MEDICINE CLINICAL PRACTICE GUIDELINE Irritable Bowel Syndrome—The Main Recommendations Viola Andresen, Jutta Keller, Christian Pehl, Michael Schemann, Jan Preiss, Peter Layer SUMMARY Background: Irritable bowel syndrome is characterized by chronic abdominal symptoms and irregular bowel movements without any cause than can be revealed by routine diagnostic assessment. In recent years, its pathophysiology has come to be much better understood, and new therapeutic approaches have been developed. These advances were taken into consideration and assessed for their relevance to clinical practice in the framework of a new interdisciplinary S3 guideline. Methods: A systematic search of the literature retrieved a total 5573 articles, from which 243 were selected on the basis of criteria relating to their form and content, individually assessed, and summarized in evidence tables. The recommendations formulated in this way were discussed in a Delphi procedure and a consensus conference, then accordingly modified and finalized. Results: Variable symptom constellations are caused by disturbances of gastrointestinal regulation at multiple levels. The diagnosis of irritable bowel syndrome requires both chronic bowel symptoms that interfere with everyday life and the exclusion of relevant differential diagnoses. Its treatment is based on general therapeutic principles, dietary recommendations, psychological components, and symptomatic medication. Bulking agents, laxatives, spasmolytics, loperamide, and probiotic agents are recommended (with variable recommendation strengths), as are—for selected patients— antidepressants, 5-HT4 agonists, 5-HT3 antagonists, and topical antibiotics. Conclusion: The first German S3 guideline on irritable bowel syndrome translates up-to-date scientific knowledge as represented in current publications into concrete recommendations for diagnosis and treatment in clinical practice. In the future, it is likely that further causative pathophysiological mechanisms will be discovered; this should lead, in turn, to the development of new, causally directed treatments, which will supplement or replace the traditional, purely symptomatic treatments that are still in use today. ►Cite this as: Andresen V, Keller J, Pehl C, Schemann M, Preiss J, Layer P: Clinical practice guideline: Irritable bowel syndrome—the main recommendations. Dtsch Arztebl Int 2011; 108(44): 751–60. DOI: 10.3238/arztebl.2011.0751 Israelitisches Krankenhaus Hamburg: Dr. MSc Andresen, Prof. Dr. med. Layer, Dr. med. Keller Kreiskrankenhaus Medizinische Klinik Vilsbiburg: PD Dr. med. Pehl Lehrstuhl für Humanbiologie, Technische Universität München: Prof. Dr. rer. nat. Schemann Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Campus Benjamin Franklin Charité-Universitätsmedizin, Berlin: Dr. med. Jan Preiss Deutsches Ärzteblatt International | Dtsch Arztebl Int 2011; 108(44): 751–60 ith the increasing knowledge on the pathogenesis, pathophysiology, and rational management of irritable bowel syndrome, the time has come to implement them in pragmatic recommendations adapted to our health care system. This was the aim of an interdisciplinary S3 guideline under the aegis of the German Society for Digestive and Metabolic Diseases (DGVS, Deutsche Gesellschaft für Verdauungs- und Stoffwechselkrankheiten) and the German Society for Neurogastroenterology and Motility (DGNM, Deutsche Gesellschaft für Neurogastroenterologie und Motilität) (eBox 1) (1), the main practice-relevant statements of which are presented in this article. For details of the recommendations and commentary on them, especially in relation to pediatric patients, the reader is referred to the full text of the guideline ([1], in German). W Methods The DGVS and DGNM formed a coordination committee, which in January 2008, in consultation with the Association of Scientific Medical Societies in Germany (AWMF, Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften), laid down the methodology for the guideline. The guideline group was made up of 69 representatives of various medical specialties, 26 of whom were named as authors (eBox 1). After the consensus conference (September 2009), a manuscript was produced, which with the agreement of all the participating medical societies was published in February 2011. For the clinical questions, a systematic literature search up to September 2008 was carried out on MedLine, PreMedLine, Psycinfo, cambase, and the Cochrane Central Register of Controlled Trials. For this, a basic search was defined to capture all relevant publications in the field (eBox 2). To answer the questions specific to each working group, the working groups defined further search terms and exclusion criteria that were linked to the basic search and special methodological filters (eBox 2). Publications included were controlled studies and observational studies with a study time of at least 4 weeks, but not case series (formal selection). The identified literature was further selected by evaluating each publication on the basis of its title, abstract, and, if necessary, the full text for whether it was suitable to answer key questions (content selection). If questions were answered by evidence level 1 publications, it was unnecessary to draw on publications of a lower evidence level. 751 MEDICINE TABLE 1 Recommendation strengths Strength of recommendation Formulation Meaning for physicians Meaning for patients Symbol Strongly for Virtually always Most patients should receive the recommended intervention Almost all patients would decide in favor of the recommended intervention; only a small minority would not ↑↑ Weakly for In most/some patients Different decisions are appropriate for different patients, depending on the patient's situation but also on personal opinions and preferences The majority of patients (>50%) would decide in favor of the intervention, but many would not ↑ Weakly against Rather not Probably don't do it The majority of patients (>50%) would decide against the intervention, but many would not Strongly against Virtually never Definitely don't do it Almost all patients would decide against the recommended intervention; only a small minority would not Unclear No recommendation should remain an exception to be justified. In clinical practice, a decision often has to be made despite the absence of data. Out of 5573 identified publications, 243 were selected, individually evaluated, summarized in evidence tables, and the tables made available to all participants as part of the consensus process. In the present short version of the guideline, selected publications are cited that form the basis of central recommendations; more recent studies that were not published at the time the guideline was being compiled are marked accordingly. After iterative processing in a modified Delphi procedure, the recommendations were modified and agreed at a consensus conference. The formulation of each recommendation strength followed a defined scheme (Table 1). Recommendations for which no consensus was reached were readdressed in a further, online Delphi round. As an aid to comprehension, some of the statements are reproduced in this article in paraphrased and commented form. Evidence level, recommendation strength, and consensus strength are given in general form in the text and more specifically in the tables in the specific treatment sections. The guideline was exclusively financed through the DGVS and was developed under conditions of editorial independence. All participants were required to declare potential conflicts of interest. The details of the methodology are provided in a comprehensive methods report (2). Definition Irritable bowel syndrome (IBS) is present when all three of the following are fulfilled: ● The patient has chronic symptoms, i.e. lasting longer than 3 months (e.g., abdominal pain, bloating), that are ascribed by both patient and 752 physician to the gut and that are usually accompanied by altered bowel habit. ● The symptoms are the reason why the patient has consulted the physician for help and/or is worried, and are so strong that the patient’s quality of life is significantly impaired by them. ● It is a precondition that no changes are present which are characteristic of other diseases that are likely to be the cause of the symptoms (strong consensus). This new definition thus differs from all its predecessors including the Rome III consensus (e1): The hitherto obligatory symptom combination of abdominal pain and altered bowel habit has been dropped; on the other hand, the typical and often particularly distressing symptom complex of bloating and flatulence is included. For the first time the severity of the symptoms, which distinguishes them from ordinary “digestive symptoms,” is mandatory for the diagnosis: Only significant impairments of quality of life indicate systematic diagnostic and therapeutic management. Pathogenesis In IBS, gastrointestinal motility, secretion, and perception are disturbed. Consistently, although always only in subpopulations, molecular and cellular alterations at the mucosal level, changes in gut flora, disturbances of superordinated regulatory systems, and increased prevalence of psychological co-morbidities are demonstrated. Interactions/interrelationships between causal and secondary alterations are unclear. These changes have been demonstrated in separate studies and are not IBS-specific, and therefore they do not allow a specific diagnosis to be made. However, they do contribute to an understanding of the causative pathological Deutsches Ärzteblatt International | Dtsch Arztebl Int 2011; 108(44): 751–60 MEDICINE TABLE 2 Pathogenic factors and proven changes in Irritable Bowel Syndrome*1 A) Pathogenetic factors Comments Development of IBS from bacterial enteritis (“postinfectious IBS”) – The risk of IBS is 8 to 15 times higher after bacterial enteritis– The more severe the acute illness, the higher the risk – Up to 30% of those who have acute bacterial enteritis may develop IBS that persists for years Altered intestinal flora – Alteration of gut flora has been shown (not yet known is whether this is a cause or a consequence of disturbed function) – IBS developing after bacterial infection of the gut (see above) – IBS developing after antibiotic therapy – Gut flora are important for barrier function and mucosal immune system (see below) – IBS symptoms are improved by probiotics or topical antibiotics Personal predisposition – Probable mechanisms: genetic factors; learned behavioral patterns Psychological factors – Traumatic events (incl. abuse), psychological co-morbidity (e.g., depression, anxiety disorder), and stress may cause exacerbation; in some subgroups they may even be causative B) Proven changes Comments Altered motility – Increased transit time in constipation-dominant IBS – Reduced transit time in diarrhea-dominant IBS – Disturbed gas transit, mainly through the small intestine, but also in the colon (in addition to increased gas production) Altered sensitivity – Reduced pain threshold during rectal balloon distension (barostat) – Altered cerebral processing of visceral stimuli Mucosal permeability – Reduced tissue resistance – Reduced barrier function – Reduced expression of tight junction protein ZO-1 Immune cells in mucosal biopsies – Intraepithelial T cells – Mast cells – Nerve–mast cell association – Increased number of CD3+ lymphocytes – Increased number and reactivity of c-kit-positive and tryptase-positive cells – Stronger local association between nerves and mast cells Immune mediators in mucosal biopsies – Tryptase and other proteases – Histamine – Proteases – Cytokines – Defensins – Increased release – Increased release – Increased released in diarrhea-dominant IBS – Increased release of IL1β in postinfectious IBS – Increased release of human β-defensin 2 Nerves in mucosal biopsies – Nerve fibers – Visceral afferents – Increased number of PGP 9.5-positive nerve fibers, increased expression of substance P – Increased expression of TRPV1 Supernatants of mucosal biopsies – Neural sensitization – Activation of enteric nervous system by histamine, serotonin, and proteases – Activation of visceral afferents Immune mediators in the blood – Cytokines – HPA axis – Antibodies – Raised Th2 cytokine concentration, raised IL6, IL8, TNFα, and IL1β concentrations – Raised ACTH and cortisol concentrations – Antibodies against bacterial flagellin Serotonin metabolism – Serotonin concentration – Enterochromaffin cells – Serotonin reuptake transporters (SERTs) Gene expression – Mucosa – Raised plasma serotonin concentration in diarrhea-dominant IBS – Increased number in mucosal biopsies – Altered SERT expression and function – Increased expression of DKFZP564O0823 (presumed function: mucus production) Stool – Mediators originating from <<please confirm>> immune cells or microbiota – Microbiota – Increased concentration of human α-defensin, proteases, S100A12, lactoferrin – Unstable microbiota *1 Changes shown in separate studies and each time only in subpopulations of the IBS patients; they are not IBS-specific and therefore do not allow a positive diagnosis ACTH, adrenocorticotropic hormone; HPA axis, hypothalamic-pituitary-adrenal axis; IL, interleukin; ZO-1, zonula occludens 1; PGP, protein gene product (pan-neuronal marker); TRPV1, transient receptor potential vanniloid receptor 1 (visceral afferent marker) Deutsches Ärzteblatt International | Dtsch Arztebl Int 2011; 108(44): 751–60 753 MEDICINE FIGURE 1 BOX 1 Symptoms lead to doctor visit Lab – abdom. US – gyn. History and PE “Organic” clues? Laboratory investigations in patients with unexplained chronic abdominal symptoms ● Generally recommended laboratory tests Yes No Diarrhea No not IBS! Yes Comprehensive diagnostic work-up Individual criteria: Symptoms: severity, duration, dynamics Patient: age, personality, degree of concern But: IBS diagnosis not yet justified Try therapy? ● Targeted further diagnostic procedures Diagnostic work-up in first-time investigation of chronic abdominal symptoms that could point to irritable bowel syndrome PE, physical examination (including rectal); abdom. US, abdominal ultrasonography; gyn., gynecological examination; IBS, irritable bowel syndrome mechanisms (Table 2), and thus form the foundation for research into new treatment options (3). Diagnosis IBS is basically a clinical diagnosis. Careful history taking to record and classify the complex of symptoms is key. The diagnosis can be made on this basis so long as other differential diagnoses can be reliably ruled out. Thus, confirmation of the diagnosis requires two components: ● The history and pattern of symptoms suggest IBS. ● Other relevant candidate diagnoses can be specifically ruled out on the basis of symptoms, especially when red flag symptoms are present (evidence level B, recommendation strength ↑↑, strong consensus). Once a reliable initial diagnosis has been made, so long as no new aspects occur, no repeat diagnostic procedure should be undertaken (evidence level A, recommendation strength ↑↑, strong consensus) Early confirmed diagnosis is important to avoid delayed diagnosis of other, more serious possible causes of the symptoms; this is particularly the case when the symptoms have not been present for very long (4) (evidence level A, recommendation strength ↑↑, strong consensus). If diarrhea is the main symptom, an irritable bowel is usually not the cause (5). However, in more than 10% of cases other constellations of symptoms without alarm symptoms or signs of inflammation are caused by an “organic” disease. On the other hand, celiac disease (6, 7, e2), chronic inflammatory bowel disease (4, 8), and also colon and ovarian carcinoma (4, 9–11, e3, e4) and chronic 754 – Full blood count – Erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP) – Urine analysis Optional laboratory tests on an individual basis – Serum electrolytes, renal retention values, hepatic and pancreatic enzymes – TSH – Blood glucose/HbA 1c – Fecal microbiology (especially in patients with diarrhea) – Celiac disease antibodies (anti-transglutaminase antibodies) – Calprotectin A/lactoferrin BOX 2 Recommendations relating to nutrition in IBS ● Investigate for carbohydrate malabsorption syndrome ● ● ● ● ● (e.g., lactose fructose, sorbitol), and, if evidence is shown, trial avoidance of the relevant sugar Investigate for other food intolerances and trial avoidance of any foods indicated, after extensive dietary advice Trial of a reduced-gluten diet is a possibility in some adults with IBS without signs of celiac disease During elimination dieting, regular monitoring is essential to prevent malnutrition; the diet should be permanently continued only if the patient shows response to treatment Consider the use of bulking agents in patients with constipation Consider the use of probiotics; choose strains according to symptoms Deutsches Ärzteblatt International | Dtsch Arztebl Int 2011; 108(44): 751–60 MEDICINE FIGURE 2 TABLE 3 Important differential diagnoses of IBS in patients with chronic abdominal IBS-like symptoms Main symptom Important differential diagnoses (among others) Diarrhea Chronic infectious enterocolitis, e.g., bacterial, parasitic, or viral (e.g., cytomegalovirus [CMV] with or without immunosuppression) pathogens; fungal infections (e.g., histoplasmosis in HIV) Crohn’s disease Ulcerative colitis Celiac disease/sprue Bacterial infection of the small intestine Symptomatic carbohydrate malabsorption (e.g., lactose or fructose malabsorption) Microscopic colitis Bile acid malabsorption Clostridium difficile colitis Motility disorders of the small intestine Exocrine pancreatic insufficiency Autonomic neuropathy (diabetes) Drug intolerance Food allergy Hyperthyroidism Incontinence Functionally active neuroendocrine tumor Colorectal carcinoma (paradoxical diarrhea) Pain Crohn’s disease Ulcer Gastrointestinal tumor Mesenteric ischemia Porphyria Endometriosis Ovarian tumor Small-bowel stenoses (e.g., radiogenic, adhesions) Postoperative functional impairment (e.g., adhesions) C1-esterase inhibitor deficiency Intestinal motility disorders (e.g., chronic intestinal pseudo-obstruction) Constipation Adverse drug effect Hypothyroidism Colorectal carcinoma (alternating with paradoxical diarrhea in patients with symptoms of stenosis) Chronic diverticulitis Motility disorders, e.g., neuropathic colonic paresis (slow-transit constipation) Functional or structural defecation disorders Bloating, distension Bacterial infection (small-intestinal bacterial overgrowth; often secondary, e.g., in smallbowel diverticula, motility disorders, etc.) Carbohydrate malabsorption (e.g., symptomatic lactose and/or fructose malabsorption) Postoperative functional disorders (e.g., adhesions) Deutsches Ärzteblatt International | Dtsch Arztebl Int 2011; 108(44): 751–60 Confirm diagnosis Guidance from physician: inform the patient, explain the disease Pain Spasmolytics Probiotics Phytotherapeutics Soluble bulking agents Poss.: antidepressants Poss.: topical antibiotics General measures Bloating Probiotics Topical antibiotics Simethicone Phytotherapeutics Diet Exercise Stool regulation Constipation PEG–electrolyte solution Bulking agents Conventional laxatives Prucalopride Probiotics Phytotherapeutics Spasmolytics Poss.: SSRIs Exercise (In some cases: lubiprostone) Drug therapy*: t
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combined Diarrhea Loperamide Cholestyramine Probiotics Topical antibiotics Bulking agents Phytotherapeutics Spasmolytics Poss.: tricyclic antidepressants The management of IBS involves reliable confirmation of the diagnosis, patient guidance, including explanation of the disease, general measures, and symptom-oriented medical therapy. *It must be borne in mind that many new drugs whose effectiveness has been confirmed are only licensed outside Germany, or are not licensed in Germany for this indication (off-label). Poss., possibly gastrointestinal motility disorders (12) often show typical “irritable bowel symptoms” as the dominant—often the first or only—clinical manifestation in 40% to 85% of those affected. A confirmed diagnosis that convinces both the patient and the physician (Figure 1) also has significance for treatment and the economics of health: a better relationship of trust and the reassurance conveyed by it makes an essential contribution to the success of treatment. The consequence is a reduction in “doctor shopping” and subsequent diagnostic procedures. Given the chronic nature of the disease, this effect is of great importance in the long-term management. In an unknown patient, a basic diagnostic procedure must always be carried out (evidence level D, recommendation strength ↑↑, strong consensus) and, depending on the history and pattern of symptoms, be supplemented by individually tailored further diagnostic steps in a carefully targeted manner (evidence level D, recommendation strength ↑, strong consensus). Overdiagnosis and the indiscriminate use of resources should be avoided. The focus is on a careful history (evidence level A, recommendation strength ↑↑, strong consensus) and the physical examination (evidence level D, recommendation strength ↑↑, strong consensus), supplemented by basic laboratory testing (evidence 755 MEDICINE TABLE 4 Recommendations for treatment of pain in IBS Therapy Try therapy Peripheral analgesics Rather not [Evidence level B (paracetamol), evidence level D for other drugs, recommendation strength , strong consensus] Opiates and opiate agonists Virtually never [Evidence level A for kappa agonists, evidence level D for µ- agonists and classical opiates, evidence level A for opiate antagonists, recommendation strength , strong consensus] Spasmolytics In most patients [Evidence level A, recommendation strength ↑, strong consensus] Soluble fiber In some patients [Evidence level A, recommendation strength ↑, strong consensus] Tricyclic antidepressants In some patients [Evidence level A, recommendation strength ↑, strong consensus] SSRIs In some patients [Evidence level A, recommendation strength ↑, strong consensus] 5-HT3 antagonists In few selected pa- [Evidence level A, recommendation tients strength ↑, consensus] Probiotics In some patients [Evidence level A, recommendation strength ↑, strong consensus] Antibiotics Rather not [Evidence level A, recommendation strength , consensus] Pregabalin/gabapentin Rather not [Evidence level B , recommendation strength , strong consensus] Phytotherapeutics In some patients [Evidence level A, recommendation strength ↑, strong consensus] Aloe vera Rather not [Evidence level A, recommendation strength , strong consensus] Pancreatic enzymes Virtually never [Evidence level D, recommendation strength , strong consensus] level B, recommendation strength ↑↑, strong consensus) (Box 1), abdominal ultrasound (evidence level D, recommendation strength ↑, consensus), and, in women, gynecological examination (evidence level B, recommendation strength ↑↑, strong consensus). After these have been carried out, if results are normal, treatment may be started on a trial basis even without a confirmed diagnosis (see below) (evidence level D, recommendation strength ↑, consensus). This should be decided on an individual basis and is justified particularly in patients with mild, non-progressive symptoms, but does not allow a diagnosis of IBS to be made (Figure 1). In patients with chronic diarrhea as an important symptom, detailed diagnostic work-up including pathogen identification in the stool and endoscopic and functional diagnostic examinations (with staged biopsies) are indicated (evidence level A, recommendation strength ↑↑, strong consensus) (Figure 1). Confirmation of IBS in an adult requires an ileocolonoscopy (evidence level D, recommendation strength ↑, consensus). 756 The diagnostic procedure should be supplemented on an individual basis by endoscopic, imaging, functional diagnostic, and, if relevant, other procedures in order to rule out other candidate diagnoses (see Table 3) that can cause symptoms typical of IBS (evidence level B, recommendation strength ↑↑, strong consensus). The criteria for this are the intensity and pattern of symptoms, patient age, duration of symptoms, symptom dynamics, and a psychological assessment of the patient. Food intolerances can be tested by trialing targeted elimination diets (evidence level D, recommendation strength ↑, consensus); testing of immunoglobulin-G titers for food allergens (evidence level D, recommendation strength ↓, consensus) and determination of quantitative parameters of stool flora (e.g., “intestinal ecograms”) should not be carried out (evidence level D, recommendation strength ↓↓, consensus). Treatment General principles of management It is important to provide the patient with a comprehensible pathophysiological model of the disease and the management plan. Ruling out possible more threatening differential diagnoses and establishing a relationship of trust between physician and patient will both promote treatment success (13). Individual triggering factors should be identified and taken into account (evidence level D, recommendation strength ↑↑, strong consensus). The measure of any treatment plan is how far symptoms improve and how well the patient tolerates it, and all treatments are trial treatments at first because it is impossible to predict the response to treatment in any particular case. This should be discussed with the patient beforehand. Any treatment regime that is successful can be continued, changed to a long-term or as-needed regimen, or interrupted for a trial withdrawal. If treatment success is inadequate, various drugs (and non-drug treatments) may be used in succession or in combination. Ineffective drugs should be terminated after 3 months at the latest (evidence level D, recommendation strength ↑, strong consensus). After careful individualized weighing up of the risks and benefits, in some cases, especially in patients with severe symptoms that are refractory to treatment, offlabel therapies may be worthwhile, if current scientific knowledge suggests there is reason to expect relevant therapeutic utility. The same applies to active substances that to date are only licensed abroad, although in this case consultation with a specialized center is advisable (evidence level D, recommendation strength ↑, consensus). As to nutrition and lifestyle there are no general prescriptions. However, nutritional and behavioral advice should be given to eliminate individual symptom triggers (e.g., stressors, defined foods, lack of exercise or sleep, and so on). Likewise, psychological influential factors and co-morbidities (e.g., depressive disorders) and extraintestinal symptoms (tendency to somatization!) should be ascertained. Deutsches Ärzteblatt International | Dtsch Arztebl Int 2011; 108(44): 751–60 MEDICINE Alternative therapies cannot be recommended at present because of a lack of data; complementary therapies may be considered in individual cases (evidence level A* for acupuncture, otherwise C/D; recommendation strength ↓; strong consensus). *A meta-analysis of several acupuncture studies found no acupuncturespecific effect on irritable bowel syndrome (e5). Nutritional recommendations Although no general dietetic measures are recommended, individualized advice orientated to the existing symptoms and individual intolerances should be given (Box 2) (evidence level B, recommendation strength ↑, strong consensus). Psychological co-morbidities To register the psychological co-morbidities that are often present in patients with IBS, it is often enough simply to ask about anxiety disorders and depressive symptoms, and (careful!) exploration of trauma and abuse. If appropriate, the patient should be referred for professional psychiatric/psychological/psychosomatic examination and/or care (evidence level D, recommendation strength ↑, strong consensus). Any signs of relevant psychosocial stress also indicate psychological diagnostic steps and possibly psychotherapy. At the same time, general medical care should be continued (evidence level A, recommendation strength ↑↑, consensus). At the general and specialist medical level, basic psychotherapeutic intervention can often be carried out to favorable effect, e.g., using self-help strategies (evidence level A, recommendation strength ↑, strong consensus). Pure relaxation therapies (autogenic training, etc.) should not be carried out as monotherapy, but should be combined with other measures (evidence level B, recommendation strength ↓, consensus). More costly and time-consuming psychological techniques (gut-directed hypnosis, cognitive behavioral therapy, psychodynamic therapy) are effective and should be integrated in an interdisciplinary therapy plan (evidence level A, recommendation strength ↑, strong consensus). Antidepressants may be indicated in the presence of psychological co-morbidities (anxiety disorder, depression) (evidence level A, recommendation strength ↑, strong consensus). Tricyclic antidepressants to treat the irritable bowel symptoms (diarrhea, pain; beware of constipation) should be given at doses lower than the usual (evidence level A, recommendation strength ↑, strong consensus); selective serotonin reuptake inhibitors (SSRIs) in particular can also be given in constipation-dominant IBS (evidence level B, recommendation strength ↑, consensus). However, irritable bowel symptoms seem not to respond to antidepressants in the absence of psychological co-morbidities. Targeted symptom-orientated therapy General treatment measures including confirmation of the diagnosis and patient information about the disease can be supplemented with symptom-orientated drug Deutsches Ärzteblatt International | Dtsch Arztebl Int 2011; 108(44): 751–60 TABLE 5 Recommendations for the treatment of diarrhea in IBS Therapy Try therapy Loperamide In some patients [Evidence level A, recommendation strength ↑, strong consensus] Racecadotril Cannot be recommended [Evidence level D, recommendation strength , strong consensus] Bulking agents (soluble fiber ) In some patients [Evidence level B, recommendation strength ↑, strong consensus] 5-HT3 antagonists In few selected patients [Evidence level A, recommendation strength ↑, consensus] Cholestyramine In some patients [Evidence level C, recommendation strength ↑, strong consensus] Probiotics In some patients [Evidence level A, recommendation strength ↑, strong consensus] Antibiotics Rather not [Evidence level C, recommendation strength , strong consensus] Phytotherapeutics In some patients [Evidence level A, recommendation strength ↑, consensus] Aloe vera Rather not [Evidence level A, recommendation strength , strong consensus] Spasmolytics In some patients [Evidence level A, recommendation strength ↑, consensus] Traditional Chinese medicine/herbal medicine Rather not [Evidence level B, recommendation strength , consensus] treatment (evidence level D, recommendation strength ↑↑, strong consensus) (Figure 2). In this guideline a conscious decision was made not to give effect sizes for individual therapies, since these would reflect neither the scientific evidence nor practical reality: ● For many therapies insufficient study quality means that no adequate data exist. ● There is a general inhomogeneity of study populations and of the criteria of treatment response (pain, irregular bowel habit, bloating, etc.), which is due to the multiplicity of symptoms, their variability, and differences in pathological mechanisms. ● The typically fluctuating course of symptoms often suggests falsely high rates of response to placebo; on the other hand, all therapies show variable rates of non-responders. For this reason, even for therapies that are highly effective in subgroups, only moderate response rates are documented in the overall patient population. In most cases, however, the relevant subgroup analyses were not carried out. Thus, the moderate response rates do not allow meaningful conclusions to be drawn about the possible success of treatment in any individual patient. Typical examples of the distribution of the published effect sizes of individual therapies compared to placebo exist for, among others: 757 MEDICINE ● TABLE 6 Recommendations for the treatment of constipation in IBS Therapy Try therapy Bulking agents in the form of soluble gelforming agents (e.g., psyllium) In most patients [Evidence level A, recommendation strength ↑, strong consensus] Osmotis laxatives of the macrogol type In some patients [Evidence level B, recommendation strength ↑, strong consensus]. Other osmotic or stimulating laxatives In some patients [Evidence level C, recommendation strength ↑, strong consensus] Prucalopride In some patients in [Evidence level B, recommendation cases (refractory strength ↑, consensus] to other treatment) Domperidone Rather not [Evidence level B, recommendation strength , strong consensus] Lubiprostone In some patients (if available) [Evidence level A, recommendation strength ↑, consensus] Antibiotics Rather not [Evidence level A, recommendation strength , consensus] Probiotics In some patients [Evidence level A, recommendation strength ↑, strong consensus] Phytotherapeutic STW 5 In some patients [Evidence level B, recommendation strength ↑, strong consensus] Other phytotherapeutics Rather not [Evidence level B, recommendation strength , strong consensus] Spasmolytics In some patients [Evidence level A, recommendation strength ↑, strong consensus] SSRIs In some patients in [Evidence level B, recommendation strength ↑, consensus] IBS-C that is refractory to treatment, esp. with pain ± psychol. co-morbidity IBS-C, constipation-dominant IBS; SSRIs, selective serotonin reuptake inhibitors TABLE 7 Recommendations for the treatment of bloating/abdominal distension/meteorism/flatulence Therapy Try therapy Probiotics In some patients [Evidence level B, recommendation strength ↑, strong consensus] Rifaximin In some patients [Evidence level A, recommendation strength ↑, consensus] Phytopharmaceuticals In some patients Evidence level B, recommendation strength ↑, strong consensus] Cholinergics/Parasympathomimetics Rather not [Evidence level A, recommendation strength , strong consensus] Antifoaming agents In some patients [Evidence level C, recommendation strength ↑, strong consensus] Pankreatic enzymes Virtually never [Evidence level D, recommendation strength , strong consensus] Analgesics Rather not [Evidence level B, recommendation strength , strong consensus] Tricyclic antidepressants and SSRIs Rather not [Evidence level B, recommendation strength , consensus] SSRIs, selective serotonin reuptake inhibitors 758 Probiotics, with moderate (!) rates of symptom improvement between 0% and 88%, not only in dependence on the study preparation and end points, but also within fixed study protocols (14, 15). ● Antidepressants, about the fundamental effectiveness of which for irritable bowel symptoms there are completely contradictory assessments: calculated overall effects range from ineffective (tending to poorer) to significantly effective (16, 17). The most important therapy recommendations in relation to main symptom are summarized below; details of formulations, recommendation strengths, evidence levels, and strength of consensus are given in the accompanying tables. Pain (Table 4): Pain often responds to spasmolytics (butylscopolamine, mebeverine, peppermint oil) (18, e6) or probiotics (14, 15) as a basic therapy; in regard to the latter it is still unclear which preparations ameliorate which symptoms, so failures of treatment attempts are to be expected at the outset. Soluble bulking agents may also trigger symptom exacerbations in some cases. In some cases antidepressants may be tried (especially in patients with psychological comorbidity) (17), or phytotherapeutics (e.g., STW 5), or, especially in patients with diarrhea, 5-HT3 antagonists (19). Classical “analgesics” (acetylsalicylic acid, paracetamol, non-steroidal anti-inflammatories, etc.) are generally unsuitable, as are opioids and opioid agonists (e7). Topical antibiotic therapy (rifaximin) is not yet recommended in the guideline, but randomized studies that have now been published indicate that they can effect lasting amelioration of symptoms in nonconstipated patients with IBS (20). Diarrhea (Table 5): In addition to classical antidiarrhetics (such as loperamide [e8]), cholestyramine, soluble bulking agents, or probiotics can be helpful. It can also be worth trying phytotherapeutics (e.g., STW 5) or spasmolytics (e.g., mebeverine, butylscopolamine, peppermint oil) or, especially where there is psychological co-morbidity, tricyclic antidepressants. Where symptoms are severe and refractory to treatment, a selective 5-HT3 antagonist (e.g., alosetron [19]) may be used, but only after careful weighing of the risks versus the benefits, because of its very rare adverse effects (ischemic colitis, severe constipation) (21). A subgroup of patients respond well to rifaximin (20) (see above), although this is not yet recommended in the guideline. Constipation (Table 6): In patients with constipation, the pathological mechanism should be identified as a first step; in particular, secondary forms of constipation (drug effects, underlying diseases) and impaired anorectal function (defecation disorders) should be ruled out. Osmotic laxatives of the macrogol type are the most effective and best tolerated (e9). Water-soluble bulking agents are also suitable, but a watch must be kept for increased pain and/or bloating (e6). Other laxatives can Deutsches Ärzteblatt International | Dtsch Arztebl Int 2011; 108(44): 751–60 MEDICINE also be tried, according to how effective they are and how well they are tolerated. If adverse effects are experienced or symptoms increase, the new prokinetic prucalopride should be used (22, 23). Other therapeutic approaches to try include probiotics, phytotherapeutics (STW 5), spasmolytics, and SSRIs; tricyclic antidepressants should be avoided in patients with constipation. In some cases lubiprostone, a chloride channel activator, may be tried, bearing in mind any contraindications and its restricted availability (it is licensed in Switzerland and the USA). The guanylate cyclase-C agonist linaclotide, which has been shown to be effective in constipation-dominant IBS (24), is expected to be licensed soon. Bloating/abdominal distension/meteorism/flatulence (Table 7): Most patients also suffer from considerable—often predominant—symptoms in the form of bloating, meteorism, and flatulence, the treatment of which is therefore very important. Improving constipation or diarrhea often also improves gas problems (evidence level A, recommendation strength ↑, strong consensus). An effective measure is modulation of the intestinal flora with probiotics (14, 25) or the topical antibiotic refaximin (20). Less well proven are phytopharmaceuticals or antifoaming agents (simethicone, dimethicone). Conflict of interest statement Dr. Preiss has received consultancy fees from Essex, authorship, co-authorship, and reviewing fees from Medac, and reimbursement of travel and accommodation costs together with lecture fees from Falk. Professor Schemann has received consultancy and lecture fees from Shire and Steigerwald. He has also received research funding into a third-party account from Steigerwald. Dr. Pehl has received consultancy fees from Movetis/Shire. He has had attendance fees at educational events and conferences and travel costs reimbursed by Falk, Lilly, Shire, Merckle-Recordati, Abbott, Essex, Sanofi-Aventis, Novo Nordisk, and Astra Seneca. He has received lecture fees from Buck Elektromedizin, Falk, Lilly, Movetis, and Shire. He has received research funding into a third-party account from Fresenius and Medtronic. Professor Layer has received consultancy fees from Abbott, Solvay, Shire, and Norgine. He has had travel and accommodation costs reimbursed by Shire and Norgine. He has also received lecture fees from Falk, Movetis/Shire, Abbott/ Solvay, Axcan, Boehringer, and Novartis. He has received fees for commissioned clinical studies by Axcan and Solvay. Dr. Andresen has received consultancy and lecture fees and reimbursement of travel and accommodation costs and attendance fees at educational events and conferences from Norgine, Falk, Axcan, Abbott/Solvay and Shire/Movetis. Dr. Keller has had attendance fees and travel and accommodation costs relating to lectures reimbursed by Aptalis Pharma and Shire. She has also received lecture fees from these companies. Manuscript received on 1 July 2011, revised version accepted on 1 August 2011. Translated from the original German by Kersti Wagstaff MA. REFERENCES 1. Layer P, Andresen V, Pehl C, et al.: S3-Leitlinie Reizdarmsyndrom: Definition, Pathophysiologie, Diagnostik und Therapie. Gemeinsame Leitlinie der Deutschen Gesellschaft für Verdauungs- und Stoffwechselkrankheiten (DGVS) und der Deutschen Gesellschaft für Neurogastroenterologie und Motilität (DGNM)1 (AWMF-Registriernummer: 021/016). Z Gastroenterol 2011; 49: 237–93. 2. Preiss JC, Andresen V, Keller J, et al.: Methodikreport zur S3-Leitlinie Reizdarmsyndrom und Intestinale Motilitätsstörungen. AWMFHomepage 2011. www.awmf.org/leitlinien/detail/ll/021–016.html Deutsches Ärzteblatt International | Dtsch Arztebl Int 2011; 108(44): 751–60 3. Spiller R, Garsed K: Postinfectious irritable bowel syndrome. Gastroenterology 2009; 136: 1979–88. 4. Garcia Rodriguez LA, Ruigomez A, Wallander MA, et al.: Detection of colorectal tumor and inflammatory bowel disease during followup of patients with initial diagnosis of irritable bowel syndrome. Scand J Gastroenterol 2000; 35: 306–11. 5. Fernandez-Banares F, Esteve M, Salas A, et al.: Systematic evaluation of the causes of chronic watery diarrhea with functional characteristics. Am J Gastroenterol 2007; 102: 2520–8. 6. Sanders DS, Carter MJ, Hurlstone DP, et al.: Association of adult coeliac disease with irritable bowel syndrome: a case-control study in patients fulfilling ROME II criteria referred to secondary care. Lancet 2001; 358: 1504–8. 7. Ford AC, Chey WD, Talley NJ, et al.: Yield of diagnostic tests for celiac disease in individuals with symptoms suggestive of irritable bowel syndrome: systematic review and meta-analysis. Arch Intern Med 2009; 169: 651–8. 8. Minderhoud IM, Oldenburg B, Wismeijer JA, et al.: IBS-like symptoms in patients with inflammatory bowel disease in remission; relationships with quality of life and coping behavior. Dig Dis Sci 2004; 49: 469–74. 9. Goff BA, Mandel LS, Melancon CH, et al.: Frequency of symptoms of ovarian cancer in women presenting to primary care clinics. JAMA 2004; 291: 2705–12. 10. Goff BA, Mandel LS, Drescher CW, et al.: Development of an ovarian cancer symptom index: possibilities for earlier detection. Cancer 2007; 109: 221–7. 11. Hamilton W, Peters TJ, Bankhead C, et al.: Risk of ovarian cancer in women with symptoms in primary care: population based casecontrol study. BMJ 2009; 339: b2998. 12. Keller J, Wedel T, Seidl H, et al.: S3-Leitlinie der Deutschen Gesellschaft für Verdauungs- und Stoffwechselkrankheiten (DGVS) und der Deutschen Gesellschaft für Neurogastroenterologie und Motilität (DGNM) zu Definition, Pathophysiologie, Diagnostik und Therapie intestinaler Motilitätsstörungen (AWMF-Registriernummer: 021/018). Z Gastroenterol 2011; 49: 374–90. 13. Owens DM, Nelson DK, Talley NJ: The irritable bowel syndrome: long-term prognosis and the physician-patient interaction. Ann Intern Med 1995; 122: 107–12. 14. Moayyedi P, Ford AC, Talley NJ, et al.: The efficacy of probiotics in the treatment of irritable bowel syndrome: a systematic review. Gut 2010; 59: 325–32. 15. McFarland LV, Dublin S: Meta-analysis of probiotics for the treatment of irritable bowel syndrome. World J Gastroenterol 2008; 14: 2650–61. 16. Quartero AO, Meineche-Schmidt V, Muris J, et al.: Bulking agents, antispasmodic and antidepressant medication for the treatment of irritable bowel syndrome. Cochrane Database Syst Rev 2005CD003460. 17. Ford AC, Talley NJ, Schoenfeld PS, et al.: Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and meta-analysis. Gut 2009; 58: 367–78. 18. Ford AC, Talley NJ, Spiegel BM, et al.: Effect of fibre, antispasmodics, and peppermint oil in the treatment of irritable bowel syndrome: systematic review and meta-analysis. BMJ 2008; 337: a2313. 19. 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: 545–55. 20. Pimentel M, Lembo A, Chey WD, et al.: Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med 2011; 364: 22–32. 21. Chang L, Tong K, Ameen V: Ischemic colitis and complications of constipation associated with the use of alosetron under a risk 759 MEDICINE management plan: clinical characteristics, outcomes, and incidences. Am J Gastroenterol 2010; 105: 866–75. 22. Camilleri M, Kerstens R, Rykx A, et al.: A placebo-controlled trial of prucalopride for severe chronic constipation. N Engl J Med 2008; 358: 2344–54. 23. Ford AC, Brandt LJ, Young C, et al.: Efficacy of 5-HT3 antagonists and 5-HT4 agonists in irritable bowel syndrome: systematic review and meta-analysis. Am J Gastroenterol 2009; 104: 1831–43; quiz 1844. 24. Johnston JM, Kurtz CB, Macdougall JE, et al.: Linaclotide improves abdominal pain and bowel habits in a phase IIb study of patients with irritable bowel syndrome with constipation. Gastroenterology 2010; 139: 1877–1886 e2. 25. Hoveyda N, Heneghan C, Mahtani KR, et al.: A systematic review and meta-analysis: probiotics in the treatment of irritable bowel syndrome. BMC Gastroenterol 2009; 9: 15. Corresponding author Dr. med. Viola Andresen Israelitisches Krankenhaus Medizinische Klinik 22297 Hamburg, Germany v.andresen@ik-h.de Permission The elements eBox 1, Table 2, Figure 1 and Table 3 are reproduced with the permission of Georg Thieme Verlag KG, Stuttgart, from: Layer P, Andresen V, Pehl C, Allescher H, Bischoff S C, Claßen M, Enck P, Frieling T, Haag S, Holtmann G, Karaus M, Kathemann S, Keller J, Kuhlbusch-Zicklam R, Kruis W, Langhorst J, Matthes H, Mönnikes H, Müller-Lissner S, Musial F, Otto B, Rosenberger C, Schemann M, van der Voort I, Dathe K, Preiß J C: S3-Leitlinie Reizdarmsyndrom: Definition, Pathophysiologie, Diagnostik und Therapie. Gemeinsame Leitlinie der Deutschen Gesellschaft für Verdauungs- und Stoffwechselkrankheiten (DGVS) und der Deutschen Gesellschaft für Neurogastroenterologie und Motilität (DGNM): Irritable Bowel Syndrome: German Consensus Guidelines on Definition, Pathophysiology and Management. Z Gastroenterol 2011; 49(2): 237–93. @ For eReferences please refer to: www.aerzteblatt-international.de/ref4411 eBoxes: www.aerzteblatt-international.de/11m0751 760 Deutsches Ärzteblatt International | Dtsch Arztebl Int 2011; 108(44): 751–60 MEDICINE CLINICAL PRACTICE GUIDELINE Irritable Bowel Syndrome—The Main Recommendations Viola Andresen, Jutta Keller, Christian Pehl, Michael Schemann, Jan Preiss, Peter Layer eReferences e1. Longstreth GF, Thompson WG, Chey WD, et al.: Functional bowel disorders. Gastroenterology 2006; 130: 1480–91. e2. O’Leary C, Wieneke P, Buckley S, et al.: Celiac disease and irritable bowel-type symptoms. Am J Gastroenterol 2002; 97: 1463–7. e3. Vine MF, Calingaert B, Berchuck A, et al.: Characterization of prediagnostic symptoms among primary epithelial ovarian cancer cases and controls. Gynecol Oncol 2003; 90: 75–82. e4. Friedman GD, Skilling JS, Udaltsova NV, et al.: Early symptoms of ovarian cancer: a case-control study without recall bias. Fam Pract 2005; 22: 548–53. e5. Lim B, Manheimer E, Lao L, et al.: Acupuncture for treatment of irritable bowel syndrome. Cochrane Database Syst Rev 2006CD005111. e6. National Institute for Health and Clinical Excellence N: Clinical Practice Guideline on Irritable Bowel Syndrome in adults: Diagnosis and management of irritable bowel syndrome in primary care. www.nice.org.uk, 2008. e7. Schafer E, Ewe K: [The treatment of irritable colon. Efficacy and tolerance of buscopan plus, buscopan, paracetamol and placebo in ambulatory patients with irritable colon]. Fortschr Med 1990; 108: 488–92. e8. Efskind PS, Bernklev T, Vatn MH: A double-blind placebo-controlled trial with loperamide in irritable bowel syndrome. Scand J Gastroenterol 1996; 31: 463–8. e9. Khoshoo V, Armstead C, Landry L: Effect of a laxative with and without tegaserod in adolescents with constipation predominant irritable bowel syndrome. Aliment Pharmacol Ther 2006; 23: 191–6. Deutsches Ärzteblatt International | Dtsch Arztebl Int 2011; 108(44) | Andresen et al.: eReferences I MEDICINE CLINICAL PRACTICE GUIDELINE Irritable Bowel Syndrome—The Main Recommendations Viola Andresen, Jutta Keller, Christian Pehl, Michael Schemann, Jan Preiss, Peter Layer eBOX 1 Members of the guideline group ● Participating medical specialist societies Coordination – German Society for Digestive and Metabolic Diseases (DGVS, Deutsche Gesellschaft für Verdauungs- und Stoffwechselkrankheiten) in coordination with – German Society for Neurogastroenterology and Motility (DGNM, Deutsche Gesellschaft für Neurogastroenterologie & Motilität In collaboration with – German Society for Internal Medicine (DGIM, Deutsche Gesellschaft für Innere Medizin) – Association of German Gastroenterologists in Private Practice (bng, Berufsverband Niedergelassener Gastroenterologen) – Society for Pediatric Gastroenterology and Nutrition (GPGE, Gesellschaft für Pädiatrische Gastroenterologie und Ernährung) – German Society for Nutritional Medicine (DGEM, Deutsche Gesellschaft für Ernährungsmedizin) – German Society for General and Visceral Surgery (DGAV, Deutsche Gesellschaft für Allgemein- und Viszeralchirurgie) – German College of General Practitioners and Family Physicians (Deutsche Gesellschaft für Allgemein- und Familienmedizin) – German Society for the Study of Pain (DGSS, Deutsche Gesellschaft zum Studium des Schmerzes) – German Society for Behavioral Medicine and Behavior Modification (DGVM, Deutsche Gesellschaft für Verhaltensmedizin und Verhaltensmodifikation) – German Society of Psychosomatic Medicine and Medical Psychotherapy (DGPM, Deutsche Gesellschaft für Psychosomatische Medizin und Ärztliche Psychotherapie) – German Society for Tropical Medicine and International Health (DTG, Deutsche Gesellschaft für Tropenmedizin und Internationale Gesundheit) – German Society for Naturopathy (Deutsche Gesellschaft für Naturheilkunde) – German Irritable Bowel Self-Help (Deutsche Reizdarmselbsthilfe e. V.) (patient organization) ● Leading authors of the guideline – – – – – – – – – – – – – – – – – – – – – – – – – – Prof. Dr. med. Peter Layer, Hamburg Dr. MSc Viola Andresen, Hamburg PD Dr. med. Christian Pehl, Vilsbiburg Prof. Dr. med. Hans-Dieter Allescher, Garmisch-Partenkirchen Prof. Dr. med. Stephan C. Bischoff, Stuttgart Dr. med. Martin Claßen, Bremen Prof. Dr. med. Paul Enck, Tübingen Prof. Dr. med. Thomas Frieling, Krefeld Dr. MSc Sebastian Haag, Essen Prof. Dr. med. Gerald Holtmann, Adelaide Prof. Dr. med. Michael Karaus, Göttingen Dr. med. Simone Kathemann, Essen Dr. med. Jutta Keller, Hamburg Dipl.-Psych. Rita Kuhlbusch-Zicklam, Krefeld Prof. Dr. med. Wolfgang Kruis, Cologne PD Dr. med. Jost Langhorst, Essen Dr. med. Harald Matthes, Havelhöhe Prof. Dr. med. Hubert Mönnikes, Berlin Prof. Dr. med. Stefan Müller-Lissner, Berlin PD Dr. med. Frauke Musial, Essen PD Dr. med. Bärbel Otto, Munich Dr. med. Christine Rosenberger, Hamburg Prof. Dr. med. Michael Schemann, Munich Dr. med. Ivo van der Voort, Berlin PD Dr. med. Katarina Dathe, Berlin Dr. med. Jan Preiss, Berlin Permission: Reproduced with the permission of Georg Thieme Verlag KG, Stuttgart from: Layer P, Andresen V, Pehl C, Allescher H, Bischoff S C, Classen M, Enck P, Frieling T, Haag S, Holtmann G, Karaus M, Kathemann S, Keller J, Kuhlbusch-Zicklam R, Kruis W, Langhorst J,Matthes H, Mönnikes H, Müller-Lissner S, Musial F, Otto B, Rosenberger C, Schemann M, van der Voort I, Dathe K, Preiss J C: S3-Leitlinie Reizdarmsyndrom: Definition, Pathophysiologie, Diagnostik und Therapie. Gemeinsame Leitlinie der Deutschen Gesellschaft für Verdauungs- und Stoffwechselkrankheiten (DGVS) und der Deutschen Gesellschaft für Neurogastroenterologie undMotilität (DGNM): Irritable Bowel Syndrome: German Consensus Guidelines on Definition, Pathophysiology and Management. Z Gastroenterol 2011; 49(2): 237–93. Deutsches Ärzteblatt International | Dtsch Arztebl Int 2011; 108(44) | Andresen et al.: eBoxes I MEDICINE eBOX 2 Example of a literature search (working group on treatment of constipation and bloating in IBS) ● Basic search ((“Colonic Diseases, Functional”[MeSH] NOT “Colonic Pseudo-Obstruction”[MeSH]) OR “functional bowel” OR (“functional gastrointestinal” NOT “dyspepsia”[MeSH]) OR bloat* OR flatulence OR “irritable bowel” OR “functional constipation” OR “functional abdominal pain” OR “functional diarrhoea” OR “functional diarrhea”)((((( OR dyspepsia ))))) {working groups 4, 6 and 9} AND ((German[LA] OR English[LA]) NOT (letter[PT] OR editorial[PT] OR historical article[PT] OR comment[PT] OR case reports[PT]) NOT (animals[MeSH] NOT humans[MeSH])) AND 1 : 2008/09/30[PDAT])) AND (systematic[SB] OR (randomized controlled trial[PT] OR controlled clinical trial[PT] OR (clinical trial[PT] OR randomized[TIAB] OR placebo[TIAB] OR dt[SH] OR randomly[TIAB] OR trial[TI] OR groups[TIAB]OR (epidemiologic studies[MeSH] OR “case control studies”[MeSH] OR “cohort studies”[MeSH] OR case control[TW] OR (cohort[TW] AND (study[TW] OR studies[TW])) OR Cohort analy*[TW] OR (follow up[TW] AND (study[TW] OR studies[TW])) OR (observational[TW] AND (study[TW] OR studies[TW])) OR longitudinal[TW] OR retrospective[TW] OR cross sectional[TW] OR “cross sectional studies”[MeSH]) OR ((economic[TIAB] AND (evaluation* OR analys*)) OR pharmacoeconomi* OR health economi* OR cost benefit* OR cost containment* OR cost effective* OR cost minimi* OR cost utilit* OR “costs and cost analysis”[MeSH] OR “economics”[MeSH])) ● Sample specific search strategy (working group 8, treatment of constipation and bloating in IBS) linked to the above basic search “Complementary Therapies”[Mesh] OR “Neurotransmitter Agents”[Mesh] OR “Serotonin Antagonists”[Mesh] OR “Receptors, Serotonin, 5-HT4”[Mesh] OR “ATI 7505 “[Substance Name] OR “Receptors, Adrenergic, alpha-2”[Mesh] OR “Clonidine”[Mesh] OR “Somatostatin”[Mesh] OR “Octreotide”[Mesh] OR “alvimopan” [Substance Name] OR “Receptors, Opioid”[Mesh] OR “Receptors, Corticotropin-Releasing Hormone”[Mesh] OR “lubiprostone” [Substance Name] OR “Cholecystokinin”[Mesh] OR “MEN 11420” [Substance Name] OR “SR 48968” [Substance Name] OR “dexloxiglumide” [Substance Name] OR “Cholinergic Antagonists” [Mesh] OR “Muscarinic Antagonists”[Mesh] OR “Antidiarrheals”[Mesh] OR “Loperamide”[Mesh] OR “Loperamide”[Mesh] OR “Benzodiazepines”[Mesh] OR “Anti-Bacterial Agents”[Mesh] OR “Neomycin”[Mesh])OR “Probiotics”[Mesh] OR “Parasympatholytics”[Mesh] OR “Dicyclomine”[Mesh] OR “Trimebutine”[Mesh] OR “Dicyclomine”[Mesh] OR “mebeverine” [Substance Name] OR “DA 3177” [Substance Name] OR “octylonium” [Substance Name] OR “pinaverium” [Substance Name] OR “Desipramine”[Mesh] OR “Amitriptyline”[Mesh] OR “Doxepin”[Mesh] OR “Trimipramine”[Mesh])OR “Mianserin”[Mesh] OR “Paroxetine”[Mesh] OR “Citalopram”[Mesh] OR “Antidepressive Agents”[Mesh] OR “Dietary Fiber”[Mesh] OR “Psyllium”[Mesh] OR “Enema/therapy”[Mesh] OR “Laxatives”[Mesh] ● Number of publications Basic search: 5573 Linked to the working group 8 strategy: 1103 After selection according to content and method: 62 II Deutsches Ärzteblatt International | Dtsch Arztebl Int 2011; 108(44) | Andresen et al.: eBoxes