Treatment of irritable bowel syndrome

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Official reprint from UpToDate www.uptodate.com 2013 UpToDate

Treatment of irritable bowel syndrome Author Arnold Wald, MD Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Nov 2013. | This topic last updated: May 7, 2013. INTRODUCTION Irritable bowel syndrome (IBS) is a gastrointestinal disorder characterized by chronic abdominal pain and altered bowel habits in the absence of any organic disorder. The approach to therapy of IBS will be reviewed here. The clinical manifestations and diagnosis of this disorder are discussed separately. (See "Clinical manifestations and diagnosis of irritable bowel syndrome".) GENERAL PRINCIPLES Irritable bowel syndrome (IBS) is a chronic condition with no known cure. As a result, the focus of treatment should be on relief of symptoms and addressing the patient's concerns. An important question to answer is why the patient is seeking help at this time. Recent exacerbating factors (medications, dietary changes), concerns about serious illness, stressors, hidden agendas (disability claims, requests for opiates), or psychiatric comorbidities are critical to establish when developing the optimum therapy [1]. Therapeutic relationship The most important component of treatment lies in the establishment of a therapeutic physician-patient relationship. The doctor should be non-judgmental, establish realistic expectations with consistent limits, and involve the patient in treatment decisions [1]. Patients with established, positive physician interactions have fewer IBS-related follow-up visits [2]. The importance of the therapeutic relationship in IBS was emphasized in a study that investigated the components of the placebo effect and patient-provider interaction in 262 patients with IBS [3]. Group 1 was assigned to a waitlist only, whereas Group 2 received sham acupuncture with little interaction with a health care provider (HCP). Group 3 received sham acupuncture but had much more interaction with a HCP. At both three and six weeks, the level of improvement in Group 3 was significantly better than Group 2, which in turn was significantly better than Group 1. The conclusion was that placebo effects are significant in IBS and that the patient-HCP interaction is the key part of that effect. Patient education Education of the proposed mechanisms of IBS helps to validate the patient's illness experience and sets the basis for therapeutic interventions. (See "Pathophysiology of irritable bowel syndrome".) Patients should be informed of the chronic and benign nature of IBS, and also informed that the diagnosis (if well-established) is not likely to be changed, and that he or she should have a normal life span. In a 29-year follow-up study of 112 patients from the Mayo Clinic, for example, only 10 of 112 patients developed an organic gastrointestinal disease; patient survival was similar to expected survival [2]. (See "Patient information: Irritable bowel syndrome (Beyond the Basics)".) Dietary modification A careful dietary history may reveal patterns of symptoms related to specific foods. A number of dietary interventions have been proposed but their efficacy has not been well established. Lactose Given the similarity that may occur in symptoms of IBS and lactose intolerance, an empiric trial of a lactose free diet should be considered in patients suspected of having irritable bowel syndrome [4,5]. Some patients diagnosed with irritable bowel syndrome may have undiagnosed lactose intolerance and can have lasting clinical
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Section Editor Nicholas J Talley, MD, PhD

Deputy Editor Shilpa Grover, MD, MPH

Treatment of irritable bowel syndrome

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improvement when placed on a lactose restricted diet [5]. (See "Lactose intolerance".) Exclusion of gas-producing foods Exclusion of foods that increase flatulence (beans, onions, celery, carrots, raisins, bananas, apricots, prunes, brussel sprouts, wheat germ, pretzels, and bagels) should be considered in patients who complain of gas [6]. Underlying visceral hyperalgesia in IBS may explain the exaggerated discomfort experienced with consumption of gas-producing foods. (See "Intestinal gas and bloating" and "Patient information: Gas and bloating (Beyond the Basics)" and "Pathophysiology of irritable bowel syndrome".) Food allergies The role of food allergy in IBS is unclear. While it is possible that food allergy has a role in the development of symptoms, there are no reliable means to identify such individuals. Testing for serum immunoglobulins directed at specific dietary antigens (and elimination of responsible foods) has been proposed but the relationship between results of such testing and improvement of symptoms requires additional study before such an approach can be recommended [7]. Other methods used in evaluating food allergies (eg, skin prick testing, RAST testing and atopy patch testing) have not been well studied in IBS. (See "Diagnostic evaluation of food allergy".) Gluten sensitivity Gluten sensitivity (without overt celiac disease) has been proposed as a cause of functional bowel disorders but there are few convincing studies that have evaluated such a relationship in terms of pathogenesis or treatment of IBS [8-10]. It is also unclear if gluten sensitivity is itself a separate clinical entity [8,11-15]. A trial of 34 patients examined the effect of a gluten-free diet in patients without celiac disease [16]. Patients were either HLA-DQ2 and HLA-DQ8 negative or had normal duodenal biopsies. Patients in the gluten arm received two gluten containing bread slices and one muffin per day, whereas the control patients received placebos. Patients in the gluten group were more likely to report inadequate symptom control compared with the placebo group (68 versus 40 percent). Carbohydrate malabsorption One theory related to IBS (and inflammatory bowel disease [IBD]) suggests that symptoms may be at least in part related to impaired absorption of carbohydrates. The theory holds that fermentable oligo-, di-, and monosaccharides and polyols (FODMAPs) in patients with IBS or IBD enter the distal small bowel and colon where they are fermented, leading to symptoms and increased intestinal permeability (and possibly inflammation) [17]. Some examples of FODMAPs include: Fructans (found in wheat, onions, and artichokes) Galactans (found in legumes, cabbage, and Brussels' sprouts) Lactose Fructose Sorbitol Xylitol Mannitol Avoidance of carbohydrates has been a long-popularized non-pharmacologic approach to reducing symptoms in IBS (and possibly modifying disease in IBD) [18] but there have been few contemporary studies. Fructose intolerance has been suggested as a possible form of carbohydrate malabsorption contributing to IBS [19]. Studies examining FODMAP restriction in patients with IBS have suggested a clinical benefit: A randomized trial with 25 patients found that patients who were given fructose and/or fructans were more likely to report inadequate symptom control compared with patients who were given glucose (70 to 79 percent versus 14 percent) [20]. In addition, symptoms were induced in a dose-dependent manner and mimicked the patients previous IBS symptoms. A single-blind crossover trial gave 15 healthy volunteers and 15 patients with IBS diets that were either low (9
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g/day) or high (50 g/day) in FODMAPs [21]. Patients with IBS had a significant increase in gastrointestinal symptoms and lethargy while on the high FODMAPs diet, whereas healthy volunteers only reported increased flatus production while on the high FODMAPs diet. Another small crossover trial of patients with IBS-D found a clinical benefit with a very low carbohydrate diet (20 g of carbohydrates per day) [22]. While diets low in FODMAPS have not been definitively shown to be of benefit, it is reasonable for patients to undergo a trial of a low FODMAPS diet, provided that their nutritional status is being monitored. Fiber An increase in the intake of fiber is often recommended, either through diet or the use of commercial bulking supplements. However, not all authorities agree. A systematic review found no beneficial effect for bulking agents over placebo for improvement of abdominal pain, global assessment or symptom scores. Subgroup analyses showed no significant benefit with either insoluble or soluble fibers [23]. A decrease in fiber intake to 12 g per day (particularly insoluble fiber such as bran) was suggested in a British guideline, because of the potential of fiber to exacerbate symptoms [24]. Proposed mechanisms for fiber's beneficial effects include: enhancement of water holding properties of the stool; formation of gels to provide lubrication; bulking of the stool; and binding of agents such as bile [25]. Despite their widespread use, a systematic review that included 13 randomized controlled trials found no convincing evidence that the commonly-used bulking agents were more effective than placebo at relieving global IBS symptoms [26]. Although the efficacy of fiber supplements has not been proven, some improvement has been demonstrated in patients with IBS whose primary complaints are abdominal pain and constipation [27]. Synthetic fiber supplements such as polycarbophil and methylcellulose are more soluble than natural fibers (psyllium). However, whether the synthetic supplements cause less bloating or are more effective than natural fiber supplements has not been determined. Some patients may experience increased bloating and gaseousness due to colonic metabolism of non-digestible fiber. Because of its safety and frequent placebo effect, a trial of fiber is reasonable in all patients with IBS, especially those with constipation-predominant symptoms. Dosages of fiber supplements such as wheat bran or psyllium should be titrated to symptoms. Administration of one-half to one tablespoon once a day is a good starting dose. Physical activity Increased physical activity may help with the symptoms of IBS. This was examined in a randomized trial that assigned 102 patients to increased physical activity to maintenance of current activity levels [28]. Increased physical activity was comprised of 20 to 60 minutes of moderate to vigorous activity three to five days per week. The amount of physical activity prescribed was determined in part by the patients baseline level of activity. Seventy-five patients completed the study (38 in the physical activity arm and 37 in the control arm). After 12 weeks, there was a trend toward more patients in the physical activity arm showing clinical improvement in the severity of IBS symptoms compared with the control group (43 versus 26 percent, p = 0.07). In addition, patients in the physical activity arm were less likely to have clinically significant worsening of their IBS symptoms (8 versus 23 percent, p <0.01). It is reasonable to recommend increased physical activity for patients with IBS given that these data suggest a potential benefit with regard to symptoms as well the general health benefits associated with increased physical activity. (See "Overview of the benefits and risks of exercise", section on 'Benefits of exercise'.) Psychosocial therapies Behavioral treatments may be considered for motivated patients who associate symptoms with stressors, although their benefits remain controversial [1,29]. Hypnosis, biofeedback, and psychotherapy help to reduce anxiety levels, encourage health promoting behavior, increase patient responsibility and involvement in the treatment, and improve pain tolerance [30].

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A 2009 meta-analysis that included 20 placebo-controlled trials of antidepressants in 1278 adults with IBS concluded that psychological therapy was significantly more effective than control therapy or usual management for at least a 50 percent reduction in symptoms (relative risk of IBS symptoms persisting 0.67, 95% CI 0.57 to 0.79) [31]. A similar conclusion was reached by the 2009 position statement on IBS by the American College of Gastroenterology Task Force on Irritable Bowel Syndrome [26]. A lesser benefit was noted in another systematic review [32]. The mechanism of benefit from psychosocial therapies is unclear. In one randomized controlled trial, mindfulness training, a cognitive behavioral technique, reduced IBS symptom severity, improved health-related quality of life, and reduced distress [33]. However, in another randomized trial, symptom improvement was independent of the effects of cognitive behavioral therapy in alleviating comorbid psychological distress [34]. MEDICATIONS Pharmacologic agents are only an adjunct to treatment in irritable bowel syndrome (IBS). Furthermore, the drug chosen varies depending on the patient's major symptoms; diarrhea-predominant IBS is treated differently from constipation-predominant disease. We suggest that the chronic use of drugs be generally minimized or avoided because of the lifelong nature of this disorder and the lack of convincing therapeutic benefit. The difficulty in demonstrating efficacy may in part be due to the heterogeneous population diagnosed with IBS, the lack of disease markers, and the high placebo response rates [35]. Antispasmodic agents Antispasmodic agents are the most frequently used pharmacologic agents in the treatment of IBS. Certain antispasmodic drugs (hyoscine, cimetropium, and pinaverium) may provide short-term relief but long-term efficacy has not been demonstrated [26]. Peppermint oil may also act as a smooth muscle relaxant (see 'Alternative therapies' below). The antispasmodic agents include those that directly affect intestinal smooth muscle relaxation (eg, mebeverine and pinaverine), and those that act via their anticholinergic or antimuscarinic properties (eg, dicyclomine and hyoscyamine) [26]. The selective inhibition of gastrointestinal smooth muscle reduces stimulated colonic motor activity and may be beneficial in patients with postprandial abdominal pain, gas, bloating, and fecal urgency [36]. A meta-analysis of 23 controlled trials of smooth muscle relaxants found that they were more effective than placebo (risk difference for global improvement of 22 percent, and overall pain improvement of 53 versus 41 percent) [37]. Only weak evidence for a benefit on abdominal pain and global assessment of symptoms was suggested in a second meta-analysis [38]. A systematic review confirmed the support for short-term use of some antispasmodic drugs [26]. In another systematic review, subgroup analyses of different types of antispasmodics found statistically significant benefits for cimetropium/dicyclomine, peppermint oil, pinaverium and trimebutine [23]. Administration of these medications in the treatment of IBS should be on an as needed basis and/or in anticipation of stressors with known exacerbating effects. Typical doses include: Dicyclomine 20 mg orally four times daily as needed Hyoscyamine 0.125 to 0.25 mg orally or sublingually three to four times daily as needed Sustained release hyoscyamine 0.375 to 0.75 mg orally every 12 hours Antidepressants Antidepressants have analgesic properties independent of their mood improving effects and may therefore be beneficial in patients with neuropathic pain [39-42]. The postulated mechanisms of pain modulation with tricyclic antidepressants (TCAs) and possibly serotonin reuptake inhibitors (SSRIs) in IBS are facilitation of endogenous endorphin release, blockade of norepinephrine reuptake leading to enhancement of descending inhibitory pain pathways, and blockade of the pain neuromodulator, serotonin [42,43]. TCAs, via their anticholinergic properties, also slow intestinal transit time [42], which may provide benefit in diarrhea-predominant IBS [44]. A 2009 meta-analysis that included 13 placebo-controlled trials of antidepressants in 789 adults with IBS concluded that antidepressants were significantly more effective than placebo for the relief of pain and global symptoms (relative risk of
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IBS symptoms persisting 0.66, 95% CI 0.57-0.78) at a duration of therapy ranging from one to three months [31]. The number need to treat to benefit one patient was four. The treatment effects were similar for SSRIs and tricyclic antidepressants. A similar conclusion was reached in a 2009 position statement from the American College of Gastroenterology Task Force on Irritable Bowel Syndrome [26] and in a subsequent systematic review [23]. By contrast, antidepressant efficacy is unproven in children [45]. This was illustrated in a multicenter trial of 83 children with functional gastrointestinal disorders who were randomly assigned to an antidepressant or placebo for four weeks [46]. The primary end point was the child's assessment of pain relief and sense of improvement. At four weeks, there was no significant difference between amitriptyline and placebo in the frequency of attaining the primary end point (63 versus 58 percent, p = 0.85). The authors noted that a longer period of treatment and a higher dose of antidepressant may have produced different results and that there may be a large placebo effect in children due to multiple factors. In another trial of 33 adolescents assigned to an antidepressant or placebo, an antidepressant was effective in reducing diarrhea and pain after a longer period of treatment (6, 8, and 13 weeks) [47]. Improvement in neuropathic pain with TCAs occurs at lower doses than required for treatment of depression. As a result, if an antidepressant is chosen for the treatment of IBS, low doses should be administered initially and titrated to pain control or tolerance. Because of the delayed onset of action, three to four weeks of therapy should be attempted before considering treatment insufficient and increasing the dose. Examples of antidepressant medications used in patients with IBS include amitriptyline, imipramine, nortriptyline, and desipramine. The initial dose should be adjusted based upon tolerance and response. TCAs should be used cautiously in patients with constipation. Amitriptyline, nortriptyline, and imipramine can be started at a dose of 10 to 25 mg at bedtime and increased every three to four weeks based upon clinical response and tolerance. Desipramine is used in a similar fashion beginning at 12.5 to 25 mg at bedtime. If the patient is intolerant of one TCA, another may be tried. Paroxetine (10 to 20 mg daily), fluoxetine (20 to 40 mg daily), sertraline (50 to 100 mg daily), or other antidepressant medications can be considered if depression is a cofactor [48]. There is less published experience with other antidepressants such as SSRIs or serotonin norepinephrine reuptake inhibitors (SNRIs), although they are used clinically. Results of the few published trials (mainly with SSRIs) have been inconsistent [48-53]. As noted above, one meta-analysis concluded that overall treatment effects were similar to tricyclic antidepressants [31]. Subgroup analyses in a systematic review demonstrated a statistically significant improvement in global assessment scores with SSRIs and an improvement in abdominal pain and symptom scores with TCAs [23]. Antidiarrheal agents In diarrhea-prone patients with IBS, the stools characteristically are loose and frequent but of normal total daily volume. A systematic review identified three controlled trials evaluating loperamide in the treatment of IBS [26,54-56]. All were of short duration, enrolled a small number of patients, and did not use standardized criteria for identifying patients. Overall, the trials suggested that loperamide was more effective than placebo for treatment of diarrhea, but not for treatment of global IBS symptoms or abdominal pain. Administration on an as needed basis is preferred to a regular scheduled dosing in patients with diarrhea. Patients who consistently develop diarrhea after meals may benefit from taking a dose before meals. Loperamide should not be used in patients with constipation and should be used only cautiously in those with symptoms alternating between diarrhea and constipation. Benzodiazepines Anxiolytic agents are of limited usefulness in IBS because of the risk of drug interactions, habituation, and rebound withdrawal. Furthermore, benzodiazepines may lower pain thresholds by stimulating gamma aminobutyric acid (GABA) receptors, thereby decreasing brain serotonin. They may, however, be useful for short-term (less than two weeks') reduction of acute situational anxiety that may be contributing to symptoms [1]. 5-hydroxytryptamine (serotonin) 3 receptor antagonists 5-hydroxytryptamine-3 receptor antagonists (such as alosetron, cilansetron, ondansetron and granisetron) modulate visceral afferent activity from the gastrointestinal tract and may improve abdominal pain [57,58]. A meta-analysis that included 14 randomized controlled trials in IBS (involving

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alosetron or cilansetron,) found a benefit in global improvement in IBS and relief of abdominal pain and discomfort [59]. Alosetron was developed for use in IBS based upon its favorable effects on colonic motility and secretion and on afferent neural systems [60]. In clinical trials the drug was most effective in female patients in whom diarrhea was predominant. However, the drug was associated with ischemic colitis and serious complications related to severe constipation, prompting the Food and Drug Administration (FDA) to remove it from the market in the United States. Evaluation of postmarketing data and demand from a subset of patients who had responded to treatment has prompted the FDA to bring the drug back to the market under tight control. (See "Alosetron hydrochloride (Lotronex) for irritable bowel syndrome".) 5-hydroxytryptamine (serotonin) 4 receptor agonists Agonists of the 5-hydroxytryptamine-4 (5-HT4) receptor stimulate the release of neurotransmitters and increase colonic motility, providing a rationale for their use in constipation predominant IBS [61]. The first of this class of drugs (tegaserod {Zelnorm}, a partial 5-HT4 receptor agonist) was approved for IBS and constipation but removed from the market in March 2007 because of cardiovascular side-effects. Lubiprostone Lubiprostone is a locally acting chloride channel activator that enhances chloride-rich intestinal fluid secretion. Lubiprostone has been approved by the United States Food and Drug Administration for treatment of irritable bowel syndrome with constipation in women 18 years and older. However, its role continues to be determined. There have been no comparisons with other options for treatment of IBS with constipation and its long-term safety remains to be established. Furthermore, the placebo response in the studies above was far lower than most studies of IBS and it is not intuitive why a secretory agent would improve symptoms other than constipation in a disorder such as IBS. Until further data are available (and because it is expensive compared with other options), it is best reserved for patients with IBS and severe constipation in whom other approaches have been unsuccessful. Approval was based upon two multicenter placebo-controlled trials involving 1154 adults (92 percent women) with irritable bowel syndrome and constipation who were randomly assigned to lubiprostone (8 micrograms twice daily) or placebo for 12 weeks [62]. Patients randomized to lubiprostone were significantly more likely to achieve an overall response (18 versus 10 percent). Serious adverse events were similar to placebo. The most common adverse event was nausea (8 versus 4 percent). A follow-up open-label study involving 522 patients showed that benefits continued or improved at 52 weeks. The approved dose (8 micrograms twice daily) is lower than the approved dose for treatment of chronic idiopathic constipation. Guanylate cyclase agonists Linaclotide is a guanylate cyclase agonist that stimulates intestinal fluid secretion and transit. Linaclotide has been approved by the US Food and Drug Administration for treatment of IBS with constipation at a dose of 290 micrograms daily [63]. However, the long-term risks of linaclotide are unknown and therefore its role on the treatment of IBS with constipation remains to be determined. Approval was based upon two randomized controlled phase III trials [64,65]. In one randomized controlled trial, 800 patients with IBS with constipation were randomly assigned to linaclotide (266 micrograms daily) or placebo for 12 weeks followed by a four-week withdrawal period [64]. During the withdrawal period, patients previously randomized to placebo received linaclotide, and patients who originally received linaclotide were randomized to either linaclotide or placebo. After 12 weeks, the percentage of patients meeting the composite endpoint (!30 percent reduction in abdominal pain, !3 complete and spontaneous bowel movements (CSBM), increase in !1 CSBM from baseline; in the same week) was significantly greater with linaclotide compared with placebo (34 versus 21 percent). Patients who received linaclotide also demonstrated a significant improvement in secondary endpoints of abdominal pain/discomfort, bloating, straining, stool consistency, number of CSBMs and spontaneous bowel movements per week, compared with placebo. After the initial 12 weeks, patients originally given linaclotide and who remained on linaclotide showed sustained improvement in abdominal pain, but patients who were switched to placebo experienced recurrence of abdominal pain. Patients initially randomized to placebo had significant improvement in abdominal pain within one week after being switched to linaclotide. Diarrhea was the most common side effect causing discontinuation of treatment in 5.7 percent of patients treated with linaclotide compared with 0.3 percent in patients receiving with placebo. A second
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randomized controlled trial assessed the efficacy of long-term use of linaclotide [65]. In this trial, 804 patients with IBS with constipation were randomly assigned to receive linaclotide (266 micrograms daily) or placebo for 26 weeks. Patients randomized to linaclotide demonstrated a significant improvement in the same composite primary endpoint compared with placebo (38 versus 14 percent). Mast cell stabilizers Ketotifen is a mast cell stabilizer that has been studied for the treatment of IBS based upon the theory that mast cell activation contributes to visceral hypersensitivity. In a randomized trial of 60 patients, the use of ketotifen for eight weeks increased the threshold for discomfort with rectal distension in patients who were hypersensitive to rectal balloon distension at baseline, but not in those with normal sensitivity at baseline [66]. While there was a suggestion of symptom improvement in patients who received ketotifen compared with those who received placebo, the results did not reach statistical significance. Antibiotics Some patients with IBS have shown improvement when treated with antibiotics [67-71]. Most of the improvement has been in symptoms of bloating, abdominal pain, or altered bowel habits. In a report of two randomized trials (TARGET 1 and TARGET 2) with 1260 patients with IBS without constipation, rifaximin, a nonabsorbable antibiotic, led to symptomatic improvement in global IBS symptoms and bloating [71]. Patients were assigned to receive either rifaximin 550 mg three times daily or placebo for a total of 14 days and were then followed for 10 weeks. During the first four weeks of follow-up, patients who received rifaximin were more likely to report adequate relief of IBS symptoms than patients who received placebo (41 versus 32 percent). They also were more likely to report adequate relief of bloating (40 versus 30 percent). Patients who received rifaximin continued to report better symptom relief during the remainder of the follow-up period. In a meta-analysis of five randomized controlled trials, rifaximin was more efficacious than placebo for global IBS symptom improvement (OR 1.57) and was significantly more likely to be associated with decreased bloating than placebo (OR 1.55) [72]. The mechanisms leading to the benefit are unclear but may be due to suppression of gas producing bacteria in the colon. Such studies do not prove the hypothesis that bacterial overgrowth in the small intestine underlies the symptoms of most patients with IBS. Furthermore, in one report, lactulose breath testing (the method used for suggesting bacterial overgrowth in some of these studies) did not discriminate patients with IBS from healthy controls [73]. Thus, the relationships between bacterial overgrowth, benefits of antibiotics in patients with IBS, and methods to test for bacterial overgrowth in IBS require further study. Given the modest benefit and relatively short-term follow-up demonstrated in the trials of rifaximin, we do not suggest the routine use of antibiotics in patients with IBS. However, in patients with moderate to severe IBS without constipation (particularly those with bloating) who have failed to respond to all other therapies, including a low carbohydrate diet and elimination of fermentable oligo-, di-, and monosaccharides and polyols (FODMAPs), it is reasonable to consider twoweek trial of rifaximin (see 'Carbohydrate malabsorption' above). Alternative therapies Multiple alternative forms of therapy for IBS have been suggested, such as herbs, probiotics, acupuncture, and enzyme supplementation [74-78]. Their role remains uncertain. (See "Probiotics for gastrointestinal diseases", section on 'Irritable bowel syndrome'.) Peppermint oil has been studied in randomized trials [79-81]: One trial included 90 patients with irritable bowel syndrome [79]. Patients were assigned to receive either a delayed release capsule with 187 mg of peppermint oil or placebo three times daily 30 minutes before meals for eight weeks. At baseline, the most common symptoms were abdominal pain, distention, and flatulence. Sixty patients completed the study (33 in the treatment arm and 27 in the control arm). At the end of the study, more patients in the treatment arm who completed the study reported being free from abdominal pain or discomfort (43 versus 22 percent in the per protocol analysis, 31 versus 13 percent in the intention to treat analysis).

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A second trial included 57 patients and assigned the patients to 225 mg of peppermint oil (28 patients) or placebo (29 patients) twice daily for four weeks [80]. The loss to follow-up in this trial was less than in the first (11 percent in the treatment arm and 10 percent in the control arm). After four weeks of treatment, more patients in the treatment arm reported at least a 50 percent reduction in symptoms than in the control arm (75 versus 38 percent in the per protocol analysis, 64 versus 34 percent in the intention to treat analysis). A third trial included 110 patients [81]. Patients were assigned to 187 mg of peppermint oil or placebo three to four times daily before meals for one month. Fifty-two patients in the treatment arm (95 percent) and 49 patients in the control arm (89 percent) completed the trial. At the end of the trial, more patients in the treatment arm were pain free (56 versus 8 percent in per protocol analysis, 53 versus 7 percent in the intention to treat analysis). Patients in the treatment arm also reported more improvement in pain severity, abdominal distention, stool frequency (decreased), borborygmi, and flatulence. MAJOR SOCIETY GUIDELINES Guidelines for the management of irritable bowel syndrome (IBS) have been issued by several organizations. The 2009 position statement from the American College of Gastroenterology Task Force on Irritable Bowel Syndrome includes recommendations on the role of dietary modification, medications, psychological and alternative therapies in the treatment of IBS (table 1) [26]. 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 5th to 6th 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 10th to 12th 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 e-mail 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 information: Irritable bowel syndrome (The Basics)") Beyond the Basics topics (see "Patient information: Irritable bowel syndrome (Beyond the Basics)" and "Patient information: High-fiber diet (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Treatment of irritable bowel syndrome (IBS) varies with the severity and type (diarrhea versus constipation predominant) of symptoms that are present. Mild symptoms Patients with mild or infrequent symptoms usually have little or no functional impairment or psychologic disturbance. Thus, we suggest treatment should focus upon the general measures described above (such as establishment of the physician-patient relationship, patient education, reassurance, dietary modification, and, if bloating is not a major factor, fiber supplementation) rather than specific pharmacologic therapy (Grade 2C). (See 'General principles' above.) Moderate symptoms Patients with moderate symptoms of IBS experience disruptions of normal daily activities due to exacerbations of symptoms; these patients also may demonstrate psychologic impairment.

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We monitor patients' symptoms for several weeks to help identify precipitating factors, such as lactose intolerance, excess caffeine, or specific stressors. Modifications in diet, behavioral changes, and psychotherapy may improve the clinical outcome. Randomized controlled trials evaluating specific pharmacologic agents have demonstrated their superiority compared with placebo. However, there have been few controlled trials evaluating specific strategies for how these drugs should be used in conjunction with other types of treatment (such as fiber therapy), how long they should be used, or whether they should be given continuously or episodically. We often use pharmacologic intervention to control symptom flares but also use continuous pharmacologic therapy (such as tricyclic antidepressant drugs) for periods of months or years. Our choice of specific therapies is based mainly upon symptoms and response to empiric trials (see 'Medications' above). Given the modest benefit and relatively short-term follow-up demonstrated in the trials of rifaximin, we suggest NOT using antibiotics routinely in patients with IBS (Grade 2B). However, in patients with moderate to severe IBS without constipation (particularly those with bloating) who have failed to respond to all other therapies, including a low carbohydrate diet and elimination of fermentable oligo-, di-, and monosaccharides and polyols (FODMAPs), it is reasonable to consider a two-week trial of rifaximin. (See 'Antibiotics' above and 'Carbohydrate malabsorption' above.) Intractable symptoms A small subset of patients with IBS present to tertiary care centers with severe, unrelenting symptoms that are often associated with underlying psychiatric impairment and frequent health care utilization. We suggest behavioral modification and the use of psychoactive drugs in such patients (Grade 2C). (See 'Medications' above.)

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responses to distension and serotonin type 3 antagonism. Dig Dis Sci 1995; 40:819. 58. Prior A, Read NW. Reduction of rectal sensitivity and post-prandial motility by granisetron, a 5 HT3-receptor antagonist, in patients with irritable bowel syndrome. Aliment Pharmacol Ther 1993; 7:175. 59. Andresen V, Montori VM, Keller J, et al. Effects of 5-hydroxytryptamine (serotonin) type 3 antagonists on symptom relief and constipation in nonconstipated irritable bowel syndrome: a systematic review and meta-analysis of randomized controlled trials. Clin Gastroenterol Hepatol 2008; 6:545. 60. Gershon MD. Serotonin and its implication for the management of irritable bowel syndrome. Rev Gastroenterol Disord 2003; 3 Suppl 2:S25. 61. Scott LJ, Perry CM. Tegaserod. Drugs 1999; 58:491. 62. Drossman DA, Chey WD, Johanson JF, et al. Clinical trial: lubiprostone in patients with constipation-associated irritable bowel syndrome--results of two randomized, placebo-controlled studies. Aliment Pharmacol Ther 2009; 29:329. 63. FDA approves Linzess to treat certain cases of irritable bowel syndrome and constipation. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm317505.htm (Accessed on September 04, 2012). 64. Rao S, Lembo AJ, Shiff SJ, et al. A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation. Am J Gastroenterol 2012; 107:1714. 65. Chey WD, Lembo AJ, Lavins BJ, et al. Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety. Am J Gastroenterol 2012; 107:1702. 66. Klooker TK, Braak B, Koopman KE, et al. The mast cell stabiliser ketotifen decreases visceral hypersensitivity and improves intestinal symptoms in patients with irritable bowel syndrome. Gut 2010; 59:1213. 67. Nayak AK, Karnad DR, Abraham P, Mistry FP. Metronidazole relieves symptoms in irritable bowel syndrome: the confusion with so-called 'chronic amebiasis'. Indian J Gastroenterol 1997; 16:137. 68. Sharara AI, Aoun E, Abdul-Baki H, et al. A randomized double-blind placebo-controlled trial of rifaximin in patients with abdominal bloating and flatulence. Am J Gastroenterol 2006; 101:326. 69. Pimentel M, Chow EJ, Lin HC. Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome. a double-blind, randomized, placebo-controlled study. Am J Gastroenterol 2003; 98:412. 70. Pimentel M, Park S, Mirocha J, et al. The effect of a nonabsorbed oral antibiotic (rifaximin) on the symptoms of the irritable bowel syndrome: a randomized trial. Ann Intern Med 2006; 145:557. 71. Pimentel M, Lembo A, Chey WD, et al. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med 2011; 364:22. 72. Menees SB, Maneerattannaporn M, Kim HM, Chey WD. The efficacy and safety of rifaximin for the irritable bowel syndrome: a systematic review and meta-analysis. Am J Gastroenterol 2012; 107:28. 73. Bratten JR, Spanier J, Jones MP. Lactulose breath testing does not discriminate patients with irritable bowel syndrome from healthy controls. Am J Gastroenterol 2008; 103:958. 74. Spanier JA, Howden CW, Jones MP. A systematic review of alternative therapies in the irritable bowel syndrome. Arch Intern Med 2003; 163:265. 75. Liu JP, Yang M, Liu YX, et al. Herbal medicines for treatment of irritable bowel syndrome. Cochrane Database Syst Rev 2006; :CD004116. 76. Lembo AJ, Conboy L, Kelley JM, et al. A treatment trial of acupuncture in IBS patients. Am J Gastroenterol 2009; 104:1489. 77. Manheimer E, Cheng K, Wieland LS, et al. Acupuncture for treatment of irritable bowel syndrome. Cochrane Database Syst Rev 2012; 5:CD005111. 78. Moser G, Trgner S, Gajowniczek EE, et al. Long-term success of GUT-directed group hypnosis for patients with refractory irritable bowel syndrome: a randomized controlled trial. Am J Gastroenterol 2013; 108:602. 79. Merat S, Khalili S, Mostajabi P, et al. The effect of enteric-coated, delayed-release peppermint oil on irritable bowel
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syndrome. Dig Dis Sci 2010; 55:1385. 80. Cappello G, Spezzaferro M, Grossi L, et al. Peppermint oil (Mintoil) in the treatment of irritable bowel syndrome: a prospective double blind placebo-controlled randomized trial. Dig Liver Dis 2007; 39:530. 81. Liu JH, Chen GH, Yeh HZ, et al. Enteric-coated peppermint-oil capsules in the treatment of irritable bowel syndrome: a prospective, randomized trial. J Gastroenterol 1997; 32:765. Topic 2631 Version 22.0

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GRAPHICS 2009 American College of Gastroenterology (ACG) recommendations for the treatment of irritable bowel syndrome (IBS)
Diet and irritable bowel syndrome
Patients often believe that certain foods exacerbate their IBS symptoms. There is, however, insufficient evidence that food allergy testing or exclusion diets are efficacious in IBS and their routine use outside of a clinical trial is not recommended.

Effectiveness of dietary fiber, bulking agents, and laxatives in the management of irritable bowel syndrome
Psyllium hydrophilic mucilloid (ispaghula husk) is moderately effective and can be given a conditional recommendation. A single study reported improvement with calcium polycarbophil. Wheat bran or corn bran is no more effective than placebo in the relief of global symptoms of IBS and cannot be recommended for routine use. Polyethylene glycol (PEG) laxative was shown to improve stool frequency - but not abdominal pain - in one small sequential study in adolescents with IBS-C.

Effectiveness of antispasmodic agents, including peppermint oil, in the management of irritable bowel syndrome
Certain antispasmodics (hyoscine, cimetropium, pinaverium, and peppermint oil) may provide shortterm relief of abdominal pain / discomfort in IBS. Evidence for long-term efficacy is not available. Evidence for safety and tolerability is limited.

Effectiveness of antidiarrheals in the management of irritable bowel syndrome

The antidiarrheal agent loperamide is not more effective than placebo at reducing pain, bloating, or global symptoms of IBS, but it is an effective agent for the treatment of diarrhea, reducing stool frequency, and improving stool consistency. Randomized controlled trials comparing loperamide with other antidiarrheal agents have not been performed. Safety and tolerability data on loperamide are lacking.

Effectiveness of antibiotics in the management of irritable bowel syndrome

A short-term course of a nonabsorbable antibiotic is more effective than placebo for global improvement of IBS and for bloating. There are no data available to support the long-term safety and effectiveness of nonabsorbable antibiotics for the management of IBS symptoms.

Effectiveness of probiotics in the management of irritable bowel syndrome

In single organism studies, lactobacilli do not appear effective for patients with IBS; bifidobacteria and certain combinations of probiotics demonstrate some efficacy.

Effectiveness of the 5-HT 3 receptor antagonists in the management of irritable bowel syndrome
The 5-HT 3 receptor antagonist alosetron is more effective than placebo at relieving global IBS symptoms in male and female IBS patients with diarrhea. Potentially serious side effects including
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constipation and colon ischemia occur more commonly in patients treated with alosetron compared with placebo. The benefits and harms balance for alosetron is most favorable in women with severe IBS and diarrhea who have not responded to conventional therapies. The quality of evidence for efficacy of 5-HT 3 antagonists in IBS is high.

Effectiveness of 5-HT 4 (serotonin) receptor agonists in the management of irritable bowel syndrome
The 5-HT 4 receptor agonist tegaserod is more effective than placebo at relieving global IBS symptoms in female IBS-C patients and IBS-M patients. The most common side effect of tegaserod is diarrhea. A small number (0.11 percent) of cardiovascular events (myocardial infarction, unstable angina, or stroke) were reported among patients who had received tegaserod in clinical trials.

Effectiveness of the selective C-2 chloride channel activators in the management of irritable bowel syndrome
Lubiprostone in a dose of 8 micrograms twice daily is more effective than placebo in relieving global IBS symptoms in women with IBS-C.

Effectiveness of antidepressant agents in the management of irritable bowel syndrome

Tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) are more effective than placebo at relieving global IBS symptoms, and appear to reduce abdominal pain. There are limited data on the safety and tolerability of these agents in patients with IBS.

Effectiveness of psychological therapies in the management of irritable bowel syndrome

Psychological therapies, including cognitive therapy, dynamic psychotherapy, and hypnotherapy, but not relaxation therapy, are more effective than usual care in relieving global symptoms of IBS.

Effectiveness of herbal therapies and acupuncture in the management of irritable bowel syndrome
Available randomized controlled trials mostly tested unique Chinese herbal mixtures, and appeared to show a benefit. It is not possible to combine these studies into a meaningful meta-analysis, however, and overall, any benefit of Chinese herbal therapy in IBS continues to potentially be confounded by the variable components used and their purity. Also, there are significant concerns about toxicity, especially liver failure, with use of any Chinese herbal mixture. A systematic review of trials of acupuncture was inconclusive because of heterogeneous outcomes. Further work is needed before any recommendations on acupuncture or herbal therapy can be made. IBS: irritable bowel syndrome; IBS-C: constipation-predominant irritable bowel syndrome; IBS-M: mixed irritable bowel syndrome; 5-HT3: 5-hydroxytryptamine (serotonin) 3 receptor agonists; 5-HT4: 5hydroxytryptamine (serotonin) 4 receptor agonists. Data from: American College of Gastroenterology IBS Task Force. An Evidence-Based Position Statement on the Management of Irritable Bowel Syndrome. Am J Gastroenterol 2009; 104:S1.

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