Irritable Bowel Syndrome (IBS)

Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder characterized by abdominal pain and altered bowel habit in the absence of a specific and unique organic pathology. Osler coined the term mucous colitis in 1892 when he wrote of a disorder of mucorrhea and abdominal colic with a high incidence in patients with coincident psychopathology. Since then, the syndrome has been referred to by sundry terms, including spastic colon, irritable colon, and nervous colon.

In the past, irritable bowel syndrome has been considered a diagnosis of exclusion; however, it is no longer considered a diagnosis of exclusion, but it does have a broad differential diagnosis.[7] No specific motility or structural correlates have been consistently demonstrated; however, experts suggest that the use of available guidelines can minimize testing and aid in the diagnosis.

Traditional theories regarding the pathophysiology of irritable bowel syndrome (IBS) may be visualized as a three-part complex of altered gastrointestinal (GI) motility, visceral hyperalgesia, and psychopathology.[8] More recently, it is believed that components of the gut microbiota potentially influence brain morphology and function, behavior, and cognition, which expands the paradigm of the gut-brain axis.[9] A unifying mechanism is still unproven.

Altered GI motility

Altered GI motility includes distinct aberrations in the small and large bowel motility.

The myoelectric activity of the colon is composed of background slow waves with superimposed spike potentials. Colonic dysmotility in irritable bowel syndrome manifests as variations in slow-wave frequency and a blunted, late-peaking, postprandial response of spike potentials. Patients who are prone to diarrhea demonstrate these alterations to a greater degree than patients who are prone to constipation.

Small bowel dysmotility manifests in delayed meal transit in patients prone to constipation and in accelerated meal transit in patients prone to diarrhea. In addition, patients exhibit shorter intervals between migratory motor complexes (the predominant interdigestive small bowel motor patterns).

Current theories integrate these widespread motility aberrations and hypothesize a generalized smooth muscle hyperresponsiveness. They describe increased urinary symptoms, including frequency, urgency, nocturia, and hyperresponsiveness to methacholine challenge.

Visceral hyperalgesia

Visceral hyperalgesia is the second part of the traditional three-part complex that characterizes irritable bowel syndrome.[10]

Enhanced perception of normal motility and visceral pain characterizes irritable bowel syndrome. Rectosigmoid and small bowel balloon inflation produces pain at lower volumes in patients than in controls. Notably, hypersensitivity appears with rapid but not with gradual distention.

Patients who are affected describe widened dermatomal distributions of referred pain. Sensitization of the intestinal afferent nociceptive pathways that synapse in the dorsal horn of the spinal cord provides a unifying mechanism.

Psychopathology

Psychopathology is the third aspect. Associations between psychiatric disturbances and irritable bowel syndrome pathogenesis are not clearly defined.

Patients with psychological disturbances relate more frequent and debilitating illness than control populations. Patients who seek medical care have a higher incidence of panic disorder, major depression, anxiety disorder, and hypochondriasis than control populations. A study has suggested that patients with irritable bowel syndrome may have suicidal ideation and/or suicide attempts strictly as a result of their bowel symptoms.[11] Clinical alertness to depression and hopelessness is mandatory. This is underscored by another study that revealed that patient complaints that relate to functional bowel disorders may be trivialized.

An Axis I disorder coincides with the onset of GI symptoms in as many as 77% of patients. A higher prevalence of physical and sexual abuse has been demonstrated in patients with irritable bowel syndrome. Whether psychopathology incites the development of irritable bowel syndrome or vice versa remains unclear.

Microscopic inflammation

Microscopic inflammation has been documented in some patients.[1] This concept is groundbreaking in that irritable bowel syndrome had previously been considered to have no demonstrable pathologic alterations.

Both colonic inflammation and small bowel inflammation have been discovered in a subset of patients with irritable bowel syndrome, as well as in patients with the onset of irritable bowel syndrome after an episode of infectious enteritis (postinfectious irritable bowel syndrome). Risk factors for developing postinfectious irritable bowel syndrome include longer duration of illness, the type of pathogen involved, smoking, female gender, an absence of vomiting during the infectious illness, and young age.[12]

Laparoscopic full-thickness jejunal biopsy samples revealed infiltration of lymphocytes into the myenteric plexus and intraepithelial lymphocytes in a subset of patients in one study.[13] Neuronal degeneration of the myenteric plexus was also present in some patients.

Patients with postinfectious irritable bowel syndrome may have increased numbers of colonic mucosal lymphocytes and enteroendocrine cells. Enteroendocrine cells in postinfectious irritable bowel syndrome appear to secrete high levels of serotonin, increasing colonic secretion and possibly leading to diarrhea.

Alterations in the intestinal biome

Small bowel bacterial overgrowth has been heralded as a unifying mechanism for the symptoms of bloating and distention, common to patients with irritable bowel syndrome. This has led to proposed treatments with probiotics and antibiotics.

The fecal microflora also differs among patients with irritable bowel syndrome versus controls. A sophisticated molecular analysis suggested an alteration in the patterns and the contents of gut bacteria.[14]

The causes of irritable bowel syndrome remain poorly defined, but they are being avidly researched.

Postulated etiologies of irritable bowel syndrome

Abnormal transit profiles and an enhanced perception of normal motility may exist. Up to one third of patients with irritable bowel syndrome may have altered colonic transit. Delayed colonic motility may be more common in patients with constipation-predominant irritable bowel syndrome than in healthy controls. Similarly, accelerated colonic transit may be more common in patients with diarrhea-predominant disease than in healthy controls.[15] Local histamine sensitization of the afferent neurons causing earlier depolarization may occur.

Causes related to enteric infection

Colonic muscle hyperreactivity and neural and immunologic alterations of the colon and small bowel may persist after gastroenteritis. Psychological comorbidity independently predisposes the patient to the development of postinfectious irritable bowel syndrome. Psychological illness may create a proinflammatory cytokine milieu, leading to irritable bowel syndrome through an undefined mechanism after acute infection.

Infection with Giardia lamblia has been shown to lead to an increased prevalence of irritable bowel syndrome, as well as chronic fatigue syndrome. In a historic cohort study of patients with G lamblia infection as detected by stool cysts, the prevalence of irritable bowel syndrome was 46.1% for as long as 3 years after exposure, compared with 14% in controls.[16]

Central neurohormonal mechanisms

Abnormal glutamate activation of N- methyl-D- aspartate (NMDA) receptors, activation of nitric oxide synthetase, activation of neurokinin receptors, and the induction of calcitonin gene–related peptide have been observed.

The limbic system mediation of emotion and autonomic response enhances bowel motility and reduces gastric motility to a greater degree in patients who are affected than in controls. Limbic system abnormalities, as demonstrated by positron emission tomography, have been described in patients with irritable bowel syndrome and in those with major depression.

The hypothalamic-pituitary axis may be intimately involved in the pathogenesis of IBS. Motility disturbances correspond to an increase in the hypothalamic corticotropin-releasing factor (CRF) production in response to stress. CRF antagonists eliminate these changes.

Additional etiologic factors

Intestinal permeability

Intestinal permeability appears to be increased, especially in diarrhea-predominant irritable bowel syndrome.[17]

Alterations in the intestinal biome

As discussed in Pathophysiology, Pimentel and colleagues have proposed that small bowel bacterial overgrowth provides a unifying mechanism for the common symptoms of bloating and gaseous distention in patients with irritable bowel syndrome.[18]

There is a relationship between the organisms that live in the intestine and the immune system, and this relationship is not yet fully understood.[17, 19]

Dietary intolerance

Bloating and distention may also occur from intolerance to dietary fats. Reflex-mediated small bowel gas clearance is more impaired by the ingestion of lipids in patients with irritable bowel syndrome than in patients without the disorder.

Studies of elimination and challenge diets have suggested that poorly absorbed short-chain carbohydrates, in the form of fructose and fructans, may create symptoms among adult patients with irritable bowel syndrome, as measured by a visual analogue scale.[20] Fructans have also been found to exacerbate the symptoms (abdominal pain, bloating, hydrogen production) in a subset of children with irritable bowel syndrome, but fructan sensitivity could not be identified on the basis of baseline gastrointestinal symptoms, dietary intake, psychosocial factors, or gas production.[21]

Evidence exists showing an association between functional variants in the sucrase-isomaltase (SI) gene and an increased risk of irritable bowel syndrome. In one study, investigators sequenced SI exons in seven familial cases, as well as screened for four congenital sucrase-isomaltase deficiency (CSID) mutations and a common SI coding polymorphism in a multicenter cohort comprised of 1887 patients and control subjects, and found that individuals affected by the SI mutations that code for defective or enzymatic activity in disaccharides had a predisposition to irritable bowel syndrome.[22] Similarly, another multinational genotype study of 2207 patients indicates that there is an increased prevalence of rare sucrase-isomaltase pathogenic variants in those affected by irritable bowel syndrome.[23]

Research suggests that neuronal degeneration and myenteric plexus lymphocytosis may exist in the proximal jejunum. Additionally, colonic lymphocytosis and enteroendocrine cell hyperplasia have been demonstrated in some patients.

Population-based studies estimate the prevalence of irritable bowel syndrome (IBS) at 10-20%[24] and the incidence of irritable bowel syndrome at 1-2% per year. However, when a 2016 population-based study compared the prevalence of irritable bowel syndrome with the Rome IV criteria versus the Rome III criteria in the United States, Canada, and the United Kingdom, investigators reported a nearly 50% reduction in its prevalence in these countries—potentially attributable to removing "discomfort" from the definition.[25]

Of people with irritable bowel syndrome, approximately 10-20% seek medical care. An estimated 20-50% of gastroenterology referrals relate to this symptom complex. The incidence is markedly different among countries.

American and European cultures demonstrate similar frequencies of irritable bowel syndrome across racial and ethnic lines. However, within the United States, survey questionnaires indicate a lower prevalence of irritable bowel syndrome in Hispanics in Texas and Asians in California. Populations of Asia and Africa may have a lower prevalence of irritable bowel syndrome. The role of different cultural influences and varying health care–seeking behaviors is unclear.

Adolescent and young adult women are most commonly affected.[9] In Western countries, women are 2-3 times more likely to develop irritable bowel syndrome than men, although males represent 70-80% of patients with irritable bowel syndrome in the Indian subcontinent. Women seek health care more often, but the irritable bowel syndrome–specific influence of this occurrence remains unknown. Other factors, such as a probably greater incidence of abuse in women, may confound the interpretation of this statistic.

Patients often retrospectively note the onset of abdominal pain and altered bowel habit in childhood. Approximately 50% of people with irritable bowel syndrome report symptoms beginning before age 35 years. The development of symptoms in people older than 40 years does not exclude irritable bowel syndrome but should prompt a closer search for an underlying organic etiology.

Irritable bowel syndrome is a chronic relapsing disorder characterized by recurrent symptoms of variable severity; however, life expectancy remains similar to that of the general population. Clinicians must be forthcoming with patients because knowledge of the condition may help allay undue fears as their disease waxes and wanes. Irritable bowel syndrome (IBS) does not increase mortality, or the risk of inflammatory bowel disease or cancer.

Patients with irritable bowel syndrome may carry an increased risk of ectopic pregnancy and miscarriage, but not stillbirth. The reasons for this are unknown. Whether the risk increases because of IBS itself, or because of another factor such as medications used for irritable bowel syndrome, is unknown.[26]

The principal associated physical morbidities of irritable bowel syndrome include abdominal pain and lifestyle modifications secondary to altered bowel habits. Work absenteeism resulting in lost wages is more frequent in patients with irritable bowel syndrome.

There appears to be an increased prevalence of comorbid anxiety and depression among patients with IBS, and these are associated with lower socioeconomic status and lower average per capita income.[27] Clinicians therefore should consider a biopsychosocial model of illness in these patients.

Patient education remains the cornerstone of successful treatment of irritable bowel syndrome. Teach the patient to identify stressors and to develop avoidance techniques. Many patients successfully manage their symptoms with attention to dietary triggers.

For patient education resources, see Digestive Disorders Center, as well as Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), and Chronic Pain.

Clinicians may also wish to refer patients to the following short video, which provides a simplified but clear and concise overview about what irritable bowel syndrome is, and its epidemiology, risk factors, and management options, as well as a brief explanation of the difference between irritable bowel syndrome and inflammatory bowel disease.

History

A meticulous history is the key to establish a diagnosis of irritable bowel syndrome, which comprises a range of manifestations and aggravation factors.[9] Indeed, there is a great deal of interindividual symptomatic variability among affected patients, which a detailed symptomatic history may aid in identifying distinct symptom subgroups and thus guide symptom management.[28] The Rome criteria provide the construct upon which questions are based (see Diagnostic Considerations).

Altered bowel habits

Constipation results in complaints of hard stools of narrow caliber, painful or infrequent defecation, and intractability to laxatives. Diarrhea usually is described as small volumes of loose stool, with evacuation preceded by urgency or frequent defecation. Postprandial urgency is common, as is alternation between constipation and diarrhea. Characteristically, one feature predominates in a single patient, but significant variability exists among patients.

Abdominal pain

Descriptions are protean. Pain frequently is diffuse without radiation. Common sites of pain include the lower abdomen, specifically the left lower quadrant. Acute episodes of sharp pain are often superimposed on a more constant dull ache. Meals may precipitate pain, and defecation commonly improves pain. Defecation may not fully relieve pain, however.

Pain from presumed gas pockets in the splenic flexure may masquerade as anterior chest pain or left upper quadrant abdominal pain. This splenic flexure syndrome is demonstrable by balloon inflation in the splenic flexure and should be considered in the differential of chest or left upper quadrant abdominal pain.

Abdominal bloating/distention

Patients frequently report increased amounts of bloating and gas. Quantitative measurements fail to support this claim. People with irritable bowel syndrome may manifest increasing abdominal circumference throughout the day, as assessed by computed tomography (CT) scan. They may also demonstrate intolerance to otherwise normal amounts of abdominal distention.

Additional symptoms consistent with irritable bowel syndrome

Clear or white mucorrhea of a noninflammatory etiology is commonly reported. Epidemiologic associations with dyspepsia, heartburn, nausea, vomiting, sexual dysfunction (including dyspareunia and poor libido), and urinary frequency and urgency have been noted. Symptoms may worsen in the perimenstrual period, and fibromyalgia is a common comorbidity. Stressor-related symptoms may be revealed with careful questioning (emphasize avoidance of stressors).

Symptoms inconsistent with irritable bowel syndrome

Symptoms not consistent with irritable bowel syndrome should alert the clinician to the possibility of an organic pathology. Inconsistent symptoms include the following:

• Onset in middle or older age

• Acute symptoms (irritable bowel syndrome is defined by chronicity)

• Progressive symptoms

• Nocturnal symptoms

• Anorexia or weight loss

• Fever

• Rectal bleeding

• Painless diarrhea

• Steatorrhea

• Gluten intolerance

Physical examination

The patient with irritable bowel syndrome has an overall healthy appearance but may be tense or anxious. The patient may present with sigmoid tenderness or a palpable sigmoid cord.

A consensus panel created and continually updates the Rome diagnostic criteria to provide a standardized diagnosis for research and clinical practice. The Rome IV criteria for the diagnosis of irritable bowel syndrome (IBS) were released in 2016 and require that patients have had recurrent abdominal pain on average at least 1 day per week during the previous 3 months that is associated with two or more of the following[2] :

• Related to defecation (may be increased or unchanged by defecation)

• Associated with a change in stool frequency

• Associated with a change in stool form or appearance

Unlike the Rome III criteria, the Rome IV criteria only require abdominal pain in defining this condition; "discomfort" is no longer included owing to its ambiguity and different meanings across cultures and languages.[2]

Supporting symptoms include the following:

• Altered stool frequency

• Altered stool form

• Altered stool passage (straining and/or urgency)

• Mucorrhea

• Abdominal bloating or subjective distention

Four bowel patterns may be seen with irritable bowel syndrome, and these remain unchanged in the Rome IV classification.[2] These patterns include the following:

• IBS-D (diarrhea predominant)

• IBS-C (constipation predominant)

• IBS-M (mixed diarrhea and constipation)

• IBS-U (unclassified; the symptoms cannot be categorized into one of the above three subtypes)

The usefulness of these subtypes is debatable. Notably, within 1 year, 75% of patients change subtypes, and 29% switch between constipation-predominant IBS and diarrhea-predominant IBS. The Rome IV criteria differ from the Rome III criteria in basing bowel habits on stool forms solely during days with abnormal bowel movements rather than on the total number of bowel movements.[2]

A comprehensive history, physical examination, and tailored laboratory and radiographic studies can establish a diagnosis of irritable bowel syndrome in most patients. The specificity of the Rome III criteria may be improved by including information about nocturnal stools, somatization, and affective disorders on the basis of the clinical history as well as including hemoglobin and C-reactive protein levels with other diagnostic studies.[30] Routine serologic or genetic testing is not indicated in patients with irritable bowel syndrome (IBS) in all US populations as it appears that celiac disease is uncommon in IBS in this country.[31]

The 2009 American College of Gastroenterologists (ACG) evidence-based position statement on the management of IBS does not recommend laboratory testing or diagnostic imaging in patients younger than 50 years with typical IBS symptoms and without “alarm features”. Alarm features include the following symptoms and history[3] :

• Weight loss

• Iron deficiency anemia

• Family history of certain organic GI illnesses (eg, inflammatory bowel disease, celiac sprue, colorectal cancer)

Although rectal bleeding and nocturnal symptoms have also been considered alarm features, they are not specific for organic disease. Patients with IBS-D or IBS-M should have serologic testing for celiac sprue. Patients aged 50 years and older should have more extensive testing, including a colonoscopy.[3]

Blood studies

A complete blood cell (CBC) count with differential to screen for anemia, inflammation, and infection is indicated. A comprehensive metabolic panel to evaluate for metabolic disorders and to rule out dehydration/electrolyte abnormalities in patients with diarrhea is also indicated.

Stool examinations

Microbiologic studies to consider include the following stool examinations:

• Ova and parasites (consider obtaining specimens for Giardia antigen as well)

• Enteric pathogens

• Leukocytes

• Clostridium difficile toxin

Hydrogen breath testing to exclude bacterial overgrowth may be considered in patients with diarrhea to screen for lactose and/or fructose intolerance. Tissue transglutaminase antibody testing and small bowel biopsy are used especially in diarrhea-predominant irritable bowel syndrome to diagnose celiac disease.

Thyroid function tests are used to screen for hyperthyroidism or hypothyroidism. Serum calcium testing is used to screen for hyperparathyroidism.

Erythrocyte sedimentation rate and C-reactive protein measurement are nonspecific screening tests for inflammation.

Gallbladder ultrasonography should be considered if the patient has recurrent dyspepsia or characteristic postprandial pain.

Abdominal computed tomography (CT) scanning is appropriate to screen for tumors, obstruction, and pancreatic disease if these are diagnostic possibilities.

CT and magnetic resonance (MR) enterography or wireless capsule endoscopy are employed if red flags exist to suggest enteritis (small bowel inflammation) or a tumor.

Colonoscopy is appropriate if alarm symptoms are present and in patients who otherwise qualify for screening colonoscopy.

Employ a lactose-free diet for 1 week in conjunction with lactase supplements. Improvement incriminates lactose intolerance, although the patient's clinical history and response to a trial may be unreliable. Therefore, some gastroenterologists recommend a formal hydrogen breath test. Fructose intolerance must also be considered.

Breath testing may also be used to evaluate for small intestinal bacterial overgrowth, as formal jejunal aspiration is rarely performed anymore.

Other dietary intolerances include FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols), gluten, and fructose. Low FODMAP diets can be helpful in this situation, though may be found very restrictive.

Anal manometry may reveal a spastic response to rectal distention or other problems. For many patients with irritable bowel syndrome, endoscopy appropriately includes flexible sigmoidoscopy to assess for inflammation or distal obstruction.

Esophagogastroduodenoscopy with possible biopsy is indicated in patients with persistent dyspepsia, if weight loss or symptoms suggest malabsorption, or if celiac disease is a concern. Colonoscopy is indicated for patients with warning signs, such as bleeding; anemia; chronic diarrhea; older age; history of colon polyps; cancer in the patient or first-degree relatives; or constitutional symptoms, such as weight loss or anorexia. A screening colonoscopy should be performed according to published guidelines.

Management of irritable bowel syndrome consists primarily of providing psychological support and recommending dietary measures. Pharmacologic treatment is adjunctive and should be directed at symptoms, such as modulation of persistent visceral hyperalgesia.[10]

The 2009 American College of Gastroenterologists (ACG) position statement recommends addressing nongastrointestinal symptoms and comorbidities to improve health-related quality of life as well as to reduce symptom severity. Evidence considered in the position statement was insufficient to recommend exclusion diets or food allergy testing.[3]

The 2014 ACG monograph on the management of irritable bowel syndrome and chronic idiopathic constipation found insufficient evidence to recommend prebiotics or synbiotics, or loperamide, in irritable bowel syndrome, and no evidence that polyethylene glycol improved overall symptoms and pain in affected patients.[32] There was high quality of evidence to support the use of antidepressants as a class, and moderate quality of evidence in favor of fiber and psyllium, for overall symptomatic relief in irritable bowel syndrome. Strong recommendations were reported for linaclotide and lubiprostone each being superior to placebo in treating the constipation-predominant disease subtype.[32]

Successful management relies on a strong patient-provider relationship. Reassure the patient that the absence of an organic pathology indicates a normal life expectancy. Emphasize the expected chronicity of the symptoms with periodic exacerbations. Teach the patient to identify stressors and to use avoidance techniques.

Frequent visits with the clinician enhance the patient-provider relationship, especially in patients who were recently diagnosed with irritable bowel syndrome. Visits can become less frequent as patients are educated and reassured.

Fiber supplementation may improve symptoms of constipation and diarrhea. Individualize the treatment because a few patients experience exacerbated bloating and distention with high-fiber diets. Polycarbophil compounds (eg, Citrucel, FiberCon) may produce less flatulence than psyllium compounds (eg, Metamucil).

The data regarding the effectiveness of fiber are controversial because 40-70% of patients improve with placebo. A Cochrane systematic review found no benefit of fiber/bulking agents on irritable bowel syndrome symptoms or global assessment.[33]

Judicious water intake is recommended in patients who predominantly experience constipation.

Caffeine avoidance may limit anxiety and symptom exacerbation. Legume avoidance may decrease abdominal bloating. Lactose and/or fructose should be limited or avoided in patients with these contributing disorders. Take care to supplement calcium in patients limiting their lactose intake.

Gluten intolerance has been associated with irritable bowel syndrome. In a small but important study, patients with irritable bowel syndrome who were well-controlled on a gluten-free diet were rechallenged in a double-blind fashion.[34] Approximately two thirds of these patients had poor symptom control with rechallenge. As with many irritable bowel syndrome studies, the placebo response was high (40%). Notably, neither intestinal inflammation nor permeability was different among the groups, and no difference in the positivity rate for celiac disease–related HLA haplotypes or antibody markers was noted. Volta et al evaluated the current evidence and suggest that patients with gluten/wheat sensitivity may be a subset of those with irritable bowel syndrome.[35]

Many patients are interested in dietary manipulation to decrease their symptoms. Several different diets have been proposed.[36] Diets low in FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) hold particular interest in reducing symptoms of irritable bowel syndrome.[37] Investigators found 10 of 54 bacterial markers differed significantly between 32 patients who responded to FODMAPs and 29 who did not; using their findings, they developed a response index that assesses gut microbial composition and has the potential to identify patients who are more likely to respond to a dietary FODMAP restriction.[38] In a preclinical, murine study, a low-FODMAP diet did not appear to exacerbate nor mitigate inflammation on a postinflammatory model of IBS.[39] However, a retrospective study (2013-2016) comprising data from 164 Irish patients with IBS found that a low-FODMAP diet provided significant all-symptomatic improvement at 3-, 6-, and 12-month follow-up.[40]

Probiotics are very interesting for treating symptoms, but it is unclear for which patients probiotics are helpful, and in what form, dose, combination, or strain.[41, 42, 43] A meta-analysis concluded that Bifidobacterium infantis may help alleviate some symptoms of irritable bowel syndrome.[44]

A systematic review and meta-analysis of 13 articles that assessed the differential expression of intestinal microbiota in 360 patients with this condition compared to 268 healthy controls found downregulation of bacterial colonization of Lactobacillus, Bifidobacterium, and Faecalibacterium prausnitzii in patients with irritable bowel syndrome.[45] Those with the diarrhea-predominant subtype had significantly different expression of Lactobacillus and Bifidobacterium. A different systematic review and meta-analysis evaluated 43 articles on probiotics and showed that probiotics helped relieve pain, bloating, and gas[46] ; however, again, it remains unknown which probiotic is the best.

A European multicenter pilot study that evaluated the effectiveness of palmitoylethanolamide/polydatin in 54 patients with irritable bowel syndrome compared to 12 healthy controls did not show any significant changes in modifying the biologic profile of the condition (eg, mast cell count); however, this combination significantly improved the severity of abdominal pain when compared to placebo.[47]

In a study of 998 adolescent Iranian girls, investigators noted a 16.9% prevalence of irritable bowel syndrome and identified several factors that appeared to be associated with an increased risk of this condition, including intrameal fluid consumption, consumption of spicy and fried food, insufficient chewing, and greater loss of teeth (≥5 teeth).[48]

Consider psychiatric referral. Previous evidence supported improvement in gastrointestinal (GI) symptoms with successful treatment of psychiatric comorbidities, but studies by Zijdenbos et al and Ford et al indicate that caution should be used when interpreting such data.[49, 50]

In a meta-analysis by Zijdenbos et al of 25 randomized trials consisting of single psychological interventions with usual care or mock intervention in patients older than 16 years, the authors found that although cognitive-behavioral therapy and interpersonal psychotherapy were effective immediately after treatment completion, there was no convincing evidence for sustained benefits with any treatment modality. Thus, Zijdenbos et al recommended that future research should focus on current irritable bowel syndrome treatment guidelines and their long-term effects.[49]

Ford et al reached similar conclusions regarding the use of psychological interventions in irritable bowel syndrome. The authors concluded that antidepressants are effective in the treatment of irritable bowel syndrome, but although the available data suggest that psychological therapies may be of comparable efficacy, there is less high-quality evidence for the routine use of psychological therapies in patients with IBS. They performed a systematic review and meta-analysis of randomized controlled trials in adults with IBS; however, their selection criteria included trials comparing antidepressants with placebo as well as those comparing psychological therapies with control therapy or usual care. The investigators noted that the quality of studies were generally good for those involving antidepressants but poor for those involving psychological therapy.[50]

A Cochrane systematic review determined that antidepressants improved both irritable bowel symptoms and global assessment scores compared with placebo. Selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants were both shown to be effective in subgroup analyses.[33]

The 2009 American College of Gastroenterologists (ACG) position statement concluded that psychological interventions, cognitive behavioral therapy, dynamic psychotherapy, and hypnotherapy, are more effective than placebo. Relaxation therapy was no more effective than usual care. In agreement with the above analysis, study quality was described as low.[3]

More recent studies suggest targeting the mediating psychological process involved in patients with irritable bowel syndrome, such as illness perceptions, maladaptive coping, and visceral sensitivity.[24]

Guidelines for the management of patients with irritable bowel syndrome (IBS) were published in July 2021 by the British Society of Gastroenterology (BSG) in Gut.[51] These are some of the highlights.

Fiber and Dietary Therapies

Food elimination diets based on immunoglobulin G (IgG) antibodies are not recommended, nor are gluten-free diets.

Soluble fiber is effective for global symptoms and abdominal pain, but insoluble fiber should be avoided.

A diet low in fermentable oligosaccharides, disaccharides, and monosaccharides and polyols is effective second-line therapy for global symptoms and abdominal pain.

Probiotics

Probiotics may be effective for global symptoms and abdominal pain, but no specific species or strain can be recommended.

First-Line Drugs for IBS

Loperamide may be effective for diarrhea. Peppermint oil and certain antispasmodics may be effective for global symptoms and abdominal pain. Polyethylene glycol may be effective for constipation.

Gut-Brain Neuromodulators

Tricyclic antidepressants (TCAs) used as gut-brain neuromodulators are effective second-line treatment for global symptoms and abdominal pain. Selective serotonin reuptake inhibitors (SSRIs) used as gut-brain neuromodulators may be effective second-line treatment for global symptoms.

Second-Line Drugs in Secondary Care

Eluxadoline, 5-hydroxytryptamine 3 (5-HT3) receptor antagonists, and rifaximin are efficacious second-line drugs for IBS with diarrhea (IBS-D) in secondary care. Linaclotide, lubiprostone, plecanatide, tenapanor, and tegaserod are efficacious second-line agents for IBS with constipation (IBS-C) in secondary care.

Psychological Therapies

IBS-specific cognitive behavioral therapy (CBT) and gut-directed hypnotherapy may be efficacious for global symptoms.

Severe or Refractory Symptoms

Severe or refractory IBS should be managed with an integrated multidisciplinary approach, with care taken to avoid iatrogenic harms.

Combination gut-brain neuromodulators (augmentation) may be considered for more severe symptoms.

The selection of pharmacologic treatment remains symptom directed. Agents used for the management of symptoms in irritable bowel syndrome (IBS) include anticholinergics, antidiarrheals, tricyclic antidepressants, prokinetic agents, bulk-forming laxatives, serotonin receptor antagonists, chloride channel activators, and guanylate cyclase C (GC-C) agonists.

A systematic review found that several antispasmodics, including peppermint oil, pinaverium, trimebutine, and cimetropium/dicyclomine, significantly outperformed placebo at improving irritable bowel syndrome symptoms and global assessment scores.[33] Pinaverium and cimetropium are not available in the United States. The National Institutes of Health's (NIH's) National Center for Complementary and Integrative Health (NCCIH) provides information regarding a small amount of research that suggests that peppermint oil may improve IBS symptoms.[4]

The 2009 American College of Gastroenterologists (ACG) position statement on the management of irritable bowel syndrome noted that the antidiarrheal agent loperamide effectively reduced stool frequency and improved stool consistency, but it did not relieve pain, bloating, or other global irritable bowel syndrome symptoms.[3] As noted earlier, the 2014 ACG monograph on the management of irritable bowel syndrome and chronic idiopathic constipation found insufficient evidence to recommend prebiotics or synbiotics, or loperamide, in irritable bowel syndrome, and no evidence that polyethylene glycol improved overall symptoms and pain in affected patients.[32] The most recent 2018 ACG monograph on the management of IBS has upheld these aforementioned recommendations.[52]

A Spanish expert consensus panel on functional digestive disorders have made evidence-based recommendations on the use of linaclotide, a GC-C receptor agonist, for the management of the constipation-predominant disease (IBS-C) subtype.[53] Their recommendations include continuous (not sporadic) use of linaclotide therapy for moderate to severe IBS-C, patient education regarding the risk of diarrhea and its management options, and the maintenance of linaclotide therapy for potentially long periods on the basis of the lack of tachyphylaxis or potential risks.[53] In 2018, another GC-C receptor agonist, plecanatide, was approved by the FDA for treatment of IBS-C in adults.[54]

Rifaximin was approved by the FDA in 2015 for IBS-D.[55] A total of 1260 patients with IBS without constipation were enrolled in the TARGET 1 and TARGET 2 phase III trials at 179 investigative sites in the United States and Canada. Results showed that treatment with rifaximin (550 mg PO tid for 14 d) provided better symptom relief (eg, bloating, abdominal pain, loose/watery stools) compared with placebo, although the placebo effect was tremendous. Similarly, a 2012 meta-analysis of five studies, incorporating 1,803 patients, determined that rifaximin is more effective than placebo for global symptom relief and bloating. Adverse event rates were similar to placebo.[56, 57]

Tegaserod was reintroduced in the United States in 2019 after it had been suspended from the market in 2007 because of cardiovascular (CV) safety concerns.[58, 59, 60] The reapproved tegaserod indication is for women younger than 65 years with IBS-C who are without a history of CV ischemic disease and who have a low risk of developing CV disease. FDA approval was based on three multicenter, double-blind, placebo-controlled trials that stratified data from women with IBS-C (N = 2470).[58, 59] Tegaserod has been "shown to improve symptoms, enhance gastric accommodation and significantly attenuate visceral pain arising from the colon in functional dyspepsia patients."[60] Evidence also exists in animal models that tegaserod may have a protective effect in inflamed colons.[60]

Class Summary

Linaclotide and lubiprostone enhance chloride-rich intestinal fluid secretions without altering the sodium and potassium concentrations in the serum. Linaclotide was approved by the FDA in August 2012 to treat chronic idiopathic constipation and irritable bowel syndrome with constipation (IBS-C) in adults.[61]

The safety and efficacy of linaclotide in the treatment of IBS-C were evaluated in 2 double-blind, placebo-controlled phase III clinical trials in which linaclotide met all four primary endpoints for changes in abdominal pain and constipation in each trial. The trials involved 1,605 patients aged 18-87 years, of which 807 were treated with linaclotide 290 mcg. Both trials showed a significantly higher proportion of responders in the linaclotide group compared with the placebo group.[61, 62, 63]

Tenapanor, an inhibitor of sodium-hydrogen exchange (NHE3) transporter, was approved in September 2019 for IBS-C. Approval was based on two phase III trials (N = 1226) that showed a statistically significant improvement in stool frequency and abdominal pain compared with those who received placebo.[6]

Lubiprostone (Amitiza)

This agent activates chloride channels on the apical part of the small bowel epithelium. As a result, chloride ions are secreted and sodium and water passively diffuse into the lumen to maintain isotonicity. This medication is FDA approved for use in idiopathic constipation and in irritable bowel syndrome with constipation.

Linaclotide (Linzess)

Guanylate cyclase agonist; activation of guanylate cyclase receptors in the intestinal neurons leads to increased cyclic guanosine monophosphate (cGMP), anion secretion, fluid secretion, and intestinal transit; it appears to work topically rather than systemically; when administered PO, linaclotide activates chloride channels in intestinal epithelial cells to increase intestinal fluid secretion; indicated to treat chronic idiopathic constipation and for IBS-C in adults.

Plecanatide (Trulance)

Plecanatide is a guanylate cyclase C (GC-C) agonist. Plecanatide and its active metabolite bind to GC-C and act locally on the luminal surface of intestinal epithelial cells. GC-C activation leads to increased cyclic guanosine monophosphate (cGMP), which, in turn, stimulates secretion of chloride and bicarbonate into the intestinal lumen, mainly by activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel, resulting in increased intestinal fluid and accelerated transit. It is indicated for IBS-C in adults.

Alosetron (Lotronex)

Alosetron is a 5-HT3 receptor antagonist. This agent controls irritable bowel syndrome symptoms through its potent and selective antagonism of serotonin 5-HT3 receptor type. These receptors are extensively located on the enteric neurons of the GI tract, and stimulation causes hypersensitivity and hyperactivity of the intestine. It is indicated only for women with severe diarrhea-predominant IBS who have: chronic IBS symptoms (generally lasting 6 months or longer), had anatomic or biochemical abnormalities of the GI tract excluded, and have not responded adequately to conventional therapy.

Limiting its use to this severely affected population is intended to maximize the benefit-to-risk ratio. The drug was previously removed from the US market but was reintroduced with new restrictions approved by the FDA on June 7, 2002. Restrictions are because of reports of infrequent but serious GI adverse reactions (eg, ischemic colitis, serious complications of constipation), including some that resulted in hospitalization and, rarely, blood transfusion, surgery, or death. In order to prescribe, physicians must be enrolled in the Prescribing Program for Lotronex.

Under the new management plan, serious adverse events have been few.[28]

Tegaserod (Zelnorm)

Tegaserod is a serotonin type-4 (5-hydroxytryptamine-4 [5-HT4]) receptor partial agonist. It stimulates the peristaltic reflex and intestinal secretions, inhibits visceral sensitivity, enhances basal motor activity, and normalizes impaired motility throughout the gastrointestinal tract. It is indicated for adult women younger than 65 years who have irritable bowel syndrome with constipation (IBS-C). Its use is further restricted to women without a history of cardiovascular risk.

Eluxadoline (Viberzi)

Eluxadoline is a mu opioid receptor agonist. It also is a delta opioid receptor antagonist and a kappa opioid receptor agonist. The multiple opioid activity is designed to treat the symptoms of IBS-D while reducing the incidence of constipation that can occur with unopposed mu opioid receptor agonists. It is indicated for IBS-D in adult men and women.

Tenapanor (Ibsrela)

Tenapanor is a locally acting inhibitor of the sodium/hydrogen exchanger 3 (NHE3), an antiporter expressed on the apical surface of the small intestine and colon primarily responsible for absorption of dietary sodium. NHE3 inhibition reduces sodium absorption from the small intestine and colon, resulting in an increase in water secretion into the intestinal lumen, which accelerates intestinal transit time and results in a softer stool consistency. It is indicated for adults with IBS-C.

Class Summary

Anticholinergic agents are antispasmodics that inhibit intestinal smooth-muscle depolarization at the muscarinic receptor. These agents help relieve symptoms of intestinal spasms in irritable bowel syndrome.

Dicyclomine hydrochloride (Bentyl)

Dicyclomine blocks the action of acetylcholine at parasympathetic sites in secretory glands, smooth muscle, and CNS. This drug decreases fecal urgency and pain. It is useful in patients with diarrhea-predominant symptoms. Adverse effects are dose dependent.

Hyoscyamine (Anaspaz, Levbid)

Like dicyclomine, hyoscyamine is useful in patients with diarrhea-predominant symptoms and blocks the action of acetylcholine at parasympathetic sites in smooth muscle, secretory glands, and the CNS, which, in turn, has antispasmodic effects. The drug decreases fecal urgency and pain.

Class Summary

These agents are nonabsorbable synthetic opioids. They prolong the GI transit time and decrease secretion via peripheral µ-opioid receptors. They reduce visceral nociception via afferent pathway inhibition.

Diphenoxylate hydrochloride 2.5 mg with atropine sulfate 0.025 mg (Lomotil)

This drug combination consists of 2.5 mg of diphenoxylate, which is a constipating meperidine congener, and 0.025 mg of atropine to discourage abuse. The preparation inhibits excessive GI propulsion and motility, but it may exacerbate constipation.

Loperamide (Imodium)

Loperamide, which is available over the counter, acts on intestinal muscles to inhibit peristalsis and to slow intestinal motility. It prolongs the movement of electrolytes and fluid through the bowel and increases the viscosity and loss of fluids and electrolytes. Loperamide improves stool frequency and consistency, reduces abdominal pain and fecal urgency, and may exacerbate constipation.

Class Summary

Tricyclic antidepressants have both antidepressive and analgesic properties. Agents such as imipramine and amitriptyline are efficacious in treating symptoms of irritable bowel syndrome. The use of tricyclic antidepressants in irritable bowel syndrome is off label.

Imipramine (Tofranil)

Imipramine increases pain threshold in the gut, thereby providing a visceral analgesic effect. It prolongs oral-cecal transit time; reduces abdominal pain, mucorrhea, and stool frequency; and increases global well-being variably. It is effective in irritable bowel syndrome in doses that are subtherapeutic for antidepressive actions, suggesting an independent mechanism of action in this disorder.

Amitriptyline (Elavil)

Like imipramine, amitriptyline provides a visceral analgesic effect at doses subtherapeutic for antidepressive actions. It also prolongs oral-cecal transit time, reduces abdominal pain, mucorrhea, and stool frequency, and increases global well-being variably.

Class Summary

Antibiotics may play a role in the treatment of irritable bowel syndrome by preventing the overgrowth of intestinal bacteria.

Rifaximin (Xifaxan)

Rifaximin is a semisynthetic derivative of rifampin and acts by binding to the beta-subunit of bacterial DNA-dependent RNA polymerase, blocking one of the steps in transcription. This results in inhibition of bacterial protein synthesis and consequently inhibits the growth of bacteria. The exact mechanism of action for IBS-D is not known, but it is thought to be related to changes in the bacterial content in the gastrointestinal tract and reduction of gas. It is indicated for IBS-D in adult men and women.

Class Summary

These products are made of natural and semi-synthetic hydrophilic polysaccharides and cellulose derivatives that dissolve or swell in the intestinal fluid, forming emollient gels that facilitate the passage of intestinal contents and stimulate peristalsis. As fiber supplements, these products may improve symptoms of constipation and diarrhea, but their use in irritable bowel syndrome is controversial.

Methylcellulose (Citrucel)

This agent promotes bowel evacuation by forming a viscous liquid and promoting peristalsis.

Psyllium (Metamucil, Fiberall, Reguloid, Konsyl)

Like methylcellulose, psyllium promotes bowel evacuation by forming a viscous liquid and promoting peristalsis.