SUPPLEMENT 1 see related editorial on page x American College of Gastroenterology Monograph on Management of Irritable Bowel Syndrome Alexander C. Ford, MB ChB, MD, FRCP1, Paul Moayyedi, BSc, MB ChB, PhD, MPH, FACG, FRCP, FRCPC, AGAF2, William D. Chey, MD, FACG, AGAF, FACP3, Lucinda A. Harris, MD, FACG4, Brian E. Lacy, MD, PhD, FACG5, Yuri A. Saito, MD, MPH, FACG6 and Eamonn M. M. Quigley, MD, MACG, FRCP, FACP, FRCPI7 for the ACG Task Force on Management of Irritable Bowel Syndrome Am J Gastroenterol https://doi.org/10.1038/s41395-018-0084-x INTRODUCTION IBS assumes considerable importance, therefore, not just for the Irritable bowel syndrome (IBS) is the most prevalent of the func- individual suferer, but for society at large. tional gastrointestinal disorders (FGIDs). Current estimates are Given the clinical heterogeneity that is a hallmark of the disor- that IBS afects up to 10–12% of adults in North America [1, 2]. der and the absence of a single efective therapy for all suferers, Although it can afect all individuals regardless of age, creed, or available therapies tend to focus on predominant symptomatol- gender, IBS is more common among women and is most com- ogy at presentation (i.e., altered bowel habits, abdominal pain, or monly diagnosed in younger individuals (<age 50) [2, 3]. IBS bloating) [4–6]. Based on their purported mode of action, many is characterized by recurrent abdominal pain and altered bowel pharmacological therapies for IBS developed in recent decades habits; bloating and distention frequently coexist. Te diagnosis have been directed towards those with a particular bowel habit, of IBS is made by taking a careful history, eliciting key symptoms, whether diarrhea or constipation. However, treating IBS patients as well as performing a physical examination and limited diagnos- can be difcult as no validated treatment algorithm exists, not all tic testing [4–6]. IBS is categorized into four main subtypes based patients respond to treatment, and patients with similar symptoms on the predominant bowel habit: IBS with constipation (IBC-C); frequently respond to the same treatment diferently. Fortunately, IBS with diarrhea (IBS-D); IBS with mixed symptomology (IBS- a variety of novel therapeutic strategies are being explored and M); and unclassifed IBS [5]. new compounds have appeared since the last iteration of the ACG IBS imposes a signifcant burden to the health care system and monograph on IBS [4]. Te goal of this document, therefore, is to to individuals. Direct medical costs attributed to IBS in the US, provide an updated, evidence-based document on the therapy of excluding prescription and over-the-counter medicines, were this common and, at times, debilitating disorder. estimated at $1.5–$10 billion per year in 2005 [7]. Patients with IBS enrolled in a large Health Maintenance Organization (HMO) had signifcantly more outpatient visits and incurred nearly 50% AN OVERVIEW OF METHODOLOGY FOR SYSTEMATIC more in total costs than individuals without IBS [8]. A retrospec- REVIEWS OF IBS THERAPY tive case-control study from another large HMO reported that Prior to the last evidence-based systematic review on the manage- patients with IBS had signifcantly more diagnostic tests, imaging, ment of irritable bowel syndrome commissioned and published and surgery compared with patients without a diagnosis of IBS [9]. by the ACG in 2014 [4], and the work that underpinned this, there Signifcant variations in care across the United States related to the had been several systematic reviews of available therapies for IBS diagnosis and treatment of IBS also play a role in excessive health [13–22]. We have previously shown that these had either not syn- care costs [10]. Te burden of IBS on individuals can be measured thesized the data correctly, or contained inaccuracies in applying in a number of ways. Studies have demonstrated consistently that eligibility criteria and data extraction [23]. We have, therefore, IBS impairs work-related activities (e.g., lost work time, reduced updated all the rigorously performed meta-analyses [24–27], productivity while at work) and also reduces quality of life [11, 12]. which informed the ACG position statement in 2014, according Te development of efective and efcient treatment strategies for to the following protocol: 1Leeds Institute of Biomedical and Clinical Sciences, University of Leeds and Leeds Gastroenterology Institute, Leeds Teaching Hospitals Trust, Leeds, UK. 2Division of Gastroenterology, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada. 3Division of Gastroenterology, Department of Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA. 4Mayo Clinic, Scottsdale, AZ, USA. 5Mayo Clinic, Jacksonville, FL, USA. 6Mayo Clinic, Rochester, MN, USA. 7Division of Gastroenterology and Hepatology, Houston Methodist Hospital and Weill Cornell Medical College, Houston, TX, USA. Correspondence: E.M.M.Q. (email: [email protected]) © 2018 The American College of Gastroenterology The American Journal of GASTROENTEROLOGY 2 Ford et al. Objectives heading (MeSH) and free text terms), and IBS, spastic colon, irrita- Primary outcome. To assess the efcacy of available pharmaco- ble colon, and functional adj5 bowel (as free text terms). logical therapies in treating IBS compared with placebo, or, in the For RCTs of dietary manipulation these were combined using case of psychological and dietary therapies, in comparison with the set operator AND with studies identifed with the terms: diet, either no treatment or standard/usual care. fat-restricted, diet, protein-restricted, diet, carbohydrate-restricted, diet, gluten-free, diet, macrobiotic, diet, vegetarian, diet, Mediterra- Secondary outcomes. To assess the efcacy of available phar- nean, diet fads, gluten, lactose intolerance, or lactose (both as MeSH macological, psychological, and dietary therapies in treating IBS terms and free text terms), or the following free text terms: FOD- according to predominant stool pattern reported (IBS-C, IBS-D, MAP$, glutens, or food adj5 intolerance. or IBS-M), and to assess adverse events with pharmacological and For RCTs of fber, antispasmodics, and peppermint oil these other therapies for IBS. were combined using the set operator AND with studies identi- fed with the terms: dietary fber, cereals, psyllium, sterculia, karaya Criteria for considering studies for this review gum, parasympatholytics, scopolamine, trimebutine, muscarinic Types of studies. Only parallel-group randomized controlled trials antagonists, or butylscopolammonium bromide (both as MeSH and (RCTs) comparing pharmacological therapies with placebo, or com- free text terms), or the following free text terms: bulking agent, paring psychological and dietary therapies with either no treatment psyllium fber, fber, husk, bran, ispaghula, wheat bran, spasmolyt- or standard/usual care, were considered for this review. Cross-over ics, spasmolytic agents, antispasmodics, mebeverine, alverine, pinav- trials were eligible for inclusion, provided extractable data were pro- erium bromide, otilonium bromide, cimetropium bromide, hyoscine vided at the end of the frst treatment period, prior to cross-over. butyl bromide, butylscopolamine, drotaverine, peppermint oil, or colpermin. Types of participants. Adults over 16 years of age recruited from For RCTs of prebiotics, synbiotics, probiotics, and antibiotics primary, secondary, or tertiary care with IBS symptoms diagnosed these were combined using the set operator AND with studies by any criteria (including clinical impression). identifed with the terms: Saccharomyces, Lactobacillus, Bifdo- bacterium, Escherichia coli, probiotics, prebiotics, synbiotics, anti- Types of interventions. Te following treatments were consid- bacterial agents, penicillins, cephalosporins, rifamycins, quinolones, ered eligible: nitroimidazoles, tetracycline, doxycycline, amoxicillin, ciprofoxacin, metronidazole, or tinidazole (both as MeSH and free text terms), or 1. Exercise, diet, and dietary manipulation the following free text terms: antibiotic, or rifaximin. 2. Fiber For RCTs of antidepressants and psychological therapies, 3. Interventions that modify the microbiota: prebiotics, synbiot- including hypnotherapy, these were combined using the set opera- ics, probiotics, and antibiotics tor AND with studies identifed with the terms: psychotropic drugs, 4. Antispasmodics and peppermint oil antidepressive agents, antidepressive agents (tricyclic), desipra- 5. Antidepressants mine, imipramine, trimipramine, doxepin, dothiepin, nortriptyline, 6. Psychological interventions amitriptyline, selective serotonin re-uptake inhibitors, paroxetine, 7. Pro-secretory agents: linaclotide, plecanatide, and lubiprostone sertraline, fuoxetine, citalopram, venlafaxine, cognitive therapy, 8. Eluxadoline psychotherapy, behavior therapy, relaxation techniques, or hypnosis 9. Loperamide (both as MeSH terms and free text terms), or the following free 10. Serotonergic agents text terms: behavioral therapy, relaxation therapy, or hypnotherapy. 11. Polyethylene glycol For RCTs of linaclotide, plecanatide, lubiprostone, eluxadoline, 12. 5-aminosalicylates and loperamide these were combined using the set operator AND with studies identifed with the terms loperamide or antidiarrheals Types of outcome measures. Subjects needed to be followed up (both as MeSH and free text terms), as well as the following for at least 1 week. Te trials needed to include one or more of the free text