Treatment of irritable bowel syndrome in adults

INTRODUCTION — 

Irritable bowel syndrome (IBS) is a chronic disorder of brain-gut interaction characterized by chronic abdominal pain and altered bowel habits that are unrelated to another diagnosis and without identifiable intestinal pathology. Approximately 10 to 15 percent of adults and adolescents have symptoms consistent with IBS, and although not all individuals with IBS seek medical care, patients with IBS make up a significant percentage of all outpatient visits to gastroenterologists and other health care providers [1,2].

This topic will review the treatment of IBS. Our recommendations are largely consistent with the American College of Gastroenterology and American Gastroenterological Association guidelines [3-6]. The clinical manifestations and diagnosis of IBS and the pathophysiology of IBS are discussed separately. (See "Clinical manifestations and diagnosis of irritable bowel syndrome in adults" and "Pathophysiology of irritable bowel syndrome".)

DETERMINING IBS SUBTYPE — 

Once IBS is diagnosed, the IBS subtype should be determined to guide the selection of pharmacotherapy. The Rome IV criteria are the most widely used symptom-based diagnostic criteria for IBS [7-9]. Using these criteria, IBS is diagnosed in patients with recurrent abdominal pain at least one day per week over at least three months, in the absence of other underlying conditions and with two or more of the following: related to defecation, associated with changes in stool frequency, or associated with changes in stool form or appearance. (See "Clinical manifestations and diagnosis of irritable bowel syndrome in adults", section on 'Diagnostic criteria'.)

Subtypes of IBS are defined based on the patient's reported predominant stool form on days with abnormal bowel movements using the Bristol stool form scale (BSFS). A two-week stool diary assists with recording bowel habits [7,8,10]. The diary should be completed off all medications that may impact bowel movements, including medications for IBS.

We also ask patients to complete a two-week diet history (form 1) alongside the stool diary as dietary modification based on symptom triggers is a key component of initial therapy. (See 'Initial dietary evaluation' below.)

The use of the BSFS and stool diary in determining the IBS subtype is presented in the algorithm (algorithm 1):

●IBS with predominant constipation (IBS-C) – In IBS-C, abnormal bowel movements are usually constipation (type 1 and 2 in the BSFS).

●IBS with predominant diarrhea (IBS-D) – In IBS-D, abnormal bowel movements are usually diarrhea (type 6 and 7 in the BSFS).

●IBS with mixed bowel habits (IBS-M) – In IBS-M, abnormal bowel movements include constipation and diarrhea with similar frequency (more than 25 percent of abnormal bowel movements are constipation [type 1 and 2 in the BSFS], and more than 25 percent are diarrhea [type 6 and 7 in the BSFS]).

●IBS unclassified (IBS-U) – Patients meeting diagnostic criteria for IBS who do not otherwise meet criteria for one of the other three IBS subtypes are classified as IBS-U.

IBS subtypes are dynamic. In one study, more than half of patients changed IBS subtypes over a one-year period [11]. Therefore, we review the patient's symptoms and stool diary periodically to confirm the IBS subtype. The IBS subtype should also be re-evaluated in patients with refractory or worsening symptoms. (See 'Refractory symptoms' below.)

INITIAL THERAPY FOR ALL PATIENTS

Establish a therapeutic alliance — Successful treatment of IBS requires the foundation of a trusting clinician-patient relationship to support the diagnosis, validate symptoms, establish realistic expectations, and ensure continuity of care [12-14]. Patient education should underscore that IBS is a chronic condition that responds best to a multidisciplinary approach. Treatment includes long-term diet and behavioral modifications, with adjunctive pharmacotherapy. Many patients need to try more than one treatment, sometimes in combination, to find the regimen that provides the greatest relief. This process requires a longitudinal partnership with a trusted health care professional. Patients should also be reassured that IBS does not increase their risk of malignancy. (See "Pathophysiology of irritable bowel syndrome" and "Patient education: Irritable bowel syndrome (Beyond the Basics)".)

Lifestyle modifications and behavioral interventions — Lifestyle modifications and behavioral interventions are first-line treatments for all patients.

●Physical activity – We advise regular physical activity as an essential component of IBS treatment. Studies suggest exercise improves global IBS symptoms. In one randomized trial of 102 patients with IBS, 12 weeks of increased physical activity (20 to 60 minutes of moderate activity, three to five days per week) produced improvement in IBS symptoms when compared with maintenance of current activity (43 versus 26 percent) [15]. In addition, patients in the physical activity arm were less likely to experience worsening of their IBS symptoms as compared with controls (8 versus 23 percent).

●Sleep hygiene – Sleep disturbances are more common in patients with IBS and correlate with IBS-related pain [16-18]. Patients with sleep disturbances should be provided with sleep hygiene guidelines (table 1) and should undergo a review of medications and other factors that sustain poor sleep over time (table 2). (See "Evaluation and diagnosis of insomnia in adults" and "Overview of the treatment of insomnia in adults".)

Melatonin has been investigated as a treatment for IBS as it plays a role in gastrointestinal motility and is frequently used as a sleep aid [18,19]. In one randomized trial of 136 patients with IBS, daily melatonin supplementation improved IBS scores, abdominal pain, subjective sleep quality, and quality of life at eight-week follow-up [19]. Further studies with larger sample sizes and longer follow-up are warranted.

●Brain-gut behavioral therapies – Studies suggest brain-gut behavioral therapies such as gut-directed hypnotherapy, mindfulness-based stress reduction, cognitive-behavioral therapy, and other stress reduction techniques may be beneficial for bowel and mental health symptoms associated with IBS [20-25]. While these are most often used as adjunctive therapy for refractory symptoms, early referral for these therapies is appropriate for patients with concomitant mood disorders and patients who express interest in nonpharmacologic treatment. These therapies are discussed in further detail below. (See 'Brain-gut behavioral therapies' below.)

Dietary modifications — Diet changes are a key component of managing IBS symptoms. A trial-and-error approach with refinements over time is often needed to arrive at a diet that provides the greatest relief.

Initial dietary evaluation — Prior to dietary modifications, patients should complete a two-week diet and stool history for clinician and dietitian review (form 1). A careful diet history may reveal patterns of symptoms related to specific foods and specific dietary triggers that can guide dietary intervention [26,27]. The stool history also plays a role in determining the IBS subtype, which assists with the selection of medical therapy. (See 'Determining IBS subtype' above.)

Dietary evaluation should also include screening for disordered eating, uncontrolled psychiatric conditions, food insecurity, or other risk factors for malnutrition as restrictive diet interventions are not appropriate for these patients. IBS treatment should focus instead on carefully supervised behavior modification therapies and medical therapy (see 'Brain-gut behavioral therapies' below and 'Medical treatment for constipation-predominant IBS (IBS-C)' below and 'Medical treatment for diarrhea-predominant IBS (IBS-D)' below). If disordered eating or uncontrolled psychiatric conditions are identified, additional specialty referrals should be made. (See "Eating disorders: Overview of epidemiology, clinical features, and diagnosis".)

While not required, we recommend a consultation with a dietitian for all patients with IBS. Registered dietitians assist with education, meal planning, and personalized modifications [28]. Studies also suggest improved diet adherence with dietitian-led advice [29]. Availability and cost may limit dietitian referrals, depending on practice location. In such cases, we use supplemental educational materials to support dietary modifications. Online diet advice is available from several professional organizations [30,31].

Traditional IBS dietary advice — We recommend traditional IBS dietary advice (table 3) as the initial dietary modification for most patients. While some guidelines recommend the low fermentable oligo-, di-, and monosaccharides and polyols (FODMAP) diet with dietitian support as first-line diet advice [3], in our experience, the traditional IBS diet can result in meaningful symptom improvement and is easier to follow and less costly to implement. In some randomized trials, traditional IBS dietary advice was similarly effective in improving IBS symptoms when compared with low-FODMAP and gluten-free diets [32,33]. However, a network meta-analysis concluded a low-FODMAP diet was the most effective strategy [34].

If the patient prefers, a low-FODMAP diet is a reasonable alternative initial diet. We also suggest a low-FODMAP diet in patients for whom symptoms persist after following traditional dietary advice. (See 'Low-FODMAP diet' below.)

●Definition – Traditional IBS dietary advice is summarized in the table (table 3). While specific advice may vary by practice location, recommendations typically include smaller meal sizes, soluble fiber supplementation, and avoidance of patient-identified triggers and gas-producing foods (table 4) [35-37]. Adequate fluid intake and modest use of alcohol and caffeine are additional key components.

●Implementation – We provide general diet advice (table 3) and use the diet and stool history to suggest personalized modifications, including foods to avoid. Specific recommendations include the following:

•Soluble fiber supplementation – We recommend daily supplementation with soluble fiber (eg, psyllium, ispaghula husk, oats). As some patients may experience increased bloating and gas, we suggest a low starting dose of 3 to 4 grams of soluble fiber per day. With commercial fiber products, the soluble fiber content varies widely (ie, per packet, teaspoon, or pill), and the product-specific label must be reviewed to determine the dose. The dose may then be titrated based on response to treatment. Numerous studies suggest that soluble fiber improves global IBS symptoms, including both constipation and diarrhea [4,36,38-41].

Insoluble fiber (eg, wheat bran) should be avoided as it is not significantly better than placebo in improving symptoms of IBS and can exacerbate bloating [36,37,42].

•Avoidance of gas-producing foods – Common foods and substances that produce gas include vegetables such as cabbage, broccoli, and cauliflower; beans and lentils; carbonated beverages; and sweeteners such as fructose and sorbitol. Additional foods associated with gas and bloating are reviewed in the table (table 4). Patients should avoid these foods and monitor their diet for individual symptom triggers.

•Lactose avoidance for some patients – Patients with known lactose intolerance and patients whose food diaries suggest lactose as a symptom trigger should try a lactose-restricted diet. We also suggest a lactose-restricted diet trial in patients who experience persistent abdominal bloating despite the exclusion of gas-producing foods.

Although the incidence of lactose malabsorption is not higher in patients with IBS, patients with IBS and lactose intolerance may have an exaggerated symptom response to lactose ingestion [43]. Additionally, some patients initially diagnosed with IBS may have undiagnosed lactose intolerance. In such patients, lactose-restricted diets can result in lasting clinical improvement [44-46]. The clinical manifestations and diagnosis of lactose intolerance are discussed in detail separately. (See "Lactose intolerance and malabsorption: Clinical manifestations, diagnosis, and management".)

●Evidence of benefit – While the evidence supporting traditional IBS diet advice is limited, we find that a substantial proportion of patients experience meaningful improvement in IBS symptoms. Theories suggest that the consumption of gas-producing foods exacerbates bloating and visceral hypersensitivity in IBS [43], which are relieved by avoiding such foods. Soluble fiber increases stool bulk, facilitating stool propulsion, and may also alter the gut microbiome and the production of gaseous fermentation products [41,47,48].

Low-FODMAP diet

●Definition – FODMAP is an acronym for "fermentable oligo-, di-, and monosaccharides and polyols," initially conceptualized as a potential dietary contributor to inflammatory bowel disease [49]. These so-called FODMAPs are short-chain carbohydrates that are poorly absorbed in the small intestine. Instead, they stay osmotically active in the intestinal lumen, where they are rapidly fermented, resulting in luminal distension, increased intestinal permeability, and symptoms of abdominal bloating and pain [50]. FODMAPs are also hypothesized to modulate visceral hypersensitivity, induce changes in the gut microbiome, and alter gastrointestinal motility [51].

We suggest a diet low in FODMAPs (table 5) in patients with continued symptoms after a trial of traditional diet modifications, including soluble fiber supplementation and avoidance of gas-producing foods [4] (see 'Traditional IBS dietary advice' above). We also support a low-FODMAP diet as the initial dietary intervention for motivated patients who wish to pursue it.

●Implementation – The low-FODMAP diet is more restrictive and challenging to follow than traditional IBS dietary advice. Whenever possible, low-FODMAP diet planning should be pursued in consultation with a trained dietitian, along with detailed diet and stool diaries (form 1). Dietitian consultation improves adherence, ensures a nutritionally replete diet, and avoids unnecessary dietary overrestriction [52].

The low-FODMAP diet follows three sequential steps [4,53]:

•Step one – Elimination of high-FODMAP foods (table 5) for four to six weeks with close monitoring of symptoms, typically using a stool diary. If IBS symptoms improve, the patient is moved to step two below. We emphasize to patients that this most restrictive step is temporary and there is no added benefit to extending its duration.

If no improvement is noted, the patient's symptoms are unlikely to be related to FODMAPs. In such patients, other dietary modifications and treatments should be pursued. (See 'Traditional IBS dietary advice' above and 'Medical treatment for constipation-predominant IBS (IBS-C)' below and 'Medical treatment for diarrhea-predominant IBS (IBS-D)' below.)

•Step two – Gradual reintroduction of high-FODMAP foods (table 5) over an additional six to eight weeks to determine individual tolerance to specific fermentable carbohydrates. Typically, one high-FODMAP food is reintroduced, with a three-day break between the introduction of new foods. Daily food diaries (form 1) must be kept in addition to continued monitoring and recording of symptoms.

•Step three – Diet personalization for long-term use based on reintroduction data and dietitian guidance.

●Evidence of benefit – Numerous studies have demonstrated an improvement in IBS symptoms with FODMAP restriction [38,54-58]. In a meta-analysis of 10 randomized trials and 511 IBS patients, a low-FODMAP diet was associated with improved IBS global symptom scores (risk ratio 1.54, 95% CI 1.18-2.0) compared with the control diet [58]. Modest improvements in stool consistency and frequency suggest that the efficacy for diarrhea-predominant IBS (IBS-D) patients may be more pronounced (mean difference -0.25, 95% CI -0.44 to -0.06 and -0.28, 95% CI -0.57 to 0.01, respectively).

In a randomized, single-blind, crossover trial, 30 patients with IBS and 8 healthy controls were assigned to 21 days of a low-FODMAP or a moderate-FODMAP Australian diet followed by a 21-day washout period before crossing over to an alternate diet [59]. Subjects with IBS had lower IBS symptom scores and improved scores for abdominal pain, bloating, flatulence, and stool consistency while on a low-FODMAP diet as compared with the moderate-FODMAP diet and their diet at baseline. In another randomized trial of 92 patients with IBS-D, both a low-FODMAP diet and a modified traditional IBS diet resulted in a similar proportion of patients reporting adequate relief of IBS symptoms as the primary endpoint [57]. However, the low-FODMAP group exhibited significantly higher rates of improvement in pain (51 versus 23 percent) and greater reductions in average daily scores for abdominal pain, bloating, stool consistency, frequency, and urgency.

Additional studies with longer follow-up are needed to define potential effects on nutrition and gut microbiota and the role of the low-FODMAP diet in the longitudinal management of IBS.

Other dietary interventions of low or uncertain benefit, including gluten-free diets, are discussed below. (See 'Treatments with limited evidence of benefit' below.)

●IBS with mixed bowel habits (IBS-M) – In IBS-M, abnormal bowel movements include constipation and diarrhea with similar frequency. In our experience, lifestyle and dietary interventions are particularly beneficial in IBS-M. Therefore, we revisit fiber supplementation and a low-FODMAP diet, even if an initial trial did not provide adequate relief (see 'Dietary modifications' above). We add pharmacotherapy for persistent global symptoms. (See 'Medical treatment for global symptoms' below.)

We also rule out primary constipation with overflow fecal diarrhea, with or without incontinence, in patients with IBS-M as this condition may present with similar symptoms. (See "Etiology and evaluation of chronic constipation in adults".)

If a predominant bowel habit (eg, constipation-predominant IBS or IBS-D) develops during treatment, we add additional treatment based on the IBS subtype. (See 'Medical treatment for constipation-predominant IBS (IBS-C)' below and 'Medical treatment for diarrhea-predominant IBS (IBS-D)' below.)

INDICATIONS FOR SPECIALTY REFERRAL — 

The presence of any of the following "alarm features" should prompt gastroenterology referral and additional investigation, including possible endoscopy, as they suggest possible undiagnosed conditions in patients with both suspected and established IBS:

●Unexplained weight loss

●Unexplained iron deficiency anemia

●Nocturnal diarrhea

●Rapidly progressing symptoms

●New symptoms and age ≥45 years

●More than minimal rectal bleeding (see "Approach to minimal bright red blood per rectum in adults", section on 'Clinical assessment')

●Family history of colorectal cancer, inflammatory bowel disease, or celiac sprue

Further details on additional testing and evaluation for patients with alarm features are discussed separately. (See "Clinical manifestations and diagnosis of irritable bowel syndrome in adults", section on 'Additional evaluation based on the presence of alarm features'.)

MEDICAL TREATMENT FOR CONSTIPATION-PREDOMINANT IBS (IBS-C) — 

We use additional pharmacotherapy for patients with persistent symptoms despite lifestyle and diet modifications, including soluble fiber supplementation with psyllium, ispaghula husk, and oats (table 3) (see 'Traditional IBS dietary advice' above). The IBS subtype guides the initial choice of pharmacotherapy (algorithm 2) (see 'Determining IBS subtype' above). We add pharmacotherapy for global symptoms if constipation improves but abdominal pain symptoms persist. (See 'Medical treatment for global symptoms' below.)

Polyethylene glycol (PEG) as our preferred initial therapy — We use polyethylene glycol (eg, PEG, PEG 3350, or polyethylene glycol 3350) as first-line pharmacotherapy and the preferred osmotic laxative in patients with IBS-C (algorithm 2). PEG is inexpensive and widely available without a prescription. PEG is also well tolerated, is easily titratable based on symptoms, and has fewer side effects than other osmotic laxatives (eg, lactulose, milk of magnesia).

●Dosing – We initiate treatment with 17 g of powder dissolved in 8 ounces of water once daily and titrate up or down to a maximum of 34 g daily based on individual response. Dosing changes may be made every two to three days until maximum relief of symptoms (eg, increase in stool frequency and improved stool consistency). Titration may take eight weeks or more to arrive at the optimal dose. We discontinue PEG if patients develop intolerable bloating or nausea and in patients who do not have any improvement in constipation at the maximum tolerated dose.

Treatment is continued for the duration of symptoms and may be tapered or discontinued if symptoms abate.

●Efficacy and adverse effects – Treatment with PEG improves constipation but not abdominal pain [60,61]. In one randomized trial of 139 adults with IBS-C, patients treated with PEG had more spontaneous bowel movements, improvement in stool consistency, and reduction in the severity of straining compared with placebo [61]. However, there was no difference in the severity of bloating or abdominal pain between groups. In adults, PEG has not been directly compared with other osmotic laxatives; randomized trials in children have demonstrated that PEG has greater or similar efficacy to lactulose and magnesium hydroxide in treating constipation [62-71]. (See "Chronic functional constipation and fecal incontinence in infants, children, and adolescents: Treatment", section on 'Polyethylene glycol'.)

Bloating, nausea, and cramping are common and may limit the use of PEG. (See "Management of chronic constipation in adults", section on 'Osmotic laxatives'.)

Alternative agents — We offer additional pharmacotherapy for patients with IBS-C who do not respond adequately to PEG. Because there are no trials directly comparing treatment options, the choice of therapy is based on patient preferences, symptoms, and side effect profiles. Agents may be trialed sequentially to determine the treatment regimen that offers optimal relief (algorithm 2).

Guanylate cyclase agonists — We use guanylate cyclase agonists as second-line pharmacotherapy for patients who have not achieved adequate relief of symptoms with PEG (algorithm 2). These medications improve abdominal pain and constipation in IBS-C and are generally well tolerated. The once-daily dosing is also more convenient when compared with other alternative agents.

●Options and dosing – Linaclotide is used for the treatment of IBS-C at a suggested dose of 290 micrograms daily on an empty stomach. If diarrhea develops, we reduce the dose to 72 or 145 micrograms daily and/or offer every-other-day dosing. We discontinue linaclotide in patients whose symptoms do not improve after a four-week trial [72].

Plecanatide is an alternative guanylate cyclase agonist with a similar mechanism of action. The suggested dose of plecanatide is 3 mg once daily, taken with or without food [73-75]. If diarrhea develops, we offer every-other-day dosing to improve tolerability. We discontinue plecanatide in patients who do not respond within four weeks.

The choice between linaclotide and plecanatide is guided primarily by availability and cost as efficacy is similar between the two agents [73]. We have a slight preference for linaclotide based on animal studies suggesting it may also modulate visceral pain [76-78].

●Efficacy and adverse effects – The efficacy of linaclotide in the treatment of IBS-C has been demonstrated in multiple studies [79-81]. In one randomized trial of 800 patients with IBS-C, 34 percent of patients receiving linaclotide 290 micrograms for 12 weeks achieved the composite primary endpoint (≥30 percent reduction in abdominal pain, ≥3 complete and spontaneous bowel movements [CSBMs] in one week, increase in ≥1 CSBM from baseline) compared with 21 percent of patients receiving placebo (number needed to treat = 8, 95% CI 5.4-15.5) [79]. Linaclotide also produced improvement in all secondary endpoints compared with placebo. A second randomized trial of linaclotide 290 micrograms daily for patients with IBS-C produced similar results sustained over 26 weeks [80]. In both trials, diarrhea was the most common adverse effect, resulting in discontinuation of treatment in 6 percent of patients receiving linaclotide.

Randomized trials of plecanatide suggest similar efficacy and tolerability [73]. In two randomized trials of 1879 patients with IBS-C, treatment with plecanatide for 12 weeks improved abdominal pain intensity, stool frequency, and stool consistency compared with placebo [74]. The incidence of diarrhea was 4 percent among the treatment group. Treatment was discontinued in 1.4 percent of individuals reporting this adverse effect.

●Mechanism of action – Both linaclotide and plecanatide act locally on the luminal surface of the intestinal epithelium to bind guanylate cyclase-C [82,83]. The subsequent increase in both intracellular and extracellular cyclic guanosine monophosphate concentrations induces increased chloride and bicarbonate secretion into the intestinal lumen. The increased intestinal fluid improves gastrointestinal transit.

Lubiprostone — We use lubiprostone in patients with IBS as an alternative option for patients who experience adverse effects or lack of improvement with PEG and guanylate cyclase agonists (algorithm 2) (see 'Polyethylene glycol (PEG) as our preferred initial therapy' above and 'Guanylate cyclase agonists' above). Diarrhea is also less frequent with lubiprostone compared with other IBS-C treatments.

While lubiprostone is an important treatment option for patients with IBS-C, several factors limit its use, including a relatively high incidence of dose-dependent nausea and twice-daily dosing [84,85]. Because only 8 percent of patients in the original trials were men, lubiprostone is also only approved by the US Food and Drug Administration for the treatment of IBS-C in women [86,87]. We use lubiprostone in men based on studies showing its efficacy and tolerability in the treatment of both men and women with chronic idiopathic constipation. (See "Management of persistent unresponsive constipation in adults", section on 'Lubiprostone'.)

●Dosing – The approved dose of lubiprostone for IBS-C is 8 micrograms twice daily. We discontinue lubiprostone in patients who fail to respond to a four-week trial [86]. In patients with some improvement and no issues with tolerability after the initial trial, we titrate lubiprostone up to 24 mcg twice daily based on dosing guidance for chronic idiopathic constipation. (See "Management of persistent unresponsive constipation in adults", section on 'Lubiprostone'.)

●Efficacy and adverse effects – The efficacy of lubiprostone has been demonstrated in two randomized trials in which the majority of patients were females [86]. In these trials, patients receiving lubiprostone 8 micrograms twice daily were more likely to achieve the study-defined overall response compared with placebo (18 versus 10 percent). The most common adverse event associated with lubiprostone was nausea (8 versus 4 percent). A follow-up open-label study that included 522 patients demonstrated that the benefits of lubiprostone were sustained or increased at 52 weeks [87].

●Mechanism of action – Lubiprostone is a chloride-2 channel activator that enhances chloride-rich intestinal fluid secretion and promotes peristalsis [88]. Studies also suggest lubiprostone may reinforce the mucosal barrier, restoring intestinal permeability [89,90].

Tenapanor — We use tenapanor in patients who do not respond to other therapies for IBS-C (algorithm 2). Because it is a newer agent for IBS-C, availability, insurance coverage, and cost may limit its use.

●Dosing – The suggested dose is 50 micrograms twice daily. Improvement may be seen within several days. We discontinue tenapanor in patients who fail to respond to a four-week trial [91].

●Efficacy and adverse effects – The efficacy of tenapanor in the treatment of IBS-C has been demonstrated in several clinical trials [91-93]. In two phase 3 studies of 1199 patients followed for either 12 or 26 weeks, patients treated with tenapanor 50 mg twice daily were more likely to achieve the composite primary endpoint (≥30 percent reduction in abdominal pain and increase of ≥1 CSBM weekly) compared with placebo (27 versus 18.7 percent in the 12-week study and 36.5 versus 23.7 percent in the 26-week study) [91,92].

Reported side effects include diarrhea, nausea, bloating, and flatulence. Diarrhea is typically mild to moderate in severity and may improve with continued medication use.

●Mechanism of action – Tenapanor is a sodium/hydrogen exchanger 3 inhibitor. It acts locally in the small intestine and colon to reduce the absorption of sodium and phosphate, increasing water retention and promoting intestinal transit [94]. Studies also suggest it improves mucosal permeability and reduces visceral hypersensitivity [94,95].

MEDICAL TREATMENT FOR DIARRHEA-PREDOMINANT IBS (IBS-D) — 

We use additional pharmacotherapy for patients with persistent symptoms despite lifestyle and diet modifications. The IBS subtype guides the initial choice of pharmacotherapy (algorithm 3) (see 'Determining IBS subtype' above). We add pharmacotherapy for global symptoms if diarrhea improves but abdominal pain symptoms persist. (See 'Medical treatment for global symptoms' below.)

Loperamide as our preferred initial therapy — We use loperamide as first-line pharmacotherapy for patients with IBS-D in whom diarrhea is the predominant symptom (algorithm 3). Loperamide is safe, effective, and widely available, and dosing is easily titrated to optimal effect.

●Dosing – We start with loperamide 2 mg given 45 minutes before every meal. Dosing may be titrated up or down based on response, with a maximum dose of 16 mg daily. Loperamide may also be given prophylactically if specific situations are identified as symptom triggers (eg, exercise, stressful situations).

Treatment is continued for the duration of symptoms and may be titrated down or discontinued if symptoms abate. In patients with alternating diarrhea and constipation, loperamide should be used in limited doses due to the risk of exacerbating constipation.

●Efficacy and adverse effects – In randomized trials evaluating loperamide in the treatment of IBS, loperamide was more effective than placebo in decreasing stool frequency and improving consistency [96-98]. However, loperamide did not appear to influence global IBS symptoms, as there was no difference in the severity of bloating, abdominal discomfort, or global IBS symptoms in patients treated with loperamide as compared with placebo. Based on these findings and some methodologic limitations of these studies, the American College of Gastroenterology preferentially endorses other treatments as first-line therapy for IBS-D [3].

●Mechanism of action – Loperamide is a synthetic peripheral opioid receptor agonist [6]. It reduces diarrhea by inhibiting peristalsis, prolonging intestinal transit time, increasing intestinal water absorption, and reducing fecal volume. It also reduces symptoms of urgency by increasing resting anal sphincter tone.

Bile acid sequestrants as second-line therapy — In patients with IBS-D with persistent diarrhea despite loperamide, we use bile acid sequestrants (eg, cholestyramine, colestipol, colesevelam) (algorithm 3). (See 'Loperamide as our preferred initial therapy' above.)

●Options and dosing – Because each agent has similar efficacy, the selection of bile acid sequestrant is based on availability, cost, and patient formulation preference (eg, pill formulation versus powder).

Bile acid sequestrants are optimally dosed at the time of bile acid release. If the patient has a gallbladder, we give bile acid sequestrants in conjunction with meals. If the patient does not have a gallbladder, we give the bile acid sequestrant in between meals and separated from other medications by at least two hours. We discontinue treatment if the patient does not respond adequately to a two-week trial. If a patient does not respond to one bile acid sequestrant, it is reasonable to try another agent before moving on to another class of pharmacotherapy.

●Efficacy and adverse effects – In one randomized trial of 24 patients with IBS-D, treatment with colesevelam twice daily increased colonic transit time by four hours on average compared with placebo [99]. Open-label studies also suggest improved bowel habits [100,101]. Additional randomized trials are warranted to confirm efficacy and tolerability.

Gastrointestinal side effects, including bloating, flatulence, abdominal discomfort, and constipation, may limit their use [3].

●Mechanism of action – Up to 50 percent of patients with functional diarrhea and IBS-D have bile acid malabsorption [102,103]. Excess bile acids cause diarrhea by stimulating colonic secretion and motility [104]. Bile acid sequestrants bind with bile acids to form an insoluble complex that is eliminated in the stool.

Alternative agents

Rifaximin — While antibiotics should not be routinely recommended in all patients with IBS, in patients with moderate-to-severe IBS-D who have had minimal response to other therapies, we suggest a two-week trial of rifaximin (algorithm 3). Rifaximin is locally acting, is well tolerated, and has modest efficacy in improving IBS symptoms, especially among patients with bloating and diarrhea as the predominant symptoms.

Rifaximin may also be used for the treatment of patients with IBS with mixed bowel habits and in patients with persistent global symptoms. (See 'Medical treatment for global symptoms' below.)

●Dosing – The suggested dose of rifaximin is 550 mg three times daily for 14 days. For patients with initial response who experience a recurrence of symptoms, we also offer retreatment with rifaximin every three to four months using the same regimen as some studies suggest modest efficacy with repeat dosing [6]. Rifaximin is not appropriate for daily longitudinal use.

●Efficacy and adverse effects – In a meta-analysis of five randomized trials, rifaximin was more effective than placebo for global IBS symptom improvement (odds ratio [OR] 1.57, 95% CI 1.22-2.01) and bloating (OR 1.55, 95% CI 1.23-1.96) [105]. In the two largest randomized trials that were included in the meta-analysis, rifaximin-treated patients also experienced improvement in diarrhea, daily stool consistency, and global IBS symptoms compared with placebo [106]. Rifaximin-treated patients also reported sustained symptom relief for up to 10 weeks following treatment. Adverse events were uncommon and similar between treatment and placebo groups.

In a subsequent randomized trial, retreatment with rifaximin in previous responders with IBS-D produced modest benefits in IBS symptoms, including abdominal pain, urgency, and quality of life, compared with placebo [107]. However, retreatment response rates were lower than those demonstrated in the original phase 3 trials, and no effect on stool consistency or bloating was demonstrated.

●Mechanism of action – Rifaximin is a locally acting antibiotic with activity against anaerobic, gram-positive, and gram-negative bacteria. Its efficacy in IBS is hypothesized to be related to alterations in the gut microbiome and a reduction in bacterial byproducts [108].

Alosetron and other 5-HT3 antagonists — We use alosetron for the treatment of severe IBS-D in patients who do not respond adequately to a trial of loperamide and at least one bile acid sequestrant (algorithm 3). Several factors limit the use of alosetron as it is approved by the US Food and Drug Administration (FDA) for the treatment of severe IBS-D in females only. Use of alosetron also requires the exclusion of gastrointestinal tract abnormalities (eg, history of mechanical obstruction, stricture, diverticulitis, severe constipation, etc) due to the risk of severe constipation and ischemic colitis.

●Dosing – We initiate alosetron at 0.5 mg once daily. If the medication is well tolerated but IBS-D symptoms persist, we increase the dose to 0.5 mg twice daily after four weeks, with a maximum dose of 1 mg twice daily. We discontinue alosetron if there is minimal response after four weeks at the maximum tolerated dose and in patients who develop constipation.

While alosetron is FDA-approved only for the treatment of IBS-D in females, we also prescribe this medication in males, using the same selection criteria and dosing guidance, based on additional trial data supporting its efficacy in males, as below.

●Efficacy and adverse effects – In a meta-analysis that included 11 randomized trials, treatment with alosetron resulted in a global improvement in IBS symptoms and relief of abdominal pain and discomfort [109]. Constipation was reported in up to 30 percent of patients in the treatment groups. Severe constipation and ischemic colitis have been reported, even at the lowest dose of alosetron [110,111]. Therefore, alosetron is contraindicated in patients with a history of gastrointestinal tract abnormalities. Alosetron should be discontinued immediately in patients who develop constipation; nonsevere constipation may be managed by resumption at a decreased dose.

Because an early phase II trial of alosetron did not show a treatment effect in males [112], subsequent phase II and III trials were performed exclusively in females. In a later randomized trial of 662 males with IBS-D, treatment with alosetron produced higher rates of relief of abdominal pain and urgency compared with placebo (53 versus 40 percent, respectively) [113].

Clinical trial data for alosetron in the treatment of IBS are discussed in more detail separately. (See "Alosetron hydrochloride (Lotronex) for irritable bowel syndrome", section on 'Clinical trials'.)

●Mechanism of action – Alosetron selectively blocks peripheral and central 5-hydroxytryptamine 3 (5-HT3) receptors, which modulates visceral afferent activity from the gastrointestinal tract, decreasing colonic motility and secretion and reducing visceral hypersensitivity [114-116]. The pharmacology of alosetron is discussed in additional detail separately. (See "Alosetron hydrochloride (Lotronex) for irritable bowel syndrome", section on 'Clinical pharmacology'.)

●Ondansetron – Ondansetron has been investigated as a potential alternative 5-HT3 antagonist with less risk of ischemic colitis. However, alosetron remains preferred for the treatment of IBS-D as ondansetron does not appear to have any effect on abdominal pain. In a randomized, crossover trial of 120 patients with IBS-D, while ondansetron improved stool consistency, frequency, and urgency, abdominal pain remained unchanged [117].

Eluxadoline — We reserve eluxadoline for the treatment of IBS-D in selected patients with severe IBS-D that is refractory to all other agents as it is associated with a high incidence of severe acute pancreatitis (algorithm 3) [6,118,119]. We ensure that patients are appropriately informed about risks and adverse effects before starting the medication. Eluxadoline is contraindicated in patients without a gallbladder and in patients with a history of biliary disorders, pancreatitis, severe liver impairment (Child-Pugh class C), and heavy alcohol use.

●Dosing – The usual dose of eluxadoline is 100 mg twice daily. For patients who experience side effects of nausea or constipation, the dose may be reduced to 75 mg twice daily. We discontinue eluxadoline in patients who do not respond adequately to a 12-week trial. Given the potential for severe side effects, we evaluate symptoms regularly and offer a trial off the medication if symptoms have fully resolved for 12 months or longer. (See 'Duration of therapy' below.)

●Efficacy and adverse effects – In two phase 3 studies of 2427 patients with IBS-D followed for either 26 or 52 weeks, more patients treated with eluxadoline 100 mg reached the primary endpoint of sustained decreased abdominal pain and improved stool consistency when compared with placebo in the first 12 weeks (25 versus 17 percent in the 26-week study and 30 versus 16 percent in the 52-week study, respectively) [120]. Response to eluxadoline was similar at 26-week follow-up in both studies.

Pancreatitis was reported in 0.3 percent of patients treated with eluxadoline. All cases of pancreatitis occurred in patients with either biliary disorders (spasm of the sphincter of Oddi and biliary sludge) or alcohol use. Common adverse events associated with eluxadoline were nausea, constipation, and abdominal pain.

●Mechanism of action – Eluxadoline is a mixed mu- and kappa-opioid receptor agonist and a delta-opioid receptor antagonist. Because opioid receptors in the gastrointestinal tract regulate gastrointestinal motility, fluid secretion, and visceral sensation, eluxadoline exerts its effect by slowing gastrointestinal transit and increasing mu-opioid receptor-mediated central analgesia [121,122].

TREATMENT FOR MIXED OR UNCLASSIFIED IBS (IBS-M OR IBS-U) — 

Unlike in diarrhea-predominant IBS (IBS-D) and constipation-predominant IBS (IBS-C), patients with IBS-M and IBS-U do not have a predominant abnormal bowel habit. In such patients, we discourage pharmacotherapy targeted to bowel habits as this may inadvertently exacerbate symptoms. Instead, we use the following subtype-guided approach. Because IBS subtypes are dynamic, we confirm the IBS subtype at every visit to ensure pharmacotherapy is targeted to the appropriate subtype. (See 'Determining IBS subtype' above.)

IBS with mixed bowel habits (IBS-M) — In IBS-M, abnormal bowel movements include constipation and diarrhea with similar frequency. In our experience, lifestyle and dietary interventions are particularly beneficial in IBS-M. Therefore, we revisit fiber supplementation and a low fermentable oligo-, di-, and monosaccharides and polyols diet, even if an initial trial did not provide adequate relief (see 'Dietary modifications' above). We add pharmacotherapy for persistent global symptoms.

We also rule out primary constipation with overflow fecal incontinence in patients with IBS-M as this condition may present with similar symptoms.

If a predominant bowel habit (eg, IBS-C or IBS-D) develops during treatment, we add additional treatment based on the IBS subtype.

IBS unclassified (IBS-U) — Because there is no associated treatment guidance for IBS-U, in practice, we reclassify these patients as IBS-C, IBS-D, or IBS-M based on our best estimate of the predominant bowel habit and treat accordingly. (See 'Medical treatment for constipation-predominant IBS (IBS-C)' above and 'Medical treatment for diarrhea-predominant IBS (IBS-D)' above.)

MEDICAL TREATMENT FOR GLOBAL SYMPTOMS — 

Global IBS symptoms include abdominal pain, cramping, and bloating. In patients with persistent global symptoms despite lifestyle and diet modifications and subtype-specific treatment, we use a combination of short-term pharmacotherapy to control symptom flares and continuous pharmacotherapy for daily or generalized symptoms (algorithm 4).

Antispasmodic agents for episodic symptoms — We use antispasmodic agents in patients with intermittent global symptoms despite diet and subtype-directed medical therapy (algorithm 4). Antispasmodics provide short-term relief of acute abdominal pain [123-128]. They are also useful in anticipation of stressors with known exacerbating effects (eg, public speaking, travel, etc). Because long-term efficacy has not been established, we use antispasmodics as needed and avoid daily use.

Treatment with antispasmodics may be combined with tricyclic antidepressants (TCAs) in patients with both episodic and persistent daily symptoms, as below. (See 'Tricyclic antidepressants for persistent symptoms' below.)

The choice of antispasmodic agent is guided by availability as agents and formulations vary depending on practice location:

●Anticholinergics – We use anticholinergics for "as-needed" treatment for acute pain episodes. Anticholinergics block the action of acetylcholine at parasympathetic sites in smooth muscle, secretory glands, and the central nervous system, resulting in short-term relief of abdominal cramping and pain. Because the only studies evaluating their efficacy are small, older trials with methodologic limitations [129-131], the American College of Gastroenterology does not recommend their use for global symptoms of IBS [3]. In our experience, however, anticholinergics are an important treatment option that may help to avoid daily medication in patients for whom polypharmacy is common.

We use hyoscyamine 0.125 to 0.25 mg orally or sublingually three to four times daily as needed (algorithm 4). We find the sublingual formulation is a useful "rescue" medication for acute, episodic abdominal symptoms, which may be reassuring for patients with symptom-related anxiety.

Constipation is a common side effect of anticholinergics, which may be an added benefit in patients with IBS and diarrhea. In patients with constipation, we use anticholinergics sparingly and with close supervision to ensure symptoms do not worsen.

●Enteric-coated peppermint oil – Peppermint oil may modestly improve abdominal pain and is a useful treatment for patients interested in herbal remedies. Peppermint oil exerts its beneficial effects through direct antimicrobial and anti-inflammatory effects, modulation of psychosocial distress, and smooth muscle relaxation [132]. In small randomized trials, peppermint oil was well tolerated and improved abdominal symptoms in patients with IBS and either constipation or diarrhea [125-127].

As it is an herbal treatment, peppermint oil formulations may vary (algorithm 4). In the studies, patients were given one to two enteric-coated capsules two to four times daily. Enteric-coated or encapsulated formulations ensure the active ingredient is released into the small bowel.

●Other agents – In a meta-analysis of 29 studies, including smaller studies of individual agents, antispasmodics were associated with a significant improvement in abdominal pain, global assessment, and symptom scores as compared with placebo [128]. Additional conclusions are limited because the class includes multiple agents with varied mechanisms of action. The following antispasmodics have been used in the treatment of IBS:

•Alverine.

•Mebeverine and pinaverium exert their effect on smooth muscle relaxation via calcium channel blockade.

•Otilonium bromide.

•Pargeverine, propinox.

•Trimebutine.

Tricyclic antidepressants for persistent symptoms — In patients with persistent, daily abdominal pain, we suggest a trial of TCAs (algorithm 4), which have analgesic properties independent of their effects on mood [44,128,133-135]. We emphasize the pain-modulating properties of TCAs when discussing their role in the treatment of IBS, which often assists with patient acceptance.

TCAs also slow intestinal transit time, which may be beneficial in diarrhea-predominant IBS (IBS-D) [6,136]. Conversely, TCAs should be used cautiously and with close supervision in patients with constipation [133,137].

For the treatment of abdominal pain in IBS, TCAs should be started at low doses (eg, 10 mg at bedtime), with dose adjustment based on tolerance and response (algorithm 4). Due to the delayed onset of action, three to four weeks of therapy should be attempted before increasing the dose. If the patient is intolerant of one TCA, another may be trialed.

In one randomized trial, 463 primary care patients with IBS were assigned to titrated low-dose amitriptyline (10 to 30 mg daily) or placebo as a second-line treatment for IBS [138]. At six months, patients treated with low-dose amitriptyline had lower IBS symptom severity scores as compared with placebo and were significantly more likely to report considerable or complete relief of IBS symptoms (36 versus 23 percent, odds ratio 1.88, 95% CI 1.20-2.95). The most common side effects were related to the anticholinergic effects of amitriptyline, but the majority were mild and did not result in discontinuation.

TCAs may be combined with antispasmodics in patients with both episodic and persistent symptoms, as above. (See 'Antispasmodic agents for episodic symptoms' above.)

Other alternatives — We use rifaximin as an additional treatment option for patients with IBS with mixed bowel habits and/or persistent global IBS symptoms using the same dosing and retreatment guidance described for its use in the treatment of IBS-D (algorithm 4). (See 'Rifaximin' above.)

BRAIN-GUT BEHAVIORAL THERAPIES — 

Brain-gut behavioral therapies such as gut-directed hypnotherapy, cognitive-behavioral therapy (CBT), and mindfulness therapy, among other therapeutic techniques, improve both IBS symptoms and psychosocial contributors to pain [23,24,139]. We prioritize these therapies in patients with symptom-driven mood disturbance (eg, anxiety, depression), patients interested in nonpharmacologic treatment, and patients with refractory symptoms. These therapies address the disordered gut-brain interaction hypothesized to underlie IBS [140,141]. Because brain-gut behavior therapy focuses on gastrointestinal symptoms, we also refer patients with primary anxiety, depression, or other mood disorders for psychologic treatment targeted at the primary mood disturbance.

The choice of treatment modality is guided by patient interest and local availability:

●CBT – CBT is a goal-oriented, problem-solving psychotherapy aimed at reducing maladaptive beliefs and stress-related behaviors [25]. It has been used in the treatment of many psychiatric and chronic pain syndromes. (See "Approach to the management of chronic non-cancer pain in adults", section on 'Cognitive-behavioral therapy'.)

CBT reduces pain, stress, depression, and anxiety in patients with IBS while improving the severity and frequency of IBS symptoms [139,142-145]. In a network meta-analysis of 19 smaller randomized trials, all forms of CBT, including telephone, face-to-face, group, and self-administered CBT were more effective than waiting list control and routine care in improving IBS symptoms, though the endpoints used to define symptom response varied widely [23].

●Gut-directed hypnotherapy – Gut-directed hypnotherapy employs therapist-guided suggestions to promote relaxation, calm the digestive tract, and divert unnecessary focus on body discomfort. We reassure patients that throughout gut-directed hypnotherapy sessions, they remain in complete control of their mind and body.

Gut-directed hypnotherapy produces sustained improvements in IBS-related quality of life [23,139,146-149]. In one randomized trial of 354 patients with IBS, 41 percent of patients receiving individual hypnotherapy achieved adequate relief of IBS symptoms at three months compared with 17 percent of patients receiving educational supportive therapy (95% CI 31.7-50.5 and 7.6-32.6, respectively). Group hypnotherapy was similarly effective, with 33 percent of patients also achieving adequate IBS relief at three months (95% CI 24.3-43.5). Improvement for both individual and group hypnotherapy was sustained at 12-month follow-up.

●MBSR therapy – Mindfulness-based stress reduction (MBSR) is a mind-body relaxation technique designed to enhance a person's ability to relax, cope with stress, and manage pain. It has been used in the treatment of several psychiatric and chronic pain syndromes. (See "Approach to the management of chronic non-cancer pain in adults", section on 'Mind-body therapies' and "Overview of complementary, alternative, and integrative medicine practices in oncology care, and potential risks and harm", section on 'Meditation and mindfulness-based stress reduction'.)

In one single-arm study in 68 patients with IBS, an eight-week MBSR program was associated with improvement in IBS severity score and quality of life score and reduced gastrointestinal-related fear and anxiety at six-month follow-up. Further studies with randomized trials are warranted to confirm these findings.

SUBSEQUENT MANAGEMENT

Refractory symptoms — Patients with IBS may experience relapsing or refractory symptoms. In such patients, we repeat stool diary and diet history to confirm treatment is appropriate for the current IBS subtype and ensure that symptoms are not due to dietary triggers (see 'Determining IBS subtype' above and 'Initial dietary evaluation' above). We also review symptoms for "alarm features" that suggest new diagnoses warranting further evaluation. (See 'Indications for specialty referral' above.)

If no alarm features are present and dietary triggers are ruled out, we focus on incremental symptom improvement using combination therapy with subtype-guided medications, as above. We also refer for psychologic therapy and dietitian guidance, which may be beneficial even for patients who have completed previous consultations. (See 'Brain-gut behavioral therapies' above.)

Duration of therapy — In our experience, IBS can remit in a small minority of patients. Therefore, if patients on pharmacotherapy achieve full symptom resolution for 12 months or longer, we offer a trial off medications, using a shared decision-making approach, especially for medications with the potential for severe adverse effects (eg, eluxadoline). In such patients, we taper slowly and monitor for symptom recurrence. We continue all effective lifestyle and dietary modifications indefinitely.

TREATMENTS WITH LIMITED EVIDENCE OF BENEFIT

Gluten avoidance — We do not recommend gluten-free diets in the treatment of IBS. Nonceliac gluten sensitivity (NCGS) has been hypothesized as an underlying pathophysiologic mechanism in IBS as gluten has been demonstrated to alter bowel barrier functions in patients with diarrhea-predominant IBS (IBS-D) [150]. However, studies of gluten avoidance in patients with IBS have yielded conflicting and inconclusive results [151-155]. For example, while two randomized trials suggested that reintroducing a gluten-containing diet increased IBS symptoms, these studies were small, unblinded, and with a substantial risk of bias [152,154]. A subsequent evaluation of the data from both trials found no difference in IBS symptoms between the gluten-free and gluten-containing diets [155].

Another study suggests that the symptomatic improvement associated with a gluten-free diet is not due to the removal of gluten but rather the reduction of fructans, a type of fermentable oligo-, di-, and monosaccharides and polyols present with high frequency in many gluten-containing foods that are known to exacerbate IBS symptoms [156] (see 'Low-FODMAP diet' above). In this randomized, crossover trial of patients with self-reported NCGS, overall IBS symptom scores were higher with fructan-containing diets compared with gluten-containing diets. There was no difference in symptom scores between gluten and placebo groups.

The diagnosis of celiac disease and testing to rule out celiac disease in patients with diarrhea and suspected IBS are discussed separately. (See "Diagnosis of celiac disease in adults" and "Clinical manifestations and diagnosis of irritable bowel syndrome in adults", section on 'Laboratory testing'.)

Other therapies — Several other therapies have been proposed for patients with IBS with limited or uncertain evidence of benefit:

●Ondansetron – Ondansetron has been evaluated as an alternative to alosetron with a similar mechanism of action. However, alosetron remains the preferred agent in this class as ondansetron appears to have minimal impact on abdominal pain. (See 'Alosetron and other 5-HT3 antagonists' above.)

●Other antidepressants – We do not use selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) for the treatment of IBS, given the lack of consistent high-quality evidence demonstrating an improvement in symptoms. Results of the few published trials evaluating SSRIs and SNRIs in the treatment of IBS have been inconsistent [128,135,157-164]. A 2015 meta-analysis that included 12 randomized trials concluded that antidepressants were significantly more effective than placebo in improving global IBS symptoms (risk ratio 1.38, 95% CI 1.08-1.77) [164]. However, in subgroup analysis, treatment with tricyclic antidepressants, but not SSRIs, showed an improvement in global symptoms as compared with the control groups [5,157,165].

●Diets based on food allergy testing – There is insufficient evidence to support routine food allergy testing and associated elimination diets in patients with IBS [166,167]. In one randomized trial, patients following an elimination diet based on elevated immunoglobulin G antibodies had similar IBS symptom severity scores at 12 weeks compared with a sham elimination diet [168]. In a smaller randomized trial evaluating sham elimination diet versus elimination diet based on leukocyte activation testing, the intervention diet modestly improved global symptom scores at four weeks (mean between-group difference 0.86, 95% CI 0.05-1.67, on a seven-point scale) [169]. There was no difference between groups for the secondary endpoints of quality of life and adequate relief of IBS symptoms.

Other methods used in evaluating food allergies (eg, skin prick testing, radioallergosorbent testing, and atopy patch testing) have not been well studied in IBS. The signs and symptoms of a food allergy and the approach to the evaluation of food allergy symptoms are discussed separately. (See "Clinical manifestations of food allergy: An overview" and "Diagnostic evaluation of IgE-mediated food allergy".)

●Probiotics – There is insufficient evidence to support the use of probiotics in the treatment of IBS [170,171]. Though many published studies exist, small sample sizes and significant heterogeneity in study design, endpoints, and probiotic combinations limit their generalizability. Although some studies suggest probiotics may improve IBS symptoms, the magnitude of benefit and the most effective species, strain, and formulation are uncertain [172,173].

●Fecal microbiota transplantation (FMT) – We do not recommend FMT in the treatment of IBS, as published trials report inconsistent results and methodologic limitations [174-177]. In one randomized trial of 90 patients with IBS-D and IBS with mixed bowel habits, fresh or frozen FMT administered via colonoscopy improved IBS symptom severity scores at three months compared with placebo (65 versus 43 percent) [174]. However, this difference was not sustained over time, and the study did not include baseline or follow-up evaluation of fecal microbial diversity. Other randomized trials have not shown any benefit of FMT over placebo [175,176]. Additional studies are needed to determine if there are subgroups of patients who may benefit from FMT and the optimal FMT dose.

●Ketotifen – Ketotifen, a mast cell stabilizer, has been studied for the treatment of IBS based on the theory that mast cell activation contributes to visceral hypersensitivity [178,179]. In one randomized trial of 108 patients with IBS-D, treatment with ketotifen 1 mg twice daily improved symptoms of urgency and gastrointestinal discomfort compared with placebo at eight weeks (76 versus 38 percent) [179]. Measures of anorectal sensitivity also improved in the ketotifen group, suggesting improvement in visceral sensitivity. Treatment with ketotifen was associated with mild drowsiness but was otherwise well tolerated. Additional studies with larger sample sizes and longer follow-up are warranted to determine the role of ketotifen in the treatment of IBS.

●STW5 (Iberogast) – STW5 (Iberogast) is an herbal product composed of a proprietary blend of nine extracts [180]. While this product improved IBS symptoms in one randomized trial [181], serious hepatotoxicity has also been reported, leading several countries to implement warnings limiting its use.

●Aldafermin – Aldafermin is an analog of the gut hormone fibroblast growth factor 19 (FGF19) that has been studied for the treatment of metabolic dysfunction-associated steatohepatitis. Aldafermin is hypothesized to also have efficacy in patients with IBS-D and bile acid diarrhea as decreased FGF19 production and increased bile acid synthesis have been noted in these patients in translational studies [182]. In a randomized trial of 31 patients with IBS and bile acid diarrhea, treatment with aldafermin reduced bile acid synthesis and secretion compared with placebo, but there was no difference in abdominal pain or stool frequency between the two groups [183]. Treatment-related adverse events including worsening diarrhea were higher in patients treated with aldafermin compared with placebo (93 versus 47 percent). Further studies with larger sample sizes are needed to determine if aldafermin has a role in IBS treatment.

●Mesalamine – Based on the evidence of low-grade intestinal inflammation in a subset with IBS, mesalamine has been tested in clinical trials. In one meta-analysis including eight randomized trials, mesalamine modestly improved global symptoms in IBS but had no effect on bowel symptoms or other patient-important outcomes [184]. Further conclusions are limited due to methodologic flaws and low quality of evidence in the included studies.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Irritable bowel syndrome".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Irritable bowel syndrome (The Basics)" and "Patient education: Low-FODMAP diet (The Basics)")

●Beyond the Basics topics (see "Patient education: Irritable bowel syndrome (Beyond the Basics)" and "Patient education: High-fiber diet (Beyond the Basics)" and "Patient education: Gas and bloating (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Initial therapy for all patients – Successful treatment of irritable bowel syndrome (IBS) requires a trusting clinician-patient relationship to validate symptoms, establish realistic expectations, and ensure continuity of care. Lifestyle modifications should include regular physical activity, improved sleep hygiene, and stress reduction. (See 'Lifestyle modifications and behavioral interventions' above.)

●Dietary modifications – Diet changes are a key component of management. First, we review the patient's diet and stool history, screen for disordered eating and risk factors for malnutrition, and refer for a dietitian consultation when available. Dietitian-led education is associated with improvement in diet adherence and IBS symptoms. (See 'Initial dietary evaluation' above.)

•Initial diet advice – We suggest traditional IBS dietary advice (table 3) as the initial dietary modification for patients with IBS, rather than other diets (Grade 2C). In our experience, traditional IBS dietary advice is reasonably effective, easier to follow, and less costly to implement than other diets. Key features of traditional IBS dietary advice include soluble fiber supplementation and avoiding gas-producing foods (table 4) and individual symptom triggers. (See 'Traditional IBS dietary advice' above.)

•Low fermentable oligo-, di-, and monosaccharides and polyols (FODMAP) diet – The low-FODMAP diet (table 5) is a reasonable alternative for patients with persistent symptoms after traditional diet changes and in patients with interest in the low-FODMAP diet as the initial intervention. FODMAP restriction improves global IBS symptom scores.

Implementation requires three sequential steps during which FODMAPs are eliminated and gradually reintroduced, typically in consultation with a dietitian. (See 'Low-FODMAP diet' above.)

●Subtype-directed medical therapy – Medical therapy is indicated if lifestyle and diet modifications do not provide adequate symptom improvement. The IBS subtype guides the initial choice of pharmacotherapy. (See 'Determining IBS subtype' above.)

•IBS with predominant constipation (IBS-C) – We suggest polyethylene glycol (PEG) as the initial pharmacotherapy for patients with IBS-C (Grade 2C). PEG is inexpensive, well tolerated, and effective in increasing spontaneous bowel movements and improving stool consistency (algorithm 2). PEG is also easily titratable and has fewer side effects than other osmotic laxatives. (See 'Polyethylene glycol (PEG) as our preferred initial therapy' above.)

Linaclotide, plecanatide, lubiprostone, and tenapanor are reasonable alternatives in patients for whom PEG is not adequately effective. The choice of therapy is guided by predominant symptoms and side effect profiles. Agents may be trialed sequentially to determine the treatment regimen that offers optimal relief. (See 'Alternative agents' above.)

•IBS with predominant diarrhea (IBS-D) – In patients with diarrhea-predominant symptoms, we suggest loperamide as initial pharmacotherapy (Grade 2C). Though loperamide does not appear to influence global IBS symptoms when compared with other options for IBS-D, loperamide is widely available, well tolerated, and effective in decreasing stool frequency and improving stool consistency (algorithm 3). Dosing may be titrated to optimal effect. (See 'Loperamide as our preferred initial therapy' above.)

In patients with inadequate symptom improvement with loperamide, we use bile acid sequestrants as second-line therapy. Bile acid sequestrants reduce excess bile acids that accumulate due to bile acid malabsorption, thereby increasing stool transit time and improving stool consistency. (See 'Bile acid sequestrants as second-line therapy' above.)

Other alternative treatment options for IBS-D include rifaximin, alosetron, and eluxadoline. The choice of therapy is guided by predominant symptoms and side effect profiles. (See 'Alternative agents' above.)

•IBS with mixed bowel habits (IBS-M) – In our experience, lifestyle and dietary interventions are particularly beneficial in treating IBS-M. Pharmacotherapy for persistent global symptoms may also be added. Treatment choice is guided by patient characteristics. (See 'Initial therapy for all patients' above and 'Medical treatment for global symptoms' above.)

If a predominant bowel habit (eg, IBS-C or IBS-D) develops, we add treatment based on the IBS subtype. (See 'Medical treatment for constipation-predominant IBS (IBS-C)' above and 'Medical treatment for diarrhea-predominant IBS (IBS-D)' above.)

•IBS unclassified (IBS-U) – Because there is no associated treatment guidance for IBS-U, we reclassify these patients as IBS-C, IBS-D, or IBS-M based on our best estimate of the predominant bowel habit and treat accordingly. (See 'Medical treatment for constipation-predominant IBS (IBS-C)' above and 'Medical treatment for diarrhea-predominant IBS (IBS-D)' above.)

●Adjunctive psychologic therapies – Gut-directed hypnotherapy, cognitive-behavioral therapy, and mindfulness therapy are effective psychologic therapies that improve IBS symptoms and psychosocial contributors to pain. These may be added alongside ongoing lifestyle, diet, and medical therapy. (See 'Brain-gut behavioral therapies' above.)

●Persistent or refractory symptoms – In patients with persistent global symptoms (eg, abdominal pain, cramping, bloating, etc) despite subtype-specific treatment, we suggest anticholinergics or other antispasmodics as short-term therapy to control symptom flares and in anticipation of known symptom triggers (eg, public speaking, travel, etc) (Grade 2C). We use tricyclic antidepressants to treat persistent daily or generalized global symptoms (algorithm 4). (See 'Medical treatment for global symptoms' above.)

Patients with refractory symptoms warrant re-evaluation to confirm the IBS subtype, review dietary triggers, and screen for new diagnoses. (See 'Determining IBS subtype' above and 'Indications for specialty referral' above.)

If no alarm features are present and a diet review is conducted, we focus on incremental symptom improvement using combination therapy with subtype-guided medications, as above, along with re-referral for psychologic therapy and dietitian guidance. (See 'Refractory symptoms' above.)