Selective serotonin reuptake inhibitors

Given that IBS is associated with psychiatric disorders, such as anxiety and depression, and pain syndromes, such as fibromyalgia, it has been postulated that antidepressants could have a role in treatment of patients with IBS symptoms. Beyond the treatment benefit for the comorbid diseases, selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants have been shown to improve IBS symptoms, independently of effect on anxiety and depression scores. Serotonin, or 5-hydroxytryptamine (5-HT), is a neurotransmitter that is largely stored in the enterochromaffin cells of the gut and plays a critical part in the motility, sensation, and secretion of the GI tract. A study by Talley and colleagues comparing imipramine, citalopram, and placebo demonstrated significant improvement in Bowel Symptom Severity Rating Scale distress and Bowel Symptom Severity Rating Scale disability in the imipramine (a tricyclic antidepressant) group compared with both placebo and citalopram (an SSRI) after 12 weeks of treatment. There were, however, no significant differences in the global adequate relief symptom end point between the antidepressants and placebo, which is a suggested end point for irritable bowel symptoms. This study, unfortunately, had a large drop-out rate in the imipramine group (50%) despite having similar side effects between the groups, which may limit its applicability to female patients. Most of the patients in this study (76% of the citalopram group, 67% of the imipramine group, and 75% of the placebo group) had IBS-D, which may explain why the citalopram group did not receive any benefit because SSRIs can increase intestinal transit, and thus potentially exacerbate symptoms in this particular group of patients.

Amitriptyline

Studies have demonstrated the effect of amitriptyline on symptoms of IBS that do not correlate with baseline anxiety and depression scores and affect GI pain at lower doses than their antidepressant effects, subsequently suggesting an alternate mechanism of action. The mechanism of action of amitriptyline is likely multifactorial, with altered gut motility, reduced ororectal transit time, and an alteration of visceral sensitivity. Most of these studies are relatively small and have used more typical antidepressant level dosing (between 50 and 75 mg/day). However, an Iranian study used low-dose amitriptyline to determine its effectiveness in patients with IBS-D. Fifty-four patients, who met inclusion criteria for IBS-D and passed an initial 2-week lactose-free diet, were randomized to receive amitriptyline, 10 mg daily, or placebo for a 60-day treatment period. Although there was no significant improvement in the mean number of symptoms at the end of the first month of treatment, there was improvement noted at the end of the second month of treatment (2 vs 0.8; P = .01). There was also an increase in the percentage of complete responders (defined as absence of all symptoms) in the amitriptyline group compared with placebo (63% vs 26%; P = .01) in the intention-to-treat analysis.

Amitriptyline may also have a role in decreasing pain sensitivity by influencing central activation pathways. A study of 19 women compared amitriptyline with placebo for a 4-week treatment period, then crossed over to the alternate treatment, and evaluated activation of the anterior cingulate cortex, the area of the brain that responds to noxious stimuli, and patient pain ratings during rectal distention. This study demonstrated decreased activation of the anterior cingulate cortex noted on MRI images of the amitriptyline patients, although no significant difference was found in the pain ratings of patients with amitriptyline. Although no improvement in symptoms was noted with amitriptyline in this short but well-designed study, extending the treatment period, as is often needed with depression, may demonstrate if patients would receive any clinically significant benefit as has been shown with other longer studies.

Neomycin

Because the putative role of small intestine bacterial overgrowth in the pathogenesis of IBS has grown, studies to determine the therapeutic value of antibiotics in IBS become more crucial. It has been demonstrated that up to 84% of IBS patients have positive lactulose breath tests. Studies comparing neomycin with placebo have shown that symptoms significantly improve in those patients treated with neomycin, and this symptom improvement is correlated with improvement in lactulose breath test results. Furthermore, a study by Pimental and colleagues demonstrated that although global improvement in IBS symptoms was noted in the neomycin group compared with placebo, the patients that were methane producers on lactulose breath testing had more improvement than hydrogen producers when treated with neomycin. The etiology of this association is unclear but it is postulated that improvement in symptoms may be secondary to improved colonic transit, decreasing methane production by bacterial overgrowth. It is known that some antibiotics, such as erythromycin and neomycin, have been demonstrated to increase GI motility; thus, the role of these antibiotics may be multiple in improving intestinal transit and decreasing bacterial overgrowth through bactericidal actions.

Rifaximin

Rifaximin has also been used in suspected small intestine bacterial overgrowth cases. Rifaximin is a broad-spectrum antibiotic with in vitro activity against gram-positive and gram-negative aerobes and anaerobes, with minimal systemic absorption. It also has some activity against Clostridium difficile . A double-blinded randomized control trial (RCT) of 87 patients compared rifaximin with placebo in patients with IBS. Study participants were randomized to a 10-day course of treatment of rifaximin, 400 mg three times daily, versus placebo, and followed-up for 10 weeks. The rifaximin group had mean global improvement scores of 36.4% (standard deviation, 31.46%) compared with 21% (standard deviation, 22.08%) for the placebo group after 10 weeks ( P = .02). The presence of these large standard deviations limits the ability to generalize these findings to all IBS patients; thus, further larger studies are needed to evaluate the effectiveness of this antibiotic. Adverse events were most commonly abdominal pain, constipation, and bad taste in the mouth, but were not statistically different from the placebo group; therefore, patient compliance with rifaximin should not be of significant concern.

Alosetron

Alosetron, a selective 5-HT ₃ receptor antagonist, has been demonstrated to improve IBS symptoms in women with severe IBS-D. However, despite a study by Chang and colleagues, which also demonstrated improvement in symptoms in men, its efficacy in men is still in question. A multicenter RCT of 801 women recruited patients with nonconstipated IBS by Rome II criteria and randomized them to alosetron, 1-mg tablets twice daily, for a 12-week treatment versus placebo and examined bowel urgency symptoms. The alosetron group demonstrated improvement in the median proportion of days (0.57 in placebo vs 0.73 in the alosetron group; P <.001) with satisfactory control of bowel urgency over the 12-week period. Bowel urgency has been cited as one of the more difficult symptoms to treat in IBS. Patients in the alosetron group were also significantly more likely to report moderate or substantial global improvement in symptoms ( P <.001). Several serious adverse events in the alosetron group were noted, including one case each of ischemic colitis, cholecystitis, pneumonia, diverticulitis, headache, migraine, and ankle fracture.

A study by Krause and colleagues compared different doses of alosetron (0.5 mg daily, 1 mg once daily, 1 mg twice daily, and placebo) to determine the optimal dose maximizing benefit while limiting adverse effects. All of the alosetron groups had statistically significant improvement in global improvement scores compared with placebo but the percentage of patients with adverse events increased with dosage, particularly with constipation. This study, unfortunately, had a large drop-out rate, with completion rates ranging between 52% (in the alosetron twice-daily group) and 66% (in the alosetron 0.5-mg daily group). One patient in the 0.5-mg daily alosetron group did develop ischemic colitis, which was thought to be related to the medication. Thus, despite apparent efficacy and decreased occurrence of adverse events with lower doses of alosetron, there is still no currently established safe dose to prevent ischemic colitis.

Chey and colleagues further evaluated the long-term safety and efficacy of alosetron in a study of 814 women with severe IBS-D symptoms, demonstrating adequate relief rate in 51.6% in the alosetron group compared with 40.9% in the placebo group ( P = .005) over a 48-week treatment period with a number-needed-to-treat of 9 (95% CI, 6–30). No serious adverse events, including ischemic colitis, occurred in this study, the first with a relatively long treatment period. Adverse events were constipation, nausea, vomiting, abdominal pain, and diarrhea. This suggests that alosetron may be used as a long-term medication, although whether there is an increase in relapse of IBS symptoms after discontinuation of long-term use of this medication has not been studied.

In its branded form (Lotronex), alosetron does carry a black box warning. As per FDA recommendations, prescribing physicians must enroll in the Prometheus Prescribing Program for Lotronex attesting to their understanding of treatment risks and benefits to decrease the risk of serious adverse events. This has certainly added to the possible lack of popularity of the drug ( Table 1 ).

Tegaserod

Tegaserod, a selective 5-HT ₄ receptor agonist, has been shown to have efficacy in the treatment of IBS-C in women. In a multicenter, double-blind, RCT of 661 women with IBS-C and IBS-mixed randomized to tegaserod or placebo, patients had satisfactory relief of IBS symptoms in both the IBS-mixed and IBS-C groups when treated with tegaserod. This is one of the first trials to focus on IBS-mixed patients, who may constitute 30% to 50% of IBS patients but have been underrepresented in many of the studies. Adverse events to tegaserod were mostly limited to diarrhea and abdominal pain. A large, multinational study used repeated treatment design and demonstrated improvement in symptoms in IBS-C with both first and repeated treatment with tegaserod. Improvement in QoL scores, improved work productivity, and higher levels of patent satisfaction compared with placebo were also significant findings.

Information from the aforementioned studies on tegaserod and alosetron demonstrates an increased efficacy of the treatments for women compared with men that further highlights the aforementioned differences in pathophysiology between the genders. This may be caused by inherent differences in visceral hypersensitivity and pain perception, but other gender differences also may have a role. Alterations in drug clearance may, for example, impact the efficacy of medication treatment because men and women have differences in drug metabolism and different body sizes and adipose content, which may cause variations in the systemic level of the drug and thus change the effective dosing on the patient.

On March 30, 2007, the US Food and Drug Administration (FDA) requested that Novartis withdraw tegaserod, marketed as Zelnorm, from shelves secondary to a proposed relationship between prescriptions of the drug and increased risks of heart attack or stroke. An analysis of data collected on over 18,000 patients demonstrated adverse cardiovascular events in 13 of 11,614 patients treated with Zelnorm (a rate of 0.11%) compared with 1 of 7031 patients treated with placebo (a rate of 0.01%). Novartis alleges all of the affected patients had preexisting cardiovascular disease or risk factors for such, and further alleges that no causal relationship between tegaserod use and cardiovascular events has been demonstrated. On the same day as the FDA announcement, Novartis Pharmaceuticals Canada announced that it was suspending marketing and sales of the drug in Canada in response to a request from Health Canada. However, some manufacturers in India, such as Cipla, still have generic tegaserod available in their listings and some online merchants may be selling the drug. In a large cohort study based on a US health insurance database, no increase in the risk of cardiovascular events was found with tegaserod treatment.

Renzapride

Renzapride is a novel mixed 5-HT ₄ receptor full agonist and 5-HT ₃ receptor antagonist, which has been shown in some small studies to improve GI motility and increase GI transit rates, and thus is a potential treatment for IBS-C. A large, double-blinded phase IIb RCT in England of 510 men and women with IBS modified to IBS-C form compared placebo with 1 mg, 2 mg, or 4 mg per day renzapride treatment for 12 weeks. Although there was a dose-dependent trend showing improvement in abdominal pain and discomfort during weeks 5 to 12 of treatment, these results did not reach statistical significance. A post hoc analysis was performed in the female patients (which accounted for 89% of the subjects) and showed a greater average weekly treatment difference from placebo in the subgroup of females compared with the overall group (12% vs 8%, respectively). This study was limited by the large drop-out rate of participants (197 [38.6%] of 510). However, 51% of the discontinuation was reportedly secondary to adverse events. Adverse events most commonly noted were diarrhea, headache, abdominal pain, aggravated constipation, nausea, dyspepsia, and vomiting. Consequently, studies evaluating the effect of renzapride should be repeated in women to determine whether a therapeutic benefit exists.

Renzapride was under development by Alizyme of the United Kingdom. However, as of April 23, 2008, all further development of the medication was ceased by Alizyme citing a Phase III trial in the United States that did not show enough efficacy over placebo to justify further study.

Leuprolide

Hormonal modulation has been postulated to play a role in IBS symptoms, because IBS is more common in women in their premenopausal years and because of the fact that women with IBS have reported an increase in their symptoms during their menstrual cycles. Thus, an Italian study randomized young premenopausal women with menstrual-related increases in IBS symptoms to leuprolide acetate (LAD; a gonadotropin-releasing hormone agonist) plus tibolone (a synthetic compound with estrogenic, androgenic, and progestogenic properties), LAD plus placebo, or placebo and subsequently evaluated the severity of bowel symptoms and QoL scores using validated surveys at baseline and after 6 months of treatment. It was found that IBS symptoms and QoL scores significantly improved in the LAD plus tibolone and LAD groups compared with placebo. However, the LAD plus placebo group had significantly decreased bone mineral density scores compared with the other two groups, although it is unclear if this will manifest in any clinical significance. No fractures were observed during this study period, but long-term administration of this drug could yield a potential risk in female patients. It is unclear if the mechanism of drug action is related to mood regulation and thus decreasing mood-based symptom perception. This study also uses validated questionnaires to assess symptoms and is the first study to evaluate the addition of tibolone to gonadotropin-releasing hormone as a treatment for IBS in women. Tibolone has previously been used in postmenopausal women to prevent bone loss. This pharmacologic therapy may be used in young premenopausal women with increased IBS symptoms during menses. Because adverse events were not specifically reported in this article, it is unknown what the potential side effects may prove to be because of the medication.

Leuoprolide was initially approved in the injection form by the FDA on April 9, 1985, specifically for the use of advanced prostate cancer, and with the many aforementioned ongoing studies, its use for treatment of IBS remains strictly off-label.

Pexacerfront

Pexacerfront is a selective antagonist of corticotrophin-releasing factor 1 (CRF ₁ ) receptor. CRF is a mediator of the stress response in the brain–gut axis and has been demonstrated in animal models to alter GI function. A double-blind study in 39 women with IBS-D, however, randomized to 50/25 mg pexacerfront versus 100/50 mg pexacerfront did not find any statistically significant differences in colonic transit time or secondary end points (number of stools, ease of passage, bloating, gas, urgency or abdominal pain) between placebo and pexacerfront groups. The results of this study are in contrast to prior study results, which demonstrated that CRF agonists affect gut motility by decreasing transit times and increasing stool frequency. CRF ₁ inhibition by the selective antagonist pexacerfront was hypothesized to increase transit time and decrease diarrheal symptoms. Future studies may need to evaluate increased doses, medication duration, or different CRF receptor subtype localization to determine whether this pathway can be used effectively in female patients with IBS-D.

Developed by Bristol-Myers Squibb with the premise of treating anxiety disorders, Pexacerfont remains in the clinical stages of development and its use is not FDA approved for IBS at the time of publication.

Fiber

Dietary fiber may be considered primarily the storage and cell wall polysaccharides of plants that cannot be hydrolyzed by human enzymes. A simpler definition for dietary fiber is specifically nonstarch polysaccharides derived from plant foods that are poorly digestible by human enzymes. Fiber can further be divided based on water solubility into soluble fiber and insoluble fiber.

Soluble fiber retains water and turns to a viscous gel during digestion. These viscous solutions delay gastric emptying and small intestinal absorption and are eventually fermented in the proximal colon by bacteria to a greater extent than insoluble fiber. The active metabolites of this fermentation are short-chain fatty acids and gas (including carbon dioxide, hydrogen, and methane). Examples of soluble fiber are found specifically in foods including oat bran, barley, nuts, seeds, beans, lentils, peas, and some fruits and vegetables.

Insoluble fiber includes cellulose, hemicelluloses, and lignins. These sources have less of an effect on the viscosity of intestinal contents. Their physiologic effect is to hold onto water and increase the size and bulk of stool because they are poorly fermented. Insoluble fiber seems to speed the passage of foods through the stomach and intestines and, by adding bulk to the stool, can make bowel movement passage easier. It is found in such foods as wheat bran, vegetables, and whole grains.

Some of these fiber sources are used as the basis for many of the products termed “bulking agents” and often sold as supplements. Metamucil and Konsyl, for example, are largely psyllium seed. Benefiber is partially hydrolyzed guar gum. The largely artificial products available commercially include Citrucel and Fibercon. Citrucel is composed of methylcellulose and semisynthetic fiber that is nonfermentable. Calcium polycarbophil is a purely synthetic fiber also resistant to bacterial degradation.

The proposed mechanism of action for fiber in the treatment of IBS and constipation is the acceleration of oral–anal transit and a decrease in intracolonic pressures, either as a direct effect or by binding bile salts. The short-chain fatty acids and gaseous products of soluble fiber metabolism decrease gut transit time and have been postulated consequently to decrease intracolonic pressure. In contrast, insoluble fiber has been thought to decrease colonic transit secondary to the change in stool viscosity. Although both types of fiber have been studied in IBS patients, the soluble fibers studied have generally included psyllium, partially hydrolysed guar gum, oligosaccharides, and calcium polycarbophil. Products rich in insoluble fiber that have been studied are wheat bran, corn bran, and defatted ground flaxseed. The results of these studies exploring the effect of different types of fiber on GI transit have been conflicting.

Depending on the source (National Cancer Institute, American Gastroenterological Association, or American Heart Association), dietary fiber recommendations are generally in the range of 20 to 35 g/day per healthy individual. Various surveys, however, have shown that the mean dietary fiber intake in the adult population of the United States is in the range of 11.1 to 13.3 g/day. This observation was widely believed to be the primary cause of IBS. That conviction has been slow to change despite numerous studies to the contrary spurred on by reports that cereal fiber worsened symptoms in 55% of secondary care IBS patients and 22% of primary care IBS patients. Nevertheless, fiber supplementation has remained the most extensively and carefully studied dietary treatment for IBS.

The use of fiber or bulking agents for treatment of IBS has been reviewed in two meta-analyses, four systematic reviews, and two comprehensive narrative reviews. The reviews uniformly concluded that fiber either has no efficacy for treatment of IBS or possible limited benefits for patients who have IBS-C. Soluble fiber showed a tendency to greater global symptom improvement than insoluble fiber. One review found that insoluble fiber worsened symptoms. An additional meta-analysis concluded that although wheat bran was not effective for treating IBS, the soluble fibers, such as psyllium, were likely effective. In contrast to the large number of studies of fiber supplementation, few studies have examined the effect of increasing fiber intake in the form of ordinary food. These have reported improvement of IBS symptoms on both high- and low-fiber diets, a result often attributed to a placebo effect. Consequently, the information has been conflicting at best and has led to little standardization in the way of official recommendations.

Systematic reviews of clinical trials of fiber for IBS have found no clear beneficial effects for fiber supplementation or bulking agents in female patients. The American College of Gastroenterology Functional Gastrointestinal Disorders Task Force’s recommendations are that fiber is appropriate for the treatment of constipation but may not be recommended for the sole treatment of IBS. A similar more recent meta-analysis of therapies for IBS does not recommend the use of bulking agents except as an adjuvant therapy.

Although dietary fiber or bulking agents do not seem to be useful as sole treatment of IBS, they may have a limited initial role in empiric therapy depending on the patient’s symptom complex, especially if constipation is the most significant symptom. The basic principles for using fiber therapy in this manner, based on limited efficacy and known potential adverse effects of worsening or causing abdominal discomfort and bloating, are to give an adequate trial, to evaluate the results early and periodically, and to start with a low dose and increase slowly. Physicians and dieticians should use insoluble fiber and soluble fiber carefully. Methods for increasing fiber intake must be individualized. One proposed method is to add additional portions of fruits and vegetable. If constipation is not improved, or if the diet cannot be tolerated or followed, a trial of soluble fiber can be instituted. Recommendations for IBS-D patients are even less clear, although some authorities use a trial of increasing soluble fiber with psyllium or partially hydrolyzed guar gum.

Fiber is commonly used in the treatment of patients with IBS; but despite a large number of trials, many with design limitations, benefits are unproved and patient tolerance may be a problem. Because most patients in all the studies evaluated are female, there may be a limited role for the careful use of dietary fiber or bulking agents in the management of some patients with IBS, especially if constipation is the dominant concern.

Probiotics

Probiotics are defined as live microorganisms that, when administered in adequate amounts, confer a health benefit to the host. Although they have been used throughout history in the management of a variety of medical disorders, any actual evidence of their possible health benefits has been limited until recently. Probiotics can occur naturally in fermented foods, such as yogurt, buttermilk, sour poi, and miso. Pure and mixed cultures of potentially beneficial organisms have been added to foods or ingested in tablets, capsules, or liquids and have subsequently provided the basis for most of the scientific studies.

Many mechanisms by which probiotics may improve IBS symptoms have been postulated. Up to 25% of patients date the onset of their problem from a GI infection, and evidence has accumulated to indicate the presence of an inflammatory response in the GI mucosa in IBS. Additionally, the observation that IBS may be exacerbated by antibiotics, coupled with reports of abnormal colonization of the small bowel in some patients, suggests that it is possible that alterations in the bacterial flora of the gut may be of relevance.

Probiotics reportedly bind to small and large bowel epithelium and produce substances with antibiotic properties that may inhibit attachment and invasion by pathogenic organisms. Probiotics may also modulate GI luminal immunity by changing the cytokine and cellular milieu from a proinflammatory to an antiinflammatory state. They also convert undigested carbohydrates into short-chain fatty acids, which act as nutrients for the cells of the colon and alter gut motility. Therefore, it has been theorized that probiotics may lead to symptomatic improvements in patients with IBS, and it has been speculated that each individual bacterial strain or a combination of strains may affect select subclasses of symptoms in the IBS patient population.

These findings formed the basis for a study examining the antiinflammatory properties of Bifidobacterium infantis in a large-scale, multicenter, clinical trial of women with IBS. Peripheral blood monocytes were extracted from IBS patients and healthy volunteers. The levels of cytokines interleukin (IL)-10 and IL-12 were assessed both at baseline and after treatment with either B infantis or Lactobacillus salivarius . At baseline the ratio of IL-10/IL-12 was significantly lower in the IBS population. After treatment with B infantis , these cytokine levels returned to levels consistent with those observed in controls and the IL-10/IL-12 ratio normalized. These findings seem to support the theory that the mechanism for symptomatic improvement shown in patients receiving B infantis in the study seems to be down-regulation of a proinflammatory state. The study also showed that B infantis , delivered in a convenient formulation over a 4-week period, is a safe and effective treatment for patients with mild to moderate IBS symptoms and has the distinct advantage that it can be given to patients with IBS, which is characterized by either diarrhea or constipation.

Two recently published metaanalyses and two comprehensive narrative reviews further explored the use of probiotics in the treatment of IBS in the female population. All concluded that probiotics may be useful but confirmed that there are many variables affecting the results, such as the type, dose, and formulation of bacteria comprising the probiotic preparation; the outcome measured; and the size and characteristics of the IBS population studied.

Although clinical evidence of efficacy is now beginning to emerge, a review of available trials emphasizes the importance of clear definition of strain selection, dose, and viability. Other probiotics may prove beneficial in the future; however, further studies are necessary before their use can be categorically recommended.

Turmeric

Turmeric is a member of the ginger family and its extract, curcumin, has antiinflammatory effects. In a partially blinded, randomized, 8-week trial of oral turmeric in 207 individuals with IBS (most of whom were female), overall symptoms improved more than 65%. However, there was no placebo control and, therefore, no conclusions can be drawn from this study. Another double-blinded, placebo-controlled trial also examined the role of turmeric in patients, predominantly female, with IBS. In this study, the global assessment of changes in IBS symptoms and psychological stress caused by IBS did not differ significantly among the various treatment arms. This additional study confirmed that turmeric did not show any therapeutic benefit over placebo in patients and hence the addition of this herb as a dietary supplement to IBS patients, female or male, cannot be firmly recommended.

St John’s wort

The herbal preparation of SJW, Hypericum perforatum , is known to effectively treat patients with mild-to-moderate depression with a reported 70% treatment response rate. Although the mechanism of action of SJW has not been clearly delineated, it is postulated to exert an effect on serotonin pathways. Aside from its neurologic effects, because 95% of serotonin is contained and released by the enterochromaffin cells of the GI tract, manipulation of serotonin and its receptors has been shown to also affect gut function. The frequent association of IBS with depression and the potential effect of SJW as an inhibitor of serotonin uptake have provided researchers rationale to evaluate its clinical effects on patients specifically with IBS.

Until a recent placebo-controlled, randomized, double-blind study, no previous exploration of the clinical efficacy of SJW in IBS patients had been undertaken. The clinical efficacy in controlling IBS symptoms of 450 mg by mouth twice daily over 12 weeks was compared with a parallel control group. Of the 225 participants screened for eligibility for the study, 70 were randomized and began the treatment phase of the study. Eighty-six percent of participants were women. Overall, 29% had IBS-C, 37% had IBS-D, and 31% had IBS-mixed. Both groups reported decreases in overall bowel symptom score from baseline, with the placebo arm having significantly lower scores at 12 weeks compared with the SJW group. These patterns of improvement were mirrored in the secondary end points with the placebo group faring better than the SJW-treated group. Significant differences were observed at Week 12 for the IBS-D group and the portion of patients reporting adequate relief of IBS symptoms during the last 4 weeks of therapy.

Consequently, this pioneering study did not show that SJW had any benefit over placebo, and placebo seemed to work better for control of IBS symptoms. Although severity of symptoms was evaluated by a baseline bowel symptoms score questionnaire, the improvement obtained with the placebo was of similar magnitude to the improvement reported in the SJW group. Although the number of participants in the study limits its power and conclusion, the results do not support the use of SJW in IBS and may even suggest that its use should be discouraged in this setting.

Peppermint

An oil extract of the peppermint plant, Mentha piperita , has been used to treat stomach upset for millennia. Peppermint oil may alleviate IBS symptoms, including abdominal discomfort. The mechanism of action of peppermint has been extensively studied and it has been found to relax intestinal smooth muscle cells by interfering with calcium channels. A fair, although limited, number of trials have been used to specifically assess the value of peppermint in female patients with IBS.

Of the short-term trials that show a positive correlation with peppermint use and a decrease in symptoms of IBS in females, the daily use of three to six enteric-coated capsules containing 0.2 to 0.4 mL of peppermint oil each has been found to improve IBS symptoms. These observations are supported by two meta-analyses. The first was based on five trials that suggested efficacy of the medicinal herb. However, although most of the patients studied were female, the use of heterogeneous diagnostic criteria and symptom scores weakened the power of the findings in this trial. Another review of four small trials, also with mostly female patients, found overall symptom improvement with peppermint oil (OR 2.7; 95% CI, 1.6–4.8). Another trial examined the role of peppermint in 110 patients who were prescreened for celiac disease and lactose intolerance. In this group, patients took four capsules daily for 4 weeks and symptoms were improved in 75% of those taking peppermint oil compared with 38% of those taking placebo ( P <.01). The strict inclusion criteria in this study limit the extrapolation of the results, but peppermint oil may be considered as an adjunct therapy for all female patients with IBS.

Peppermint oil capsules are often specifically enteric-coated to prevent gastroesophageal reflux. Patients should be reminded not to chew the capsules. Perianal burning and nausea have been reported side effects.

Tong xie yao fang

Tong xie yao fang is an herbal formula commonly used in traditional Eastern medicine. A meta-analysis of different variations of this formula included 12 Chinese studies examining its use in patients with IBS. Studying a patient population that was predominantly female, the study preliminarily found tong xie yao fang formulations to be more effective than placebo (relative risk, 1.35; 95% CI, 1.21–1.50). However, it is important to note that the trials were heterogeneous and essentially of poor quality. Additionally, the formulations of tong xie yao fang were not standardized and the doses used were inconsistent. Among an additional three trials that used different traditional Chinese medical herbal formulas containing the ingredients of tong xie yao fang, two demonstrated efficacy but the other did not. These studies again suffered from the same deficiencies as the ones mentioned in the meta-analysis.

Cognitive behavioral therapy

Because there is no specific medical treatment approach for IBS that works for all patients, physicians have turned to the evaluation of psychological therapies to provide relief for their patients. Although the evidence is based on small, often poorly designed studies, cognitive-behavioral therapy (CBT) is one of the most studied of the mind–body therapeutics.

Patients undergoing CBT are trained to recognize and correct thoughts and behaviors that amplify symptoms or undermine well-being. This is combined with psychological strategies for coping with symptoms and illness to allow the patient to exert greater control over symptoms. Five controlled trials have evaluated CBT in the treatment of IBS with mixed results. Although all trials had mostly female patients, none of the trials found that women reported more success in their symptom management than their male counterparts. Three trials used individualized CBT with thought correction techniques, with the largest (N = 431) trial demonstrating that 12 weekly sessions improved symptoms more than did simply providing patients with information to recognize symptoms and triggers (response rate to therapy 70% vs 37%; P = .0001). Of the two smaller trials, one found CBT to be equivalent to a relaxation technique and the other was limited by a dropout rate of more than 50%. The remaining two trials used group CBT; one (N = 45) found that symptoms and well-being improved more with CBT than a wait-list control, but the other (N = 188) found that group CBT was not superior to psychoeducational support. Although initially optimistic, the information from these studies is in no way uniform in recommendations regarding the use of CBT for female patients with IBS.

However, because of the lack of harm with CBT, psychological interventions can be considered for most patients with IBS. The specific intervention used can depend on many factors, including patients’ preference, cost, and the availability of trained providers. Clinicians trained in CBT can consider providing it to their IBS patients but patients should be aware that CBT is certainly not a panacea and they may benefit from also continuing with traditional therapies.

Hypnotherapy

The field of hypnotherapy was initially pioneered by the mid-nineteenth century Scottish physician James Braid to evaluate eye and muscular conditions during what he termed the state of “nervous-sleep.” It is Braid’s early evaluation of hypnotherapy that today forms the basis for the use of therapeutic suggestions to help patients deal with physiologic ailments.

Gut-directed hypnotherapy is a specific technique that combines suggestions related to emotional well-being and intestinal health. It is hypothesized that hypnotherapy could provide benefit for IBS, by affecting parts of the brain that experience abdominal pain or influence the movement of the bowel. Studies evaluating this type of hypnotherapy have involved mostly female patients, accurately representing the greater prevalence of the syndrome in this population.

Its use in IBS was first reported in a small trial of 30 patients, in which improvements in symptoms were greater after 7 weekly sessions of hypnotherapy than they were with supportive psychotherapy alone. This was one of four trials identified in a Cochrane review of hypnotherapy in IBS. The other three trials were also positive compared with medical treatment controls. In the largest trial, 81 IBS patients in primary care received either five weekly sessions and self-hypnosis audiotapes daily or no treatment (neither medical nor psychological). Patients, most of whom were female, who received hypnotherapy had a greater decline in symptom scores at 3 months (mean change in score of 13 out of 100 points vs 4.5 points in the control group; P = .008). It is important to note, however, that overall QoL scores did not reach statistical significance. Other systematic reviews have yielded similar borderline positive results, with one review reporting an outlier of 87% as the median response rate to hypnosis treatment.

As safety and potential long-term benefits add to the appeal of hypnotherapy for adjuvant therapy in IBS, documented clinical experience by experts in the field suggests that some patients are more “hypnotizable” than others. There is no mention in the literature if women are more susceptible to the benefits of hypnotherapy than men. Additionally, results of the included studies need to be interpreted with caution because of small size and methodologic limitations. Consequently, because of the essentially benign nature of therapy and lack of harm, it is reasonable to advise patients to consider a trial with a therapist trained in gut-directed hypnotherapy to augment other therapies that have already been initiated by their gastroenterologist.