitz M.
      • Ullrich R.
      Predictors of clinical response to gluten-free diet in patients diagnosed with diarrhea-predominant irritable bowel syndrome.
      A third RCT found similar improvement in IBS-SSS; in addition, patients who were HLA-DQ2– or HLA-DQ8–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.
      • Aziz I.
      • Trott N.
      • Briggs R.
      • North J.R.
      • Hadjivassiliou M.
      • Sanders D.S.
      Efficacy of a gluten-free diet in subjects with irritable bowel syndrome-diarrhea unaware of their HLA-DQ2/8 genotype.

       Exercise

      A few studies have examined exercise as an approach to reduce symptoms in IBS. In a Swedish trial, initially over 12 weeks
      • Johannesson E.
      • Simrén M.
      • Strid H.
      • Bajor A.
      • Sadik R.
      Physical activity improves symptoms in irritable bowel syndrome: a randomized controlled trial.
      and subsequently with median follow-up of 5.2 years (range, 3.8-6.2 years),
      • Johannesson E.
      • Ringström G.
      • Abrahamsson H.
      • Sadik R.
      Intervention to increase physical activity in irritable bowel syndrome shows long-term positive effects.
      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 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 reported to be beneficial for patients with IBS, with yoga tending to reduce the severity of IBS and somatic symptoms and walking improving overall gastrointestinal tract symptoms, negative affect, and anxiety.
      • Shahabi L.
      • Naliboff B.D.
      • Shapiro D.
      Self-regulation evaluation of therapeutic yoga and walking for patients with irritable bowel syndrome: a pilot study.

      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 microorganisms that can affect the composition of the intestinal microorganisms. Probiotics may have anti-inflammatory and antinociceptive properties.
      • Kamiya T.
      • Wang L.
      • Forsythe P.
      • et al.
      Inhibitory effects of Lactobacillus reuteri on visceral pain induced by colorectal distension in Sprague-Dawley rats.
      • O'Mahony L.
      • McCarthy J.
      • Kelly P.
      • et al.
      Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles.
      • Verdú E.F.
      • Bercík P.
      • Bergonzelli G.E.
      • et al.
      Lactobacillus paracasei normalizes muscle hypercontractility in a murine model of postinfective gut dysfunction.
      • Verdú E.F.
      • Bercik P.
      • Verma-Gandhu M.
      • et al.
      Specific probiotic therapy attenuates antibiotic induced visceral hypersensitivity in mice.
      Two trials of prebiotics in IBS were reported in the past 3 years. An RCT of 12 weeks' duration compared 6-g partially hydrolyzed guar gum, a prebiotic fiber, to placebo in 121 patients with IBS of all subtypes
      • Niv E.
      • Halak A.
      • Tiommny E.
      • et al.
      Randomized clinical study: partially hydrolyzed guar gum (PHGG) versus placebo in the treatment of patients with irritable bowel syndrome.
      and found 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 (900 mg) in children with IBS, and none of the 6 symptoms of IBS tested improved, in contrast to significant improvements with synbiotic treatment (5×109 colony-forming units [CFU] of Bifidobacterium lactis B94 and 900 mg of inulin) and probiotic treatment (5×109 CFU of B lactis B94) tested over 4 weeks.
      • Baştürk A.
      • Artan R.
      • Yılmaz A.
      Efficacy of synbiotic, probiotic, and prebiotic treatments for irritable bowel syndrome in children: a randomized controlled trial.
      In a meta-analysis published in 2014, 35 trials of probiotics involving 3452 patients with IBS
      • Ford A.C.
      • Quigley E.M.
      • Lacy B.E.
      • et al.
      Efficacy of prebiotics, probiotics, and synbiotics in irritable bowel syndrome and chronic idiopathic constipation: systematic review and meta-analysis.
      found 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 with placebo.
      More recent meta-analyses of probiotics suggest benefit for overall symptoms in patients with IBS treated with Bifidobacterium infantis (5 RCTs),
      • Yuan F.
      • Ni H.
      • Asche C.V.
      • Kim M.
      • Walayat S.
      • Ren J.
      Efficacy of Bifidobacterium infantis 35624 in patients with irritable bowel syndrome: a meta-analysis.
      Saccharomyces cerevisiae CNCM I-3856 (2 trials),
      • Cayzeele-Decherf A.
      • Pélerin F.
      • Leuillet S.
      • et al.
      Saccharomyces cerevisiae CNCM I-3856 in irritable bowel syndrome: an individual subject meta-analysis.
      and single probiotics at relatively lower dosage of organisms (<1010 CFU/d) and shorter duration (<8weeks).
      • Zhang Y.
      • Li L.
      • Guo C.
      • et al.
      Effects of probiotic type, dose and treatment duration on irritable bowel syndrome diagnosed by Rome III criteria: a meta-analysis.
      A meta-analysis of 15 trials that included 1793 patients reported improvement of general symptoms (7 trials) and of pain, distention, bloating, and flatulence in 2 to 3 trials each.
      • Didari T.
      • Mozaffari S.
      • Nikfar S.
      • Abdollahi M.
      Effectiveness of probiotics in irritable bowel syndrome: updated systematic review with meta-analysis.
      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.
      • Whelan K.
      Editorial: The importance of systematic reviews and meta-analyses of probiotics and prebiotics.

       Other Herbal Therapies

      The efficacy of other herbal therapies in IBS is unclear. Iberogast is a mixture of diverse extracts of flower, leaves, fruit, root, and herbs
      • Madisch A.
      • Melderis H.
      • Mayr G.
      • Sassin I.
      • Hotz J.
      A plant extract and its modified preparation in functional dyspepsia: results of a double-blind placebo controlled comparative study [in German].
      with antispasmodic effects on gastrointestinal smooth muscle
      • Ammon H.P.
      • Kelber O.
      • Okpanyi S.N.
      Spasmolytic and tonic effect of Iberogast (STW 5) in intestinal smooth muscle.
      through diverse mechanisms
      • Simmen U.
      • Kelber O.
      • Okpanyi S.N.
      • Jaeggi R.
      • Bueter B.
      • Weiser D.
      Binding of STW 5 (Iberogast) and its components to intestinal 5-HT, muscarinic M3, and opioid receptors.
      and secretory effect on diverse chloride channels.
      • Krueger D.
      • Gruber L.
      • Buhner S.
      • et al.
      The multi-herbal drug STW 5 (Iberogast) has prosecretory action in the human intestine.
      In an RCT of 208 patients with IBS,
      • Madisch A.
      • Holtmann G.
      • Plein K.
      • Hotz J.
      Treatment of irritable bowel syndrome with herbal preparations: results of a double-blind, randomized, placebo-controlled, multi-centre trial.
      there was improvement in global symptoms and abdominal pain scores with Iberogast compared with placebo.
      The benefits of Chinese herbal medicines in IBS are inconsistent.
      • Bensoussan A.
      • Talley N.J.
      • Hing M.
      • Menzies R.
      • Guo A.
      • Ngu M.
      Treatment of irritable bowel syndrome with Chinese herbal medicine: a randomized controlled trial.
      • Bensoussan A.
      • Kellow J.E.
      • Bourchier S.J.
      • et al.
      Efficacy of a Chinese herbal medicine in providing adequate relief of constipation-predominant irritable bowel syndrome: a randomized controlled trial.
      • Leung W.K.
      • Wu J.C.
      • Liang S.M.
      • et al.
      Treatment of diarrhea-predominant irritable bowel syndrome with traditional Chinese herbal medicine: a randomized placebo-controlled trial.

      Medications for Pain

      Numerous pharmacological agents for treatment of IBS are currently available, with varying modes of action, efficacy, quality of data, and adverse events (Table).
      TableSummary of Current Pharmacological Treatments for Irritable Bowel Syndrome
      Mode of actionTherapyEfficacyQuality of dataAdverse eventsLimitations of data
      Smooth muscle relaxationAntispasmodic drugs+/−LowDry mouth, dizziness, and blurred visionNo high-quality trials, heterogeneity between studies, possible publication bias, and only a small number of RCTs assessing each individual antispasmodic
      Peppermint oil+ModerateNo increase in AEsHeterogeneity between studies
      SecretagoguesLubiprostone+ModerateNausea more common vs placeboOnly a modest benefit over placebo in published RCTs
      Linaclotide+HighDiarrhea more common vs placeboNone
      Plecanatide+HighDiarrhea more common vs placeboNone
      Tenapanor+/−ModerateDiarrhea more common vs placeboAwaiting phase 2B/3 trials
      NeuromodulatorsAntidepressants+ModerateDry mouth and drowsinessFew high-quality trials, heterogeneity between studies, possible publication bias, and some atypical trials included
      Neurokinin NK2 antagonistPromising in phase 2B RCTModerateNo increase in AEsAwaiting phase 3 trials
      Histamine H1 antagonistPromising in single-center trialLowNo increase in AEsAwaiting phase 2B trials
      TSPO inhibitor+/−LowModest efficacy in a single proof of concept trialAwaiting phase 2B trials
      OpioidsLoperamide+/−LowLimited dataFew RCTs, with a small number of participants, not all of whom had IBS
      Eluxadoline+HighSerious AEs: acute pancreatitis and sphincter of Oddi spasm. Nausea and headache common vs placeboOnly a modest benefit over placebo in published RCTs. No benefit over placebo in terms of abdominal pain
      5-HT3 receptor antagonists+HighSerious AE with alosetron: ischemic colitis; constipation more common vs placeboFewer RCTs of ramosetron and ondansetron. Ondansetron may have no benefit over placebo for abdominal pain
      5-HT4 receptor agonists+/−HighDiarrhea, cramping, and cardiovascular AEs with “old-generation” drugs in this classData available for tegaserod and mosapride, not for “new-generation” drugs in this class: prucalopride, naronapride, velusetrag, YKP10811
      Bile acid sequestrants?LowLimited dataNo published RCTs
      Rifaximin+ModerateNo increase in AEsOnly a modest benefit over placebo in published RCTs
      AE = adverse event; 5-HT = 5-hydroxytryptamine (serotonin); IBS = irritable bowel syndrome; RCT = randomized controlled trial; TSPO = translocator protein; + = positive; − = negative; ? = unknown.

       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 have documented weak evidence for the benefit of some antispasmodics for abdominal pain and global symptom relief,
      • Quartero A.O.
      • Meineche-Schmidt V.
      • Muris J.
      • Rubin G.
      • de Wit N.
      Bulking agents, antispasmodic and antidepressant medication for the treatment of irritable bowel syndrome.
      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.
      • Tack J.
      • Fried M.
      • Houghton L.A.
      • Spicak J.
      • Fisher G.
      Systematic review: the efficacy of treatments for irritable bowel syndrome—a European perspective.
      In a meta-analysis of 22 separate RCTs involving 1778 patients and 12 different antispasmodic drugs,
      • Ford A.C.
      • Talley N.J.
      • Spiegel B.M.
      • et al.
      Effect of fibre, antispasmodics, and peppermint oil in the treatment of irritable bowel syndrome: systematic review and meta-analysis.
      antispasmodics were more effective than placebo, with an NNT of 5 overall and slightly lower NNTs with hyoscine (NNT, 3.5) (426 patients enrolled in 3 trials), otilonium (NNT, 4.5) (435 patients enrolled in 4 trials,), cimetropium (NNT, 3) (158 patients enrolled in 3 trials), and pinaverium (NNT, 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 FDA for the treatment of IBS in the United States, and promising data for those medications are reviewed elsewhere.
      • Camilleri M.
      • Ford A.C.
      Invited Review: Pharmacotherapy for irritable bowel syndrome.

       Safety

      Antispasmodics cause more adverse 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.
      • Hawthorn M.
      • Ferrante J.
      • Luchowski E.
      • Rutledge A.
      • Wei X.Y.
      • Triggle D.J.
      The actions of peppermint oil and menthol on calcium channel dependent processes in intestinal, neuronal and cardiac preparations.
      • Amato A.
      • Liotta R.
      • Mulè F.
      Effects of menthol on circular smooth muscle of human colon: analysis of the mechanism of action.
      Menthol also induces analgesia by activating the temperature-sensing ion channel, TRP cation channel subfamily M member 8,
      • Liu B.
      • Fan L.
      • Balakrishna S.
      • Sui A.
      • Morris J.B.
      • Jordt S.E.
      TRPM8 is the principal mediator of menthol-induced analgesia of acute and inflammatory pain.
      which has antinociceptive properties in visceral afferents.

       Efficacy

      Peppermint oil was more effective than placebo in a meta-analysis of 4 trials including 392 patients with IBS (NNT of 2.5).
      • Ford A.C.
      • Talley N.J.
      • Spiegel B.M.
      • et al.
      Effect of fibre, antispasmodics, and peppermint oil in the treatment of irritable bowel syndrome: systematic review and meta-analysis.
      The same methodological issues described for antispasmodics apply, and the estimate of efficacy (NNT) is likely inaccurate.
      In a later meta-analysis of 5 RCTs of peppermint oil including 197 patients receiving active treatment and 195 receiving placebo, peppermint oil resulted in global improvement of IBS symptoms (5 studies) and abdominal pain (5 studies).
      • Khanna R.
      • MacDonald J.K.
      • Levesque B.G.
      Peppermint oil for the treatment of irritable bowel syndrome: a systematic review and meta-analysis.
      A novel formulation with sustained release in the small intestine
      • Cash B.D.
      • Epstein M.S.
      • Shah S.M.
      A novel delivery system of peppermint oil is an effective therapy for irritable bowel syndrome symptoms.
      was tested in a 4-week trial in 72 patients with IBS-D or IBS with mixed symptoms, and there was no superiority over placebo for total IBS symptom score, although both treatment arms produced 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 coexistence of psychological disorders in IBS,
      • Henningsen P.
      • Zimmermann T.
      • Sattel H.
      Medically unexplained physical symptoms, anxiety, and depression: a meta-analytic review.
      evidence that depression modifies the central nervous system response to painful stimuli,
      • Schmid J.
      • Langhorst J.
      • Gaß F.
      • et al.
      Placebo analgesia in patients with functional and organic abdominal pain: a fMRI study in IBS, UC and healthy volunteers.
      the benefits of antidepressants in chronic painful disorders,
      • McQuay H.J.
      • Tramèr M.
      • Nye B.A.
      • Carroll D.
      • Wiffen P.J.
      • Moore R.A.
      A systematic review of antidepressants in neuropathic pain.
      • Saarto T.
      • Wiffen P.J.
      Antidepressants for neuropathic pain.
      and correction of altered intestinal transit. Thus, tricyclic antidepressants (TCAs) prolong orocecal and intestinal transit times, whereas selective serotonin reuptake inhibitors (SSRIs) decrease orocecal transit time.
      • Gorard D.A.
      • Libby G.W.
      • Farthing M.J.
      Influence of antidepressants on whole gut and orocaecal transit times in health and irritable bowel syndrome.
      Based on this difference, 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
      • Morgan V.
      • Pickens D.
      • Gautam S.
      • Kessler R.
      • Mertz H.
      Amitriptyline reduces rectal pain related activation of the anterior cingulate cortex in patients with irritable bowel syndrome.
      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-analysis
      • Ford A.C.
      • Quigley E.M.
      • Lacy B.E.
      • et al.
      Effect of antidepressants and psychological therapies, including hypnotherapy, in irritable bowel syndrome: systematic review and meta-analysis.
      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 end points, questionable generalizability, uncharacteristic response levels of the placebo arm (14%)
      • Vahedi H.
      • Merat S.
      • Rashidioon A.
      • Ghoddoosi A.
      • Malekzadeh R.
      The effect of fluoxetine in patients with pain and constipation-predominant irritable bowel syndrome: a double-blind randomized-controlled study.
      or the antidepressant (63%),
      • Vahedi H.
      • Merat S.
      • Momtahen S.
      • et al.
      Clinical trial: the effect of amitriptyline in patients with diarrhoea-predominant irritable bowel syndrome.
      and evidence of heterogeneity between studies and possible publication bias raise questions about 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 2 RCTs.
      • Vahedi H.
      • Merat S.
      • Rashidioon A.
      • Ghoddoosi A.
      • Malekzadeh R.
      The effect of fluoxetine in patients with pain and constipation-predominant irritable bowel syndrome: a double-blind randomized-controlled study.
      • Vahedi H.
      • Merat S.
      • Momtahen S.
      • et al.
      Clinical trial: the effect of amitriptyline in patients with diarrhoea-predominant irritable bowel syndrome.
      Three trials of antidepressants in IBS have found no correlation between improvement in IBS symptoms and depression scores,
      • Tabas G.
      • Beaves M.
      • Wang J.
      • Friday P.
      • Mardini H.
      • Arnold G.
      Paroxetine to treat irritable bowel syndrome not responding to high-fiber diet: a double-blind, placebo-controlled trial.
      • Tack J.
      • Broekaert D.
      • Fischler B.
      • Van Oudenhove L.
      • Gevers A.M.
      • Janssens J.
      A controlled crossover study of the selective serotonin reuptake inhibitor citalopram in irritable bowel syndrome.
      • Vij J.C.
      • Jiloha R.C.
      • Kumar N.
      • Madhu S.V.
      • Malika V.
      • Anand B.S.
      Effect of antidepressant drug (doxepin) on irritable bowel syndrome patients.
      and a fourth trial of a TCA revealed greater benefit in nondepressed individuals.
      • Drossman D.A.
      • Toner B.B.
      • Whitehead W.E.
      • et al.
      Cognitive-behavioral therapy versus education and desipramine versus placebo for moderate to severe functional bowel disorders.
      Three open-label trials have studied the effects of duloxetine, a serotonin-norepinephrine reuptake inhibitor (SNRI) that has had efficacy in the treatment of IBS, such as in IBS-SSS (symptom severity), pain, bowel dysfunction, and quality of life.
      • Brennan B.P.
      • Fogarty K.V.
      • Roberts J.L.
      • Reynolds K.A.
      • Pope Jr., H.G.
      • Hudson J.I.
      Duloxetine in the treatment of irritable bowel syndrome: an open-label pilot study.
      • Kaplan A.
      • Franzen M.D.
      • Nickell P.V.
      • Ransom D.
      • Lebovitz P.J.
      An open-label trial of duloxetine in patients with irritable bowel syndrome and comorbid generalized anxiety disorder.
      • Lewis-Fernández R.
      • Lam P.
      • Lucak S.
      • et al.
      An open-label pilot study of duloxetine in patients with irritable bowel syndrome and comorbid major depressive disorder.
      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 comorbid depressive or generalized anxiety disorders are required.

       Safety

      Adverse effects are considerably more common with TCAs, the most frequent of which are drowsiness and dry mouth. Based on population studies,
      • Lee C.W.
      • Lin C.L.
      • Sung F.C.
      • Liang J.A.
      • Kao C.H.
      Antidepressant treatment and risk of dementia: a population-based, retrospective case-control study.
      • Breining A.
      • Bonnet-Zamponi D.
      • Zerah L.
      • et al.
      Exposure to psychotropics in the French older population living with dementia: a nationwide population-based study.
      long-term use of some classes of psychotropic drugs for nonpsychiatric indications may be linked to dementia, 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.
      • Camilleri M.
      • Lembo A.
      • Katzka D.A.
      Opioids in gastroenterology: treating adverse effects and creating therapeutic benefits.

       Efficacy

      Loperamide and diphenoxylate, μ-opioid agonists, are antidiarrheal agents that have been in use for the treatment of chronic functional diarrhea for many years,
      • Kasich A.M.
      Treatment of diarrhea in irritable colon, including preliminary observations with a new antidiarrheal agent, diphenoxylate hydrochloride (Lomotil).
      based on limited evidence from small studies conducted around 30 years ago. One small trial of 21 patients with IBS-D found that loperamide improved stool consistency, pain, and urgency.
      • Lavö B.
      • Stenstam M.
      • Nielsen A.L.
      Loperamide in treatment of irritable bowel syndrome—a double-blind placebo controlled study.
      A second trial
      • Hovdenak N.
      Loperamide treatment of the irritable bowel syndrome.
      of 60 patients with either functional diarrhea or IBS-D confirmed reduction in stool frequency, improved consistency, and fewer days with pain. A third trial
      • Efskind P.S.
      • Bernklev T.
      • Vatn M.H.
      A double-blind placebo-controlled trial with loperamide in irritable bowel syndrome.
      of loperamide in unselected patients with IBS reported 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.
      • Ford A.C.
      • Moayyedi P.
      • Lacy B.E.
      • et al.
      Task Force on the Management of Functional Bowel Disorders
      American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation.
      Eluxadoline is a novel κ- and μ-opioid receptor agonist and δ-opioid receptor antagonist. Based on 3 trials with approximately 3000 patients with IBS treated over 12 weeks, it was efficacious in the relief of diarrhea or the composite end point of diarrhea and pain.
      • Dove L.S.
      • Lembo A.
      • Randall C.W.
      • et al.
      Eluxadoline benefits patients with irritable bowel syndrome with diarrhea in a phase 2 study.
      • Lembo A.J.
      • Lacy B.E.
      • Zuckerman M.J.
      • et al.
      Eluxadoline for irritable bowel syndrome with diarrhea.
      The recommended dose is 100 mg twice a day unless not tolerated or if there is hepatic impairment, in which case the 75-mg twice a day 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 3 alcoholic drinks per day.

       Off-Label Approaches for Visceral Pain

       Histamine H1 Receptor Antagonist Ebastine

      Mast cells and their mediators, in particular histamine, seritonin and proteases, contribute to the pathogenesis of IBS.
      • Wouters M.M.
      • Vicario M.
      • Santos J.
      The role of mast cells in functional GI disorders.
      Histamine released by colonic biopsies from patients with IBS can sensitize (via H1 histamine receptors) the TRP cation channel subfamily V member 1 on neurons in dorsal root ganglia (on afferent pathways) and on human submucosal neurons in rectal biopsies.
      • Wouters M.M.
      • Balemans D.
      • Van Wanrooy S.
      • et al.
      Histamine receptor H1-mediated sensitization of TRPV1 mediates visceral hypersensitivity and symptoms in patients with irritable bowel syndrome.
      Ebastine, a nonsedating antagonist of H1 receptors, has been reported to reduce visceral hypersensitivity, overall IBS symptoms, and abdominal pain in patients with IBS.
      • Wouters M.M.
      • Balemans D.
      • Van Wanrooy S.
      • et al.
      Histamine receptor H1-mediated sensitization of TRPV1 mediates visceral hypersensitivity and symptoms in patients with irritable bowel syndrome.
      However, it is not approved for use in the United States at this time.

       γ-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. Three studies have assessed the effects of gabapentin and pregabalin on rectal and colonic sensation and compliance in patients with IBS-D or healthy controls, and overall the results suggest that these agents reduce senation without significantly affecting compliance. This findings suggests an effect exclusively on sensory mechanisms.
      • Lee K.J.
      • Kim J.H.
      • Cho S.W.
      Gabapentin reduces rectal mechanosensitivity and increases rectal compliance in patients with diarrhoea-predominant irritable bowel syndrome.
      • Iturrino J.
      • Camilleri M.
      • Busciglio I.
      • Burton D.
      • Zinsmeister A.R.
      Effect of the α2δ ligand, pregabalin, on colonic sensory and motor functions in healthy adults.
      • Houghton L.A.
      • Fell C.
      • Whorwell P.J.
      • Jones I.
      • Sudworth D.P.
      • Gale J.D.
      Effect of a second-generation α2δ ligand (pregabalin) on visceral sensation in hypersensitive patients with irritable bowel syndrome.
      A preliminary report of a randomized, controlled, 12-week clinical trial of pregabalin (dose-escalation regimen to a maximum of 225 mg twice a day) conducted at Mayo Clinic, Rochester, Minnesota, in 85 patients with IBS revealed lower average pain scores during weeks 9 through 12 and lower mean IBS-SSS with pregabalin compared with placebo.
      • Saito Y.A.
      • Almazar A.E.
      • Tilkes K.
      • et al.
      A placebo-controlled trial of pregabalin for irritable bowel syndrome.

       Future Approaches to Pain Relief in IBS

      A new generation of peripherally active visceral analgesics,
      • Camilleri M.
      Towards an effective peripheral visceral analgesic: responding to the national opioid crisis.
      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 treatment in patients with IBS.

      Medications for Diarrhea

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

       5-HT3 Receptor Antagonists

       Mechanism

      Of the total body serotonin (5-HT), 90% is found within intestinal enterochromaffin cells.
      • Berger M.
      • Gray J.A.
      • Roth B.L.
      The expanded biology of serotonin.
      • Gershon M.D.
      • Wade P.R.
      • Kirchgessner A.L.
      • Tamir H.
      5-HT receptor subtypes outside the central nervous system: roles in the physiology of the gut.
      Serotonin 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.
      • Atkinson W.
      • Lockhart S.
      • Whorwell P.J.
      • Keevil B.
      • Houghton L.A.
      Altered 5-hydroxytryptamine signaling in patients with constipation- and diarrhea-predominant irritable bowel syndrome.
      The 5-HT3 receptor antagonists such as alosetron
      • Viramontes B.E.
      • Camilleri M.
      • McKinzie S.
      • Pardi D.S.
      • Burton D.
      • Thomforde G.M.
      Gender-related differences in slowing colonic transit by a 5-HT3 antagonist in subjects with diarrhea-predominant irritable bowel syndrome.
      retard colonic transit. The 5-HT3 receptors are also important mediators of visceral pain.
      • Hicks G.A.
      • Coldwell J.R.
      • Schindler M.
      • et al.
      Excitation of rat colonic afferent fibres by 5-HT(3) receptors.

       Efficacy

      Alosetron is an effective agent based on the results of several meta-analyses of high quality, large RCTs that have all reported consistent results.
      • Andresen V.
      • Montori V.M.
      • Keller J.
      • West C.P.
      • Layer P.
      • Camilleri M.
      Effects of 5-hydroxytryptamine (serotonin) type 3 antagonists on symptom relief and constipation in nonconstipated irritable bowel syndrome: a systematic review and meta-analysis of randomized controlled trials.
      • Ford A.C.
      • Brandt L.J.
      • Young C.
      • Chey W.D.
      • Foxx-Orenstein A.E.
      • Moayyedi P.
      Efficacy of 5-HT3 antagonists and 5-HT4 agonists in irritable bowel syndrome: systematic review and meta-analysis.
      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.
      • Fukudo S.
      • Kinoshita Y.
      • Okumura T.
      • et al.
      Ramosetron reduces symptoms of irritable bowel syndrome with diarrhea and improves quality of life in women.
      • Matsueda K.
      • Harasawa S.
      • Hongo M.
      • Hiwatashi N.
      • Sasaki D.
      A randomized, double-blind, placebo-controlled clinical trial of the effectiveness of the novel serotonin type 3 receptor antagonist ramosetron in both male and female Japanese patients with diarrhea-predominant irritable bowel syndrome.
      In a crossover clinical trial
      • Garsed K.
      • Chernova J.
      • Hastings M.
      • et al.
      A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea.
      in 122 patients with IBS-D, ondansetron had significant effects on stool consistency, urgency, frequency, and bloating but no significant beneficial effect on pain.

       Safety

      As a drug class, 5-HT3 antagonists can cause constipation, but it is usually manageable by adjusting the dose. Alosetron, unlike other drugs in this class, is associated with ischemic colitis (∼1:800 treated patients).
      • Chang L.
      • Chey W.D.
      • Harris L.
      • Olden K.
      • Surawicz C.
      • Schoenfeld P.
      Incidence of ischemic colitis and serious complications of constipation among patients using alosetron: systematic review of clinical trials and post-surveillance marketing data.

       Bile Acid Sequestrants

      Approximately 25% of patients with IBS-D have evidence of bile acid malabsorption.
      • Aziz I.
      • Mumtaz S.
      • Bholah H.
      • Chowdhury F.U.
      • Sanders D.S.
      • Ford A.C.
      High prevalence of idiopathic bile acid diarrhea among patients with diarrhea-predominant irritable bowel syndrome based on Rome III criteria.
      • Valentin N.
      • Camilleri M.
      • Altayar O.
      • et al.
      Biomarkers for bile acid diarrhoea in functional bowel disorder with diarrhoea: a systematic review and meta-analysis.
      Although no RCTs of bile acid sequestrants in IBS have been reported, a Mayo Clinic open-label trial of colesevelam, 1875 mg twice daily for 10 days,
      • Camilleri M.
      • Acosta A.
      • Busciglio I.
      • et al.
      Effect of colesevelam on faecal bile acids and bowel functions in diarrhoea-predominant irritable bowel syndrome.
      in patients with IBS-D and increased fecal bile acid excretion documented reduction in stool consistency and frequency. Another open-label study of colestipol, 1 g twice a day for 8 weeks,
      • Bajor A.
      • Törnblom H.
      • Rudling M.
      • Ung K.A.
      • Simrén M.
      Increased colonic bile acid exposure: a relevant factor for symptoms and treatment in IBS.
      found improvements in IBS-SSS, stool frequency, and adequate relief of symptoms in patients with IBS-D and bile acid malabsorption (a selenium Se 75 homocholic acid taurine retention <20%).

       Antibiotics

      Rifaximin is a nonabsorbable antibiotic that has improved global symptoms and bloating in IBS in 2 phase 3 RCTs.
      • Pimentel M.
      • Lembo A.
      • Chey W.D.
      • et al.
      TARGET Study Group
      Rifaximin therapy for patients with irritable bowel syndrome without constipation.
      • Pimentel M.
      • Chow E.J.
      • Lin H.C.
      Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome.
      These trials included more than 1200 patients with nonconstipated IBS. Rifaximin, 550 mg 3 times a day 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 posttreatment. The NNT of 10 was confirmed for global symptoms and bloating in a meta-analysis of 5 RCTs of rifaximin
      • Menees S.B.
      • Maneerattannaporn M.
      • Kim H.M.
      • Chey W.D.
      The efficacy and safety of rifaximin for the irritable bowel syndrome: a systematic review and meta-analysis.
      including 1803 patients. However, stool consistency, frequency of bowel movements, and urgency were not improved.
      With repeated courses of rifaximin separated by 10 weeks, 550 mg 3 times a day for 2 weeks in each course, there was significant benefit for urgency, bloating, and combined abdominal pain and stool consistency with each of 2 repeated treatment courses compared with placebo. Rifaximin is approved for patients with IBS-D, with up to 2 repeated treatments in case of symptom recurrence. It is worth noting that rifaximin
      • Acosta A.
      • Camilleri M.
      • Shin A.
      • et al.
      Effects of rifaximin on transit, permeability, fecal microbiome, and organic acid excretion in irritable bowel syndrome: a randomzed, double-blinded trial.
      accelerated ascending colon emptying and overall colonic transit at 48 hours in patients with 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; conversely, it may explain the reported improvement in IBS-C (bloating, constipation, and straining) with combined neomycin plus rifaximin compared with neomycin with placebo.
      • Pimentel M.
      • Chang C.
      • Chua K.S.
      • et al.
      Antibiotic treatment of constipation-predominant irritable bowel syndrome.
      Importantly, there is no evidence of adverse effects with rifaximin compared with placebo and no increased risk of Clostridium difficile.

      Medications for Constipation

       Intestinal Secretagogues

      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.
      • Camilleri M.
      • Bharucha A.E.
      • Ueno R.
      • et al.
      Effect of a selective chloride channel activator, lubiprostone, on gastrointestinal transit, gastric sensory, and motor functions in healthy volunteers.
      The drug is approved at a dose of 8 μg twice daily for women with IBS-C
      • Drossman D.A.
      • Chey W.D.
      • Johanson J.F.
      • et al.
      Clinical trial: lubiprostone in patients with constipation-associated irritable bowel syndrome—results of two randomized, placebo-controlled studies.
      and 24 μg twice daily for men and women with chronic constipation.
      • Johanson J.F.
      • Morton D.
      • Geenen J.
      • Ueno R.
      Multicenter, 4-week, double-blind, randomized, placebo-controlled trial of lubiprostone, a locally-acting type-2 chloride channel activator, in patients with chronic constipation.
      • Fukudo S.
      • Hongo M.
      • Kaneko H.
      • Takano M.
      • Ueno R.
      Lubiprostone increases spontaneous bowel movement frequency and quality of life in patients with chronic idiopathic constipation.
      There are general improvements in abdominal pain scores that parallel the improved straining and stool consistency. Nausea is the most common adverse effect, experienced by 8% of patients, but it is generally relatively mild and self-limited.
      • Cryer B.
      • Drossman D.A.
      • Chey W.D.
      • Webster L.
      • Habibi S.
      • Wang M.
      Analysis of nausea in clinical studies of lubiprostone for the treatment of constipation disorders.
      Linaclotide is a minimally absorbed guanylate cyclase C receptor agonist that causes secretion of chloride and bicarbonate into the intestinal lumen via the cystic fibrosis transmembrane conductance regulator. This results in parallel sodium and water secretion. The activation of cystic fibrosis transmembrane conductance regulator results from increase in intracellular cyclic guanosine monophosphate, which has also been found to affect sensory afferent neurons, leading to inhibition of pain. In clinical trials conducted in patients with IBS-C (as well as others with chronic constipation), linaclotide relieved constipation and significantly improved abdominal discomfort and bloating.
      • Lembo A.J.
      • Schneier H.A.
      • Shiff S.J.
      • et al.
      Two randomized trials of linaclotide for chronic constipation.
      • Chey W.D.
      • Lembo A.J.
      • Lavins B.J.
      • et al.
      Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety.
      • Rao S.
      • Lembo A.J.
      • Shiff S.J.
      • et al.
      A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation.
      Three dose levels are approved: 72, 145, and 290 μg per day: 72-μg and 145-μg doses are for chronic idiopathic constipation, and the 290-μg dose is for IBS-C (in men and women). The 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 analogue of uroguanylin, which is an endogenous guanylate cyclase C receptor agonist
      • Shailubhai K.
      • Barrow L.
      • Talluto C.
      • et al.
      Plecanatide, a guanylate cyclase C agonist, improves bowel habits and symptoms associated with chronic constipation in a phase IIa clinical study.
      released into the intestine from goblet cells. Plecanatide, 3 or 6 mg per day, is also efficacious in treating chronic idiopathic constipation
      • Miner Jr., P.B.
      • Koltun W.D.
      • Wiener G.J.
      • et al.
      A randomized phase III clinical trial of plecanatide, a uroguanylin analog, in patients with chronic idiopathic constipation.
      and IBS-C,
      • Fogel R.
      • Dorn S.D.
      • Krause R.
      • et al.
      Efficacy and safety of plecanatide in patients with irritable bowel syndrome with constipation: results from 2 randomized, double-blind, placebo-controlled clinical trials.
      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 documented efficacy in patients with IBS-C. Tegaserod (available in come countries but not in the United States) 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.
      • Layer P.
      • Keller J.
      • Loeffler H.
      • Kreiss A.
      Tegaserod in the treatment of irritable bowel syndrome (IBS) with constipation as the prime symptom.
      Repeated treatments with tegaserod are effective, and tegaserod is associated with improvements in quality of life and work productivity.
      • Layer P.
      • Keller J.
      • Loeffler H.
      • Kreiss A.
      Tegaserod in the treatment of irritable bowel syndrome (IBS) with constipation as the prime symptom.
      Adverse effects associated with tegaserod are diarrhea, cramping, and rare cardiovascular events, with the lattermost attributed to off-target effects on other 5-HT receptors (eg, 5-HT2A and 5-HT2B antagonist). However, in a matched cohort study conducted within a large US health insurance database involving 52,229 patients, there was no increased risk of cardiovascular ischemic events.
      • Loughlin J.
      • Quinn S.
      • Rivero E.
      • et al.
      Tegaserod and the risk of cardiovascular ischemic events: an observational cohort study.
      Mosapride (approved in some countries but not in the United States) improved symptoms in 10 patients with IBS-C in a pilot study.
      • Nakamura M.
      • Ohmiya N.
      • Miyahara R.
      • et al.
      Are symptomatic changes in irritable bowel syndrome correlated with the capsule endoscopy transit time? a pilot study using the 5-HT4 receptor agonist mosapride.
      However, a 12-month study in a larger cohort of 69 patients found no significant improvements in overall or specific IBS symptoms (pain, bloating, stool frequency or consistency) or quality of life with mosapride over placebo.
      • Mansour N.M.
      • Ghaith O.
      • El-Halabi M.
      • Sharara A.I.
      A prospective randomized trial of mosapride vs. placebo in constipation-predominant irritable bowel syndrome.

       Cognitive Behavioral Therapy and Hypnotherapy

      Where available, cognitive behavioral therapy and hypnotherapy may be used in the management of patients with IBS. Recent systematic reviews have found that psychological interventions are efficacious, including long-term benefits, and that the gains are not dependent on the number of sessions. Indeed, cognitive behavioral therapy and hypnosis appear efficacious in minimal-contact formats as well as various technologies (eg, Internet, telephone, smartphone apps), self-help interventions, and engaging trained nonprofessional mental health professionals to deliver interventions.
      • Radziwon C.D.
      • Lackner J.M.
      Cognitive behavioral therapy for IBS: how useful, how often, and how does it work?.

      Conclusion

      Currently, the treatment of IBS remains focused on treating the patient's most troublesome symptom. These treatments are quite efficacious for bowel dysfunction, although 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 lattermost not discussed here) should be considered to relieve symptoms in a holistic approach to the patient's symptoms. Pharmacotherapies have not been proved 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.

      Acknowledgments

      The funding organization had no role in the design and execution of the study, in the collection, analyses, and interpretation of the data, or in the preparation, review, or approval of the submitted manuscript.

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