Management of Irritable Bowel Syndrome (IBS) in Adults: Conventional and Complementary/Alternative Approaches Saunjoo L

amr Review Article

Management of Irritable Bowel Syndrome (IBS) in Adults: Conventional and Complementary/Alternative Approaches Saunjoo L. Yoon, PhD, RN; Oliver Grundmann, PhD; Laura Koepp, BSN, RN; Lana Farrell, BSN, RN

Abstract the United States go undiagnosed; 75 percent of Irritable bowel syndrome (IBS) is a chronic gastrointestinal those diagnosed suffered at least two years or more, disorder with a range of symptoms that significantly affect and one-third of these suffered for over 10 years quality of life for patients. The difficulty of differential prior to diagnosis.4,5 Lack of definitive diagnosis diagnosis and its treatment may significantly delay initiation and treatment and the chronic, debilitating nature of optimal therapy. Hence, persons with IBS often self-treat of IBS often compel patients to change or limit symptoms with non-prescribed pharmacological regimens their diets,2 seek non-prescribed pharmacological and/or complementary and alternative medicines (CAM) and regimens (complementary and alternative medi- by modifying diet and daily activities. In addition, most cine [CAM] therapies in particular),6,7 and modify common pharmacological approaches target IBS symptom routine daily activities8-10 in order to manage management rather than treatment, and prescribed symptoms. medications often result in significant side effects. The The purposes of this review article are to: (1) purposes of this review article are to: (1) address current address current issues related to IBS including issues related to IBS, including symptom presentation, symptom presentation, diagnosis, and current diagnosis, and current treatment options; (2) summarize treatment guidelines; (2) summarize benefits and Saunjoo L. Yoon, PhD, RN – benefits and side effects of currently available pharmacologi- side effects of currently available pharmacological Associate Professor, College cal regimens and other symptom management strategies, regimens and other symptom management of Nursing, Department of with an emphasis on commonly used CAM therapies and diet strategies, with an emphasis on commonly used Adult and Elderly, University of Florida, Gainesville modification; and (3) outline recommendations and future CAM therapies and diet modification; and (3) Correspondence address: directions of IBS management based on systematic reviews, recommend future directions of IBS management Department of Adult and meta-analyses, and research findings. based on systematic reviews, meta-analyses, and Elderly, University of Florida College of Nursing, HPNP (Altern Med Rev 2011;16(2):134-151) research findings. Complex, P.O. Box 100187, Gainesville, FL 32610 Introduction IBS: Prevalence and Diagnosis Email: [email protected] IBS is defined as “abdominal pain or discomfort Depending on how IBS criteria are defined, Oliver Grundmann, PhD – that occurs in association with altered bowel habits overall prevalence rates range from 2.1-22 percent. Assistant Professor, College over a period of at least three months.”1 Symptoms Women are about 1.5-2 times more likely to of Pharmacy, Department of 1,5,11,12 Medicinal Chemistry, Univer- of IBS include abdominal pain, change in bowel develop IBS than men. Although it is present sity of Florida, Gainesville habits (diarrhea or constipation), bloating, and in all age groups, prevalence of IBS seems to incomplete defecation.2 However, symptom decline with advanced age.5 According to Rome III Laura Koepp, BSN, RN – 3 Virginia Mason Medical presentation and severity vary. Since current criteria, an IBS diagnosis can be made if recurrent Center, Seattle, WA diagnostic criteria are based on symptoms,1 abdominal pain has been present for at least three definitive diagnosis of IBS presents challenges due days per month during the preceding three months, Lana Farrell, BSN, RN – Palm Beach Gardens Medical to overlap in symptom presentations with other accompanied by two of the following three symp- Center, Juno Beach, FL diseases or associated conditions (e.g., lactose toms: relief with defecation, onset of symptoms intolerance, inflammatory bowel disease, celiac with a change of stool consistency, and stool sprue, small intestinal bacterial overgrowth). More frequency without any obvious biochemical than 75 percent of patients suffering from IBS in abnormalities or morphological changes.13 Since

current differential diagnosis of IBS is not based on Impact on Quality of Life (QOL) Key words: IBS, irritable morphological changes or characterized by bio- The most frequently reported symptoms bowel, GI, gastrointestinal, iberogast, padma lax, chemical dysregulation, the only way to differenti- negatively impacting QOL in persons with IBS are peppermint, TCM, ate IBS from other functional bowel disorders abdominal pain, bowel difficulties, bloating, and probiotics, yoga, hypnosis, (FBD) is by exclusion. Despite the advocated use of limitations in eating/diet restrictions.4,14 While TXYF, curcuma, herbal, turmeric, curcumin, artichoke, Rome II and III criteria to diagnose IBS (Table 1), a constipation-predominant IBS and diarrhea-pre- 2,14 cynara, food allergy, turmeric, recent systematic review published by the dominant IBS similarly impact QOL, bloating menthe, bifidobacterium, American College of Gastroenterology (ACG) Task and diarrhea have the most negative impact on lactobacillus, B. coagulans, S. boulardii Force reported that the accuracy of this criteria has patient self-confidence and often lead to avoidance not been well established.1 This has been reflected of social settings.15 IBS affects daily functioning, in this review by referring to IBS as a symptom work and lifestyle,4 and interrupts sleep, which complex, where individual symptoms have limited leads to increased fatigue.16 For example, many diagnostic accuracy. persons with IBS are forced to stay close to a toilet (>50%), are distressed by symptoms (69%), experience lack of control over their lives (57%), and are emotionally Table 1. Rome II and III IBS Diagnostic Criteria disturbed (upset, depressed, less Rome III criteria Rome II criteria confident, or worried). The degree of interruption of daily life is also Diagnostic criterion† At least 12 weeks of abdominal discomfort or pain related to co-existing or co-occurring Recurrent abdominal pain or discomfort‡ at that has two out of three features, which need not conditions such as depression and anxiety. Relationships between least three days/month in last three months be consecutive, in the preceding 12 months: stress and IBS have been reported by associated with two or more of the researchers,17-21 and most patients following: suffering from IBS identify stress and anxiety as symptom aggrava- 1. Improvement with defecation. 1. Relieved with defecation; and/or tors.2 Psychological stress can 2. Onset associated with a change in 2. Onset associated with a change in frequency of increase severity of IBS symptoms,17 frequency of stool. stool; and/or and a correlation between slow onset 3. Onset associated with a change in form 3. Onset associated with a change in form of IBS symptoms and common stress (appearance) of stool. (appearance) of stool. disorders such as depression and anxiety was noted by Mayer et al.21 It is therefore important to consider In pathophysiology research and clinical Symptoms that cumulatively support the each individual’s lifestyle, medical trials, a pain/discomfort frequency of at diagnosis of IBS: history, and co-existing conditions least two days a week during the screening – Abnormal stool frequency (for research (e.g., diet, physical activity, recent evaluation is recommended for subject purposes “abnormal” may be de ned as bowel infection, family history of eligibility. greater than three bowel movements per day and colon cancer) when diagnosing less than three bowel movements per week); patients.22,23 – Abnormal stool form (lumpy/hard or loose/watery stool); Health Care Costs – Abnormal stool passage (straining, urgency, or Associated with IBS feeling of incomplete evacuation); The direct and indirect costs associated with IBS are estimated at – Passage of mucus; $200 billion worldwide.24 This is – Bloating or feeling of abdominal distension. related to the high incidence (approximately 250-300 cases of IBS † Criterion ful lled for the last three months with symptom onset at least six months prior to diagnosis. diagnosed per 100,000 people) and ‡ “Discomfort” means an uncomfortable sensation not described as pain. prevalence of IBS compared to other FBDs, such as inflammatory bowel Adapted from: Drossman DA, Douglas A, eds. Rome III: The Functional Gastrointestinal Disorder. 3rd edition ed: disease (IBD). Moreover, the costs of Degnon Associates; 2006. IBS in the United States have significantly increased during recent

years. In 1998, direct costs (e.g., medical services, Conventional Pharmacological hospitalizations) were estimated to be $1.4 billion. Treatments Indirect costs (e.g., loss of work hours/productivity IBS can be classified as either diarrhea predomi- due to time spent in medical services/treatment, nant (IBS-D), constipation predominant (IBS-C), or lost future earnings if job was lost) were estimated a mixed form (IBS-M).22 The diagnosis leads to to be $205 million, adding up to a total cost burden treatment recommendations with limited effective- of $1.6 billion. By 2000, this number increased to ness for IBS management. Due to the wide range of $1.8 billion.25 symptoms that may be experienced, the available pharmacological treatments are mainly targeted at Pathogenesis and Pathophysiology symptom reduction. In addition, some patients The pathophysiology of IBS is distinguishable may have coexisting conditions that contribute to from celiac disease and inflammatory bowel the severity of IBS symptoms, requiring further diseases (e.g., ulcerative colitis, Crohn’s disease) consideration when choosing treatment since IBS does not present with gross organic or options.34,35 Based on predominant GI motility biochemical abnormalities.26-28 Although the pathogenesis of IBS is not known, a multi-factorial involve- Table 2. Conventional Pharmacological Treatments for IBS ment of diet, gene mutations, psychosocial factors, and immune- Drugs/Compounds mediated processes is hypoth- Indication Drug Target Physiological E ect Examples esized.29 The contribution of these factors varies and in many cases no IBS-M serotonergic and adrenergic ↑compliance, venlafaxine, uoxetine single cause can be determined. receptors ↔ motility One theory regarding the pathophysiology of IBS involves interfer- ence of neurotransmission between intestinal ora ↔ motility, probiotics the central nervous system (CNS) ↓ bloating, and the intestines. A number of ↓ pain structures in the CNS are connected with the gut via serotonergic and cholinergic receptor ↓ intestinal motility, cimetropium, pinave- cholinergic nerves – referred to as antagonists ↓ pain rium, hyoscine, the enteric nervous system otilonium, mebeverine (ENS).30,31 Independent of the afferent connections, the intestine IBS-D 5-HT receptor antagonists ↓ intestinal motility, ondansetron, alosetron, uses serotonin itself to regulate gut ↓ pain cilansetron motility. Serotonin binds to 5-HT4 and 5-HT3 receptors, and its signal- ing activity is terminated by binding selective M receptor ↓ intestinal motility zamifenacin, darifenacin to the specific serotonin reuptake antagonists transporter.32,33 It has been shown that the activity of this transporter α agonist ↓ intestinal motility, clonidine is reduced in several GI disorders ↓ pain sensation (including IBS) that present with common symptoms of dysregulated µ-opioid receptor agonist ↓ intestinal motility, loperamide intestinal motility caused by persis- ↓ peripheral pain tent serotonin release at its respective receptors.33 Based on this theory, a variety of treatment approaches IBS-C chloride channel modulator ↑ intestinal motility, lubiprostone have been suggested that temporar- ↑ water secretion ily treat the symptoms rather than the cause of IBS, since there is still 5-HT agonists ↑ intestinal motility, tegaserod, considerable lack of knowledge about ↑ water secretion metoclopramide, IBS pathogenesis and domperidone, cisapride pathophysiology.

dysfunction, loperamide and codeine for the Antispasmodics for Various Forms of IBS treatment of diarrhea in IBS-D, laxatives and Antispasmodics are the most common class of prokinetics for the treatment of constipation in pharmacological drugs used for managing various IBS-C, and antispasmodics for all types of IBS have forms of IBS. Antispasmodics predominantly act as been used extensively to reduce the respective antagonists at cholinergic receptors and thereby symptoms. Current pharmacological treatments reduce contraction of the GI tract. Commonly used are summarized in Table 2. antispasmodics that have proven to be effective in the treatment of IBS spasms are cimetropium, IBS-D Treatments pinaverium, hyoscine, and otilonium.47 Depending Loperamide is an opioid receptor agonist that is on the symptoms, antispasmodics are adminis- not absorbed from the GI tract after oral adminis- tered up to three times daily in conjunction with tration, acting locally to reduce GI motility and prokinetics or laxatives to normalize GI motility spasms.36 Similar to loperamide, codeine can without causing constipation. reduce abdominal and visceral pain37 as well as GI motility, but may affect the CNS, causing sedation Effect of Antidepressants on IBS Symptoms and potential drug abuse.38 Many patients with In addition to normalization of GI motility with IBS-D also suffer from nausea and vomiting due to antispasmodics, tricyclic antidepressants (TCAs)

serotonin stimulation of 5-HT3 receptors in the and selective serotonin reuptake inhibitors (SSRIs)

intestines. There are a number of 5-HT3 antago- have become a mainstay of supportive treatment nists that were originally prescribed for the for IBS.48 Both drug classes were initially used to treatment of chemotherapy-related nausea, but are treat co-existing mental disorders such as depres- now often used to reduce symptoms of IBS-D.39 For sion and anxiety in patients with IBS, but clinical instance, ondansetron, granisetron, alosetron, and trials have shown that IBS patients without a

cilansetron are all specific 5-HT3 receptor antago- depressive disorder can benefit from low-dose TCA nists that reduce nausea and vomiting and act as therapy.49 Surprisingly, both TCAs and SSRIs do visceral analgesics in IBS-D.40 not interfere with serotonin concentrations in the intestines, which would otherwise further increase IBS-C and IBS-M Treatments IBS symptoms. Instead, they appear to normalize Although it was more effective than a placebo, GI motility and reduce visceral pain.50,51 Long-term the use of the prokinetic tegaserod in IBS-C and outcomes of these therapies are, however, not well IBS-M has been limited due to adverse ischemic understood and require more research.1 In spite of cardiovascular events.1,41 Several other prokinetics currently available pharmacological treatments to such as metoclopramide, domperidone, and reduce symptoms of IBS and improve QOL, the cisapride are used off-label, even without a specific search for more effective therapies with fewer side indication for IBS treatment.42 Lubiprostone is effects continues.1 another recently approved prokinetic drug that acts on chloride channels to increase water secre- Use of CAM for IBS tion into the intestines. Prokinetics increase GI CAM is often used for chronic medical condi- motility and provide visceral analgesia by acting as tions, health promotion, and/or disease preven- dopamine antagonists, serotonin antagonists at tion.52-55 Currently available systematic reviews

the 5-HT3 receptor, and serotonin agonists at the provide conflicting findings about the effectiveness 43,44 5-HT4 receptor. of CAM therapies for IBS. The American College of Increasing dietary fiber intake is an important Gastroenterology Task Force on IBS1 reported that treatment option that should be considered before CAM therapies have not demonstrated any strong prescribing tegaserod or lubiprostone for patients evidence-based support for positive outcomes. with IBS-C. Fiber stimulates GI motility and Other systematic reviews, however, indicate loosens stool consistency.45 Laxatives may also be evidence of effectiveness.6,56,57 considered as initial treatment if fiber intake alone In recent studies, up to 50 percent of individuals does not alleviate constipation. Use of laxatives suffering from IBS reported using CAM,6,7 which is such as polyethylene glycol, or the stool softener not surprising considering currently available docusate, should be monitored with care since pharmacological treatments for IBS have shown electrolyte imbalances may occur. Overall, the limited benefit and significant side effects. About effectiveness of laxatives and stool softeners in the 50 percent of self-prescribed herbal supplement treatment of IBS-C is limited.46 users perceived benefits of using herbal

supplements for IBS, while the other half reported extract, and artichoke leaf. Common combinations equivocal effects.7 Considering the chronic but of multiple herbs used for IBS include a variety of variable nature of IBS, it is not surprising that Chinese herbal formulas, the Tibetan herbal many IBS patients using CAM are unsure of its mixture Padma Lax®, and a combination of nine effectiveness. Among various types of CAM, herbal herbs referred to as STW 5, marketed under the products including Chinese herbal mixtures, trade name Iberogast®.58 hypnosis, relaxation technique, acupuncture, dietary changes, probiotics, and exercise have been Enteric-coated Peppermint studied for their potential benefits.6 Steam distillation oil extracts from the peppermint plant (Mentha piperita, Lamiaceae) are among Herbal Therapies the oldest remedies for treatment of GI problems. Although a limited number of well-designed These extracts are believed to improve IBS symp- studies are available, various herbal remedies have toms by exerting a spasmolytic effect on the been tested for managing IBS, either as a single smooth muscles in the digestive tract.59 In addition herb or herbal combination. Single herbs that have to a number of case reports and small, uncon- been studied include peppermint oil, turmeric trolled studies,60-64 two randomized, double-blind,

Table 3. Single Herbal Medicines for IBS

Sample Sample Study Reference size characteristics design Dose of active Duration Outcome Enteric-coated peppermint oil capsules Capello et al (2007) 57 All IBS forms, IBS R,D,P 225 mg peppermint oil per 4 weeks rx; 4 Signi cant reduction in IBS determined by cap; 2 caps bid weeks follow-up symptoms after 4 weeks in Rome II criteria peppermint oil group vs. placebo group

Merat et al (2010) 90 All IBS forms, IBS R,D,P 187 mg peppermint oil tid, 8 weeks Signi cant reduction in determined by 30 min before meals abdominal pain and severity Rome II criteria in peppermint oil group vs. placebo, signi cant increase in QOL in peppermint oil group vs. placebo Turmeric extract (standardized) Bundy et al (2004) 207 All IBS forms, IBS R, 2 doses, 72 mg (1 tablet) 8 weeks Signi cant improvement in determined by non-D, or 144 mg (2 tablets) daily IBS QOL at end of trial Rome II criteria non-P compared to baseline for both treatment groups Artichoke leaf extract Walker et al (2001) 279 All IBS forms, R, 320 mg artichoke leaf 6 weeks Signi cant reduction of meeting at least non-D, extract per cap; 2 caps tid IBS-related symptoms 3 out of 5 Rome non-P w/ meals evaluated on a Likert scale at II criteria end of study compared to baseline

Bundy et al (2004) 208 All IBS forms, R, 320 mg (1 capsule) or 640 8 weeks Signi cant reduction in NDI meeting at least non-D, mg (2 capsules) of 1:5 QOL score at end of trial 3 out of 5 Rome non-P artichoke leaf extract daily compared to baseline II criteria

R: Randomized, D: Double-blind, P: Placebo-controlled NDI=Nepean Dyspepsia Index

placebo-controlled trials report a beneficial effect evaluation by the American Academy of Pediatrics, of peppermint oil for the treatment of IBS but with cautions due to potential side effects of symptoms.65,66 heartburn or respiratory depression and lack of In one study, after four weeks of treatment, a availability of standardized dosages. It is suggested group receiving two enteric-coated capsules to give 0.1-0.2 mL three times daily for no longer containing 225 mg of peppermint oil twice daily than two weeks under the guidance of a health care (n=28) showed a statistically significant improve- practitioner.67 ment in overall IBS symptoms compared with a placebo group (n=29). The peppermint oil was Turmeric effective in alleviating constipation, bloating, Turmeric (Curcuma longa, Zingiberaceae) has diarrhea, abdominal pain, passage of gas or mucus, been traditionally used for managing abdominal urgency at defecation, pain during evacuation, and pain, indigestion, and abdominal bloating. feelings of incomplete evacuation. Efficacy was Effectiveness of turmeric on improvement of IBS evaluated via intensity and frequency score using a symptoms and QOL was investigated in 207 IBS Likert scale (0-4) for each symptom.65 patients. Statistically significant improvements A randomized, double-blind clinical trial with 90 based on symptoms and quality of life (IBS-QOL IBS patients (45 subjects in each group) confirmed questionnaire) were found after eight weeks of that both pain severity and general health turmeric intervention at a dose of 72 or 144 mg improved after eight weeks of administration with daily, compared to screening and baseline phases an enteric-coated product (Colpermin®, containing (but no placebo group). There were no differences 187 mg peppermint oil) three times daily compared between the two groups, indicating a dose-inde- to placebo. Outcomes were measured using the pendent or threshold effect.68 SF-36 questionnaire as well as an intensity and frequency score with a Likert scale (0-3).66 Artichoke Leaf Extract The use of peppermint oil for the treatment of Two studies on artichoke (Cynara scolymus, IBS in children has also received a positive Asteraceae) leaf extract (ALE) indicated IBS symptom improvement. According to a post-marketing surveillance study of 279 subjects, two Table 4. Herbs in Iberogast capsules ALE three times daily with meals (320 mg ALE per capsule) relieved abdominal pain, cramps, Herb-Extract ratio In 100 mL bloating, flatulence, and constipation in subjects Plant (Latin name) (alcoholic extracts) Iberogast with dyspepsia and at least three of five commonly Bitter candytuft (Iberis amara) 1:1.5-2.5 15.0 mL observed IBS symptoms (evaluated by physicians and patients using a Likert scale).69 Angelica root (Angelica archangelica) 1:2.5-3.5 10.0 mL In another open, post-marketing study involving 208 subjects, the Nepean Dyspepsia Index (NDI) Chamomile owers (Matricaria recutita) 1:2.5-4.0 20.0 mL indicated that there was a significant decrease in overall IBS symptoms, including abdominal pain, Caraway fruits (Carum carvi) 1:2.5-3.5 10.0 mL diarrhea and/or constipation, urgency, straining, feeling of incomplete passage, and passage of Milk thistle fruits (Silybum marianum) 1:2.5-3.5 10.0 mL mucus after two months of intervention with 320 mg or 640 mg ALE daily. In addition to normaliza- Lemon balm leaves (Melissa o cinalis) 1:2.5-3.5 10.0 mL tion of bowel movements, an increased QOL was 70 Peppermint leaves (Mentha x piperita) 1:2.5-3.5 5.0 mL reported with use of ALE. Although the two ALE studies were conducted by Celandine (Chelidonium majus) 1:2.5-3.5 10.0 mL some of the same researchers with the same artichoke extract, it is not clear why the dosage was Licorice root extract (Glycyrrhiza glabra) 1:2.5-3.5 10.0 mL so different between the two studies69,70 (assuming the correct dosages were provided by the study Adapted from: Vinson B. Development of Iberogast: Clinical evidence for multicomponent authors). herbal mixtures. In: R. Cooper and F. Kronenberg, eds. Botanical Medicine: From Bench to Bedside. Mary Ann Liebert Inc. 2009.

Combination Herbal Formulas Multiple herbal preparations Table 5. The Pharmacological Effects of Iberogast such as Iberogast, Padma Lax, and Tong Xie Yao Fang (TXYF) Acid Oxidative Symptoms / Botanical have shown promising out- secretion In ammation processes Hypomotility Hypermotility comes for managing IBS. Peppermint leaf extract W S S N M Iberogast, a combination of nine herbal extracts (Table 4), Chamomile ower extract S W M M S was shown in several clinical trials to improve symptoms of Licorice root extract W S W N M functional dyspepsia at a dose of 20 drops three times Angelica root extract M W M N S daily.71-73 While symptoms of functional dyspepsia are often Caraway fruit extract M S W N W similar to IBS in terms of Milk thistle fruit extract gastrointestinal disturbances, M M M N M pain, and reduced quality of life, Melissa leaf extract M M S N W only limited clinical data are available regarding its effective- Celandine herb extract N M M M N ness for specific IBS symptoms. The symptoms of functional Bitter candytuft extract M S W M W dyspepsia are often predominantly related to food consump- N=No eect, W=Weak eect, M=Moderate eect, S=Strong eect tion, with resulting gastric acid From: Wagner H. Multitarget therapy – the future of treatment for more than just functional dyspepsia. Phytomedicine 2006;13 suppl 5:122-129. secretion leading to gastrointestinal symptoms without detectable functional problems. placebo (n=52) (20 drops three times daily for four Iberogast has been shown to interact with several weeks). Both STW 5 and STW 5-II were found to be receptors in the GI tract that play an important effective in reducing abdominal pain severity role in regulation of motility and pain perception, (evaluated via abdominal pain scale) and improving including serotonin, muscarine, and opioid overall symptoms (using the IBS symptom scale) receptors. For example, the different extracts in compared to placebo or bitter candytuft alone. Iberogast bind to the 5-HT serotonin receptor as 3 The complex Tibetan preparation, Padma Lax agonists, while antagonizing the 5-HT and 4 (herbs in formula are listed in Table 6), has been muscarine M receptor in a similar manner to 3 shown to be effective in alleviating symptoms of current synthetic drugs. Overall, the pharmacologi- IBS-C.77 In a three-month, double-blind, random- cal effects of Iberogast are complex in nature, ized observational trial, 482 mg twice daily (once affecting acid secretion, inflammation, oxidative daily in seven patients who got loose stool from processes, as well as both hyper- and hypomotility the twice-daily dosage) was superior to a placebo to varying degrees (Table 5).74 for reducing constipation, abdominal pain, and Although some case reports provide evidence for flatulence.78 Furthermore, rat studies demonstrate effectiveness of Iberogast in alleviating abdominal Padma Lax exerts part of its activity through pain and normalizing gut motility,75 only one cholinergic receptors by reducing contractility of clinical trial with a double-blind, placebo-controlled smooth muscles in the colon as well as procontrac- design has been conducted in 208 patients with tile stimulation.79 IBS.76 In this study, patients were randomly Traditional Chinese medicine (TCM), in the form assigned to commercially available Iberogast (STW of standardized combinations or formulas tailored 5; n=51), a research preparation of some of the specifically to the individual symptom presenta- herbs in Iberogast (bitter candytuft, chamomile tions, improved common IBS symptoms compared flower, peppermint leaves, caraway fruit, licorice to placebo as evaluated in a double-blind, placebo- root, and lemon balm leaves referred to as STW controlled, randomized study.56 The study was 5-II; n=52), bitter candytuft alone (n=53), or conducted on 116 patients who received placebo, a

standard mixture of 33 herbs, or an individualized mixture of herbs selected by a TCM specialist from Table 6. Botanicals in Padma Lax a list of 81 herbs. After 16 weeks, patients in the active treatment groups showed significant Plant part (Latin name) improvements in bowel symptom scores (as Ginger rhizome (Zingiber o cinalis) evaluated by visual analog scales) and increased QOL compared to placebo. Chinese rhubarb root (Rheum o cinale) A specific TCM herbal mixture, Shugan Jianpi, Frangula bark (Rhamnus rubra) was found to reduce the number of serotonin- positive cells compared to a placebo in patients Cascara sagrada bark (Rhamnus purshiana) with IBS.80 The 24 patients received standard care that included cognitive-behavioral therapy and a Gentian root (Gentiana lutea) whey protein (lactein). The placebo group did not Chebulic myrobalan fruit (Terminalia chebula) receive any additional medication, while the Shugan Jianpi groups took 24 g of the herbal Elecampane rhizome (Inula helenium) mixture three times daily or 24 g of the herbal Aloe extract (Aloe vera and/or Aloe ferox) mixture plus 15 g Smecta® (a high viscosity muco-protective agent) three times daily for two Calumba root (Jateorhiza calumba) weeks prior to biopsy to measure number of serotonin-positive cells. The authors did not Condurango bark (Gonolobus condurango) evaluate any subjective or other objective clinical Long pepper fruit (Piper longum) parameters.80 Tong Xie Yao Fang (TXYF), a Chinese herbal Nux vomica seed (Strychnos nux vomica) preparation and a variation (TXYF-A) have the 57,81 (From http://www.naturalhealthconsult.com/ potential to improve global symptoms in IBS-D. Monographs/padmaLax.html) Although a systematic review of TXYF-A indicated its potential effectiveness for reducing IBS symptoms, more studies with rigorous designs are warranted.82 The standard preparation of TXYF is Table 7. Modified TXYF Formula composed of four traditional herbs – Cang zhu (Atractylodes chinensis), Bai shao (Paeonia lactiflora), Chinese name Plant part (Latin name) Dosage (g/day) mandarin orange (Citrus reticulata), and Fang feng (Saposhnikovia divaricata). Based on the individual Bai zhu Rhizome (Atractylodes macrocephala) 15 symptoms, additional herbs may be added to the Huang qui Root (Astragalus membranaceous) 15 mixture, with the resultant formula referred to as TXYF-A. The review evaluated 12 randomized Bai shao Peeled root (Paeonia lacti ora) 15 studies with 1,125 participants for the short- and Cang zhu Rhizome (Atractylodes chinensis) 12 long-term effects of TXYF-A in reducing clinical IBS symptoms. The heterogeneity of the study Chai hu Root (Bupleurum chinense) 9 design and duration of the studies complicated the definition of end points. Overall, the preparations Chen pi Peel (Citrus reticulata) 9 improved various IBS symptoms, including Fang feng Root (Saposhnikovia divaricata) 9 abdominal pain, distension, flatulence, and diarrhea for as long as six months after the Jiu li xiang Twigs (Murraya paniculata) 9 intervention ended. 83 Shi liu pi Rind (Punica grantum) 9 Leung and colleagues compared a preparation of 11 herbal extracts (Table 7) comprising a Ma chi xian Aerial parts (Portulaca oleracea) 30 modification of the traditional TXYF formula Huang lian Rhizome (Coptis chinensis) 6 (n=60) with a placebo (n=59) in a controlled, randomized, blinded design. They found that global assessment scales and QOL did not differ between the TCM herbal preparation and placebo after eight weeks of treatment. Based on this study, TCM herbal preparations may not be beneficial to all IBS

patients but may show promise for specific IBS in rigorous clinical trial designs are warranted to symptoms. More clinical data utilizing rigorous confirm the observed treatment effects. clinical trial designs are required to further support their use. Mind-Body Therapies In summary, a number of single herbal remedies Among mind-body therapies, hypnotherapy and or herbal combinations (Table 8) are reportedly cognitive-behavioral therapy (CBT) seem to be the effective for relieving IBS symptoms. Further most widely accepted by IBS patients. studies investigating the potential mechanisms of pharmacological action and symptom management

Table 8. Summary of Studies on Herbal Combinations for IBS

Sample Sample Study Reference size characteristics design Dose Duration Outcome Iberogast® Madisch et al 203 All IBS forms, IBS R,D,P STW 5, STW 5-II, or 4 weeks Signi cant reduction of (2004) determined by bitter candytuft extract, IBS symptoms and Rome II criteria 20 drops tid abdominal pain in Iberogast and research solution compared to placebo Padma Lax® Sallon et al (2002) 61 IBS-C, IBS R,D,P 482 mg Padma Lax 12 weeks Signi cant reduction in determined by (n=34) or placebo symptom severity scores Rome I criteria (n=27), bid (once daily and abdominal pain in in subjects w/ loose Padma Lax compared to stool) placebo Traditional Chinese Herbal Medicine Bensoussan et al 116 All IBS forms, R,D,P Standard TCM mixture of 16 weeks Signi cant reduction in (1998) determined by 33 herbs (n=43), bowel symptom scores Rome criteria individualized formula and increase in QOL for (not speci ed) (n=38), or placebo individual preparation (n=35), 5 capsules tid and standard TCM compared to placebo

Wang et al (2008) 24 All IBS forms, R,non-D,P 24 g Shugan Jianpi 2 weeks Signi cant reduction in evaluation not granules tid, 24 g serotonin positive cells in speci ed Shugan Jianpi granules both Shugan Jianpi plus 15 g Smecta® tid, or groups compared to cognitive therapy and standard care lactein treatment as standard care

Leung et al (2006) 119 IBS-D, IBS R,D,P See Table 7 for daily 8 weeks No signi cant improve- determined by dose of each herb ment in SF-36 or global Rome II criteria (n=60) or placebo symptoms compared to (n=59) placebo

R: Randomized, D: Double-blind, P: Placebo-controlled

Hypnotherapy and improvement in visceral sensations.90 It has According to several clinical trials hypnotherapy therefore been proposed that GI symptom has the potential to be effective in managing IBS improvement is a result of central effects that symptoms (Table 9).84-86 Hypnotherapy was modulate cortical brain circuits involved with pain effective in improving health-related QOL and and vigilance modulation.91 However, further anxiety, tiredness, and physical symptoms, but not well-designed studies should be conducted to depression, after 12 weeks of intervention without conclusively establish efficacy of hypnotherapy as a randomization,86 while three systematic reviews87-89 supportive treatment for IBS. reported that hypnotherapy can be used to treat abdominal pain and improve QOL, as well as Cognitive-Behavioral Therapy reduce anxiety and depression. A nonsignificant Cognitive-behavioral therapy is another poten- reduction in depression scores was seen in the tial alternative approach to managing IBS, aforementioned study,86 while systematic reviews although according to a recent Cochrane database of hypnotherapy for IBS provide evidence for a review there does not seem to be concrete, reliable reduction in depressive symptoms.87-89 This evidence to prove its efficacy.92 A primary concern difference in outcomes may be due to heterogene- with psychotherapeutic interventions is the ity of study designs. influence of psychological factors on a patient’s

Table 9. Studies of Hypnotherapy for IBS

Sample Sample Study Number Reference size characteristics design of sessions Duration Outcome

Gonsakorale et al 250 All IBS forms, IBS non-R, 12 hypnotherapy 12 weeks Signi cant improvements (2002) determined by non-D, sessions followed by in HADS scores and IBS Rome I criteria non-P self-study symptoms compared to baseline

Gonsakorale et al 204 All IBS forms, IBS non-R, Retrospective analysis of Signi cant reduction in (2003) determined by non-D, IBS symptoms one year IBS symptoms and HADS Rome I criteria non-P after hypnotherapy scores as well as reduction in medication use in hypnotherapy- responsive patients compared to non-responsive patients

Smith (2006) 75 All IBS forms, IBS non-R, 5-7 hypnotherapy 12 weeks Signi cant improvement determined by non-D, sessions over three in IBSQOL scores, Rome II criteria non-P months with follow-up abdominal pain and distension, and anxiety compared to baseline

R: Randomized, D: Double-blind, P: Placebo-controlled

Although the precise mechanisms of action for perception of IBS symptoms.93 Since IBS is diag- hypnotherapy are not known, several psychological nosed based on exclusion criteria and is associated and physiological changes have been observed in with significant psychosomatic relations, patients many of the studies, including improvement in who reject psychological interventions or whose cognitive function, reductions in anxiety and symptoms are not severe enough are not consid- depression scores, decreased colonic contractions, ered potential candidates for CBT. In many cases, a

combination of CBT with pharmacological treat- treatment.102,104-106 In addition, the self-administra- ment provides the best outcome.1 According to Van tion of relaxation techniques provided long-term Dulmen and colleagues,94 eight two-hour sessions relief of most IBS symptoms as assessed by a of CBT intervention over a period of three months one-year follow-up study.104 The retrospective was effective in significantly decreasing abdominal study reviewed 10 patients with IBS, who initially discomfort, enhancing coping strategies, and participated in a three-month study on the use of diminishing avoidance behavior (impacting QOL) relaxation response meditation. After one year, in IBS patients. The patients were asked to keep a participants were evaluated for abdominal pain, daily record of the activities they avoided because diarrhea, distension, and flatulence – all of which of their IBS symptoms.94 presented with significant reductions compared to In a randomized, controlled trial with three arms baseline.104 (CBT, relaxation therapy [RT], or routine clinical care [RCC]) involving 105 subjects, individuals Acupuncture and Moxibustion were treated weekly over an eight-week period with Acupuncture can cause physiological changes follow-up at 26 and 52 weeks. Although results that affect various endogenous neurotransmitter showed significant improvement after eight weeks systems. Of specific interest to the treatment of with all three interventions compared to baseline IBS is the influence of acupuncture and moxibus- in all parameters measured, there were no signifi- tion on the serotonergic and cholinergic neuro- cant differences among the three treatment groups transmission of the brain-gut axis. Both animal during the follow-up period. It was concluded that and human trials indicate specific targets for RCC was as effective as CBT or RT.95 acupuncture on serotonergic, cholinergic, and A number of additional clinical trials and glutamatergic pathways as well as reductions in meta-analyses found similar results; CBT was as blood cortisol levels.107-110 effective as current standard pharmacological In a controlled, randomized pilot study, 30 treatments for IBS. A combination of both may subjects received routine clinical care or acupunc- provide additive symptom relief to patients.96-100 ture for IBS. After three months of treatment, The ACG Task Force on Irritable Bowel Syndrome outcomes of acupuncture intervention revealed supports the use of CBT for the treatment of statistically and clinically significant improvements certain forms of IBS.1 in symptom severity, including pain, distension, bowel habits, and QOL compared to usual care only. Relaxation Techniques In this study, however, the type of IBS was not Relaxation techniques have been studied for defined for the sample population.111 their potential role in alleviating IBS symptoms. In a large, randomized, controlled study, 230 Multiple studies have indicated positive correla- subjects with IBS were assigned to one of three tions among psychological distress, daily stress, groups. The two intervention groups were either and GI symptom aggravation17-20,101 that triggered three weeks of true or sham acupuncture following IBS symptoms.2,102 Women with IBS tend to report a three-week run-in period of sham acupuncture a higher amount of psychological distress and therapy with a “limited” (friendly, interactive) lifetime psychopathology than those with no GI patient-practitioner relationship, while the third symptoms.103 Relaxation training may be beneficial arm was a waitlist control group. Findings indi- for symptom improvement and appears to be at cated no significant difference in global outcome least as effective as standard pharmacological measurements between real and sham acupuncture, treatment. The relaxation techniques used in this but both interventions showed significant study included progressive muscle relaxation, improvement over the waitlist control group.112 release-only, cue-controlled, and applied relaxation, In another similar study, Schneider and col- in addition to standard clinical care.95 Inclusion of leagues randomized 43 subjects to receive either autogenic training, a relaxation technique that acupuncture or sham acupuncture for 10 sessions serves to increase self-directed awareness tension (an average of two per week).113 Although the through conscious breathing, slowing of the Functional Diseases QOL questionnaire (FDDQL) heartbeat, and muscle relaxation, and other in this study revealed that both groups improved relaxation techniques improve IBS-related GI significantly in overall QOL, there was no difference symptoms as well as QOL and increase symptom- between the two groups, suggesting that the effect free days compared to standard pharmacological of acupuncture was primarily a placebo response.

According to Anastasi and colleagues, a combina- and diarrhea, thus exacerbating IBS symptoms.117 tion of acupuncture and moxibustion (acu/moxa) Other types of sugar-alcohols proposed to aggra- can be highly effective in IBS treatment. Twenty- vate IBS symptoms include mannitol, xylitol, nine subjects who met Rome II criteria were erythritol, lactitol, maltitol, and isomalt.117 Due to randomized into either individualized acu/moxa the multitude of variables related to IBS symptoms, treatments or sham/placebo acu/moxa treatments. study results are difficult to validate and challeng- Results indicated that acu/moxa reduced abdomi- ing to interpret. nal pain, significantly reduced gas and bloating, and improved stool consistency over a four-week, Fiber eight-session intervention period.114 A Cochrane Fiber intake from fruits and vegetables is meta-analysis suggests larger-scale studies are inversely correlated to bloating.9 The addition of warranted to confirm the benefits of acu/moxa in psyllium fiber, especially for persons with IBS-C, alleviating IBS symptoms.115 reduced IBS symptoms in some people,117,122,123 while either wheat bran or a low-fiber diet was Diet Modification found to be an ineffective management measure as A primary goal of all IBS interventions is to evaluated by two meta-analyses of a total of 30 provide the patient with relief of symptoms and studies.123 Because most of the evaluated studies improve the quality of life. Although the data from had small sample sizes, the results are highly clinical trials may in some cases not provide strong variable. Other widely variable factors included the evidence for benefits of dietary modification, it amount of soluble (5-30 g) and insoluble (4.1-36 g) remains the primary non-pharmacological clinical fiber added to the diet and the duration of study intervention for IBS patients; exclusion diets are intervention (3-16 weeks). Overall, consumption successfully used by many clinical practitioners.1 of soluble fiber resulted in a decrease in global IBS Food intolerances or allergies are strong con- symptoms and constipation, whereas insoluble tributors to the exacerbation of IBS symptoms. fiber demonstrated a less significant effect. Neither Individuals with IBS often discover that certain intervention, however, decreased abdominal pain foods aggravate symptoms,2,116-118 while others have in IBS patients. Due to its moderate effectiveness, found relief from IBS symptoms by modifying their additional intake of soluble fiber maybe recom- daily diet and increasing exercise activities.2,8-10 mended for IBS-C patients. Studies also revealed Symptoms of IBS may be associated with visceral that pain relief was not associated with increased hyperactivity, GI motility disturbances, sugar fiber intake and that the addition of insoluble fiber malabsorption, gas-handling disturbances, and such as nuts or whole grains to the diet had either abnormal intestinal permeability.13,22,119 Elimination no effect or exacerbated IBS symptoms.122 diets are often employed that remove the most common allergens from the diet.120 Although some Lactose Intolerance patients reported that removing wheat, dairy Patients with IBS were found to have signifi- products, eggs, coffee, yeast, potatoes, and citrus cantly more subjective lactose intolerance com- fruits from their diets is helpful, such restrictions plaints (bloating, distention, and diarrhea) than may be difficult to follow.118 Dietary restrictions those without IBS and to have increased likelihood may provide patients with relief of IBS symptoms of lactose malabsorption than the general popula- over time, while entirely skipping meals has been tion.124 Thus, decreased intake of lactose can found to worsen IBS symptoms.118,121 benefit some IBS patients.125 It is hypothesized that, following ingestion of lactose, hydrogen gas is Macronutrients: Fat, Sugar, and Sugar Alcohols produced and gut distention is promoted due to IBS studies indicate a positive relationship bacterial fermentation of the unabsorbed lactose. between fat intake and increased stool number and Interestingly, the majority of IBS sufferers, how- diarrhea.9,121 Intake of carbohydrates can also ever, failed to test positive for hydrogen breath aggravate IBS symptoms.118 Offending carbohy- tests that indicate lactose intolerance.125 drates include fructose and fructose-containing products such as soft drinks, cereals, and packaged/ Probiotics baked goods. Sorbitol and other sugar-alcohols Probiotics have been extensively studied for the found in most sugar-free or reduced-sugar prod- treatment of IBS. A thorough review of the research ucts are poorly absorbed in the GI tract and may is beyond the scope of this article. A number of cause increased flatulence, abdominal discomfort, studies have examined the effect of single

organisms on IBS symptoms and/or quality of life. Exercise Most studies used various species of Lactobacillus, Exercise can help maintain GI function and Bifidobacterium, and Streptococcus strains given in reduce stress, which can help relieve some IBS concentrations of 108-1010 colony forming units per symptoms. Studies of IBS indicate positive rela- day (cfu/day). The primary endpoints of many tionships between physical activity and symptom studies are reductions in bloating, abdominal pain, relief.10,121,132 Physical activity, such as pedaling a and flatulence, as well as evaluation of global bicycle, protects against GI symptom aggravation symptoms using the IBS severity scoring system. and alleviates gas in several studies.10,121,132 In a randomized, controlled trial, 44 IBS patients Although one study revealed an inverse relation- were given either Bacillus coagulans strain GBI-30, ship between exercise and all GI symptoms except 6086 or placebo for eight weeks. B. coagulans constipation,9 another study reported constipation resulted in significant relief of abdominal pain and improved with mild exercise, therefore, potentially bloating from baseline during each of seven benefiting IBS-C patients.8 evaluation weeks; the placebo group experienced The practice of yoga has also demonstrated only significant relief in abdominal pain at the reduction of IBS symptoms in both adult and sixth and eighth week.126 In another study, 52 adolescent populations.133,134 Pranayama yoga has patients with IBS-D were randomized to receive been identified as an exercise regimen that either this same strain of B. coagulans or placebo increases sympathetic tone, which is decreased in once daily for eight weeks. The average number of IBS-D patients.135 In a two-month study, a yoga bowel movements daily significantly decreased in intervention group practiced twice daily, while the the treatment group compared to placebo.127 conventional treatment group received 2-6 mg There was a slight but statistically significant loperamide daily. Results indicated that yoga reduction in symptom severity observed in 60 demonstrated improvement of IBS symptoms patients with mild IBS randomly assigned to equivalent to conventional treatment.135 Lactobacillus plantarum in a rosehip tea or rosehip tea alone for four weeks. L. plantarum strain DSM Summary 9843 at a dose of 2x1010 cfu/day was found to The goal of current standard pharmacological decrease pain and flatulence compared to those treatment is to alleviate clinical symptoms of IBS. taking only rosehips.128 Because conventional treatments typically do not At least two studies have evaluated the effects of get to the root of the problem or provide anything Bifidobacterium infantis 35624. One randomized, but symptomatic relief, patients often seek CAM controlled trial (n=362 women with IBS of all therapies, including cognitive-behavioral therapy, types) found a dose of 108 cfu/day for four weeks herbal therapies, probiotics, mind-body therapies, (but not 106 or 1010) was effective in reduced acupuncture, dietary changes, and exercise. bloating, abdominal pain, and flatulence, as well as Although most CAM therapies reviewed in this global IBS symptoms compared to placebo.129 In article seem to provide some benefit in alleviating the second study, 77 IBS patients were randomly IBS, it is apparent that the duration, dosages, and assigned to B. infantis 35624, Lactobacillus sali- specifics of the intervention greatly affect the varius UCC4331, each (1010 cfu/day), or placebo for outcomes. More studies need to be conducted to eight weeks. B. infantis resulted in significant establish the subtle nuances associated with these reduction in symptom scores and inflammatory treatments (e.g., specific probiotics, standardiza- cytokines compared to either L. salivarius or tion of herbal extracts, yoga style, etc.) to provide placebo.130 the most significant benefit for IBS. A beneficial yeastSaccharomyces boulardii has also been tested for IBS treatment. Subjects received References either S. boulardii (n=34) or placebo (n=33) for four 1. American College of Gastroenterology Task Force on weeks. The S. boulardii group experienced signifi- Irritable Bowel Syndrome, Brandt LJ, Chey WD, et cant improvement in IBS-QOL but not individual al. An evidence-based position statement on the symptom scores compared to placebo.131 management of irritable bowel syndrome. Am J In addition to these individual organisms, more Gastroenterol 2009;104:S1-S35. than a dozen studies, just in the last five years, 2. Lacy BE, Weiser K, Noddin L, et al. Irritable bowel have examined the effect of multiple probiotic syndrome: patients’ attitudes, concerns and level of strains on IBS. knowledge. Aliment Pharmacol Ther 2007;25:1329-1341.

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