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Kerbage A, Loesch J, Hamza E, Khan S, Nero N, Simons M, Lembo A. Evaluating Equity in Clinical Trial Accessibility: An Analysis of Demographic, Socioeconomic, and Educational Disparities in Irritable Bowel Syndrome Drug Trials. Am J Gastroenterol 2025; 120:873-882. [PMID: 39315667 DOI: 10.14309/ajg.0000000000003099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Accepted: 09/13/2024] [Indexed: 09/25/2024]
Abstract
INTRODUCTION Irritable bowel syndrome (IBS), a disorder of gut-brain interaction, imposes a significant economic burden because of its high prevalence and the chronic nature of its symptoms. IBS currently has 7 United States Food and Drug Administration-approved treatments. Despite efforts to improve diversity in randomized controlled trials' participation, significant disparities remain in various medical fields; yet, these have not been thoroughly examined within the context of IBS. We aimed to investigate the demographic, socioeconomic, educational, and geographic disparities in IBS drug trials. METHODS We conducted a systematic review of phase 3 randomized controlled trials on United States Food and Drug Administration-approved drugs for the treatment of IBS with constipation and IBS with diarrhea in the United States. Data on participant demographics and trial site locations were extracted and analyzed to identify disparities. RESULTS Our analysis included 17 studies encompassing 21 trials with 17,428 participants. Approximately 77.3% of participants were female, with a mean age of 45.4 years. Race was reported in 95% of the trials, but only 35% disclosed ethnicity. White participants constituted the majority at 79.3%. Hispanics accounted for only 5.9%. Counties without trial sites had smaller average population sizes compared with trial and trial-adjacent counties. Socioeconomic indicators such as poverty rates, median household income, educational attainment, and broadband internet access were lower in counties without trial sites, with higher average Area Deprivation Index scores indicating greater deprivation. DISCUSSION The findings highlight significant disparities in IBS trial participation across race, ethnicity, gender, and socioeconomic backgrounds. This raises potential concerns about generalizability of trial outcomes and underscores the need for strategies to enhance inclusivity in clinical research.
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Affiliation(s)
- Anthony Kerbage
- Department of Internal Medicine, Cleveland Clinic, Cleveland, Ohio, USA
| | - Jack Loesch
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Eyad Hamza
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Sulman Khan
- Department of Internal Medicine, Cleveland Clinic, Cleveland, Ohio, USA
| | - Neil Nero
- Cleveland Clinic Floyd D. Loop Alumni Library, Cleveland Clinic, Cleveland, Ohio, USA
| | - Madison Simons
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Anthony Lembo
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio, USA
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Deljavan Ghodrati A, Comoglu T. Rifaximin and alternative agents in the management of irritable bowel syndrome: A comprehensive review. Arch Pharm (Weinheim) 2024; 357:e2400356. [PMID: 39041415 DOI: 10.1002/ardp.202400356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 06/29/2024] [Accepted: 07/01/2024] [Indexed: 07/24/2024]
Abstract
Rifaximin, a broad-spectrum antibiotic, boasts a unique chemical composition and pharmacokinetic profile, rendering it highly effective in treating irritable bowel syndrome (IBS). Its minimal systemic absorption confines its impact to the gastrointestinal (GI) tract, where it yields significant therapeutic benefits. This review examines rifaximin's physico-chemical attributes and its role in managing IBS symptoms. Its molecular structure facilitates intestinal lumen retention postoral administration, minimizing systemic exposure and adverse effects. This targeted action is crucial in addressing the gut microbiota's role in IBS pathophysiology. By modifying microbial populations and their metabolite production, rifaximin mitigates symptoms like bloating, irregular bowel habits, and abdominal pain associated with IBS. It achieves this by reducing pathogenic bacteria and altering bacterial metabolism, enhancing mucosal and immune function. Clinical trials affirm rifaximin's superiority over placebo and conventional therapies in alleviating overall IBS symptoms and addressing small intestine bacterial overgrowth (SIBO). Despite its promising efficacy and sustained symptom relief, further research is essential to optimize long-term effectiveness and dosing regimens. Rifaximin stands as a vital treatment option for IBS due to its distinctive properties and clinical utility; yet, ongoing investigation is imperative for maximizing its therapeutic benefits.
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Affiliation(s)
- Aylin Deljavan Ghodrati
- Department of Pharmaceutical Technology, Ankara University Faculty of Pharmacy, Ankara, Turkey
- Graduate School of Health Sciences, Ankara University, Ankara, Turkey
| | - Tansel Comoglu
- Department of Pharmaceutical Technology, Ankara University Faculty of Pharmacy, Ankara, Turkey
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Xu Y, Wang J, Wu X, Jing H, Zhang S, Hu Z, Rao L, Chang Q, Wang L, Zhang Z. Gut microbiota alteration after cholecystectomy contributes to post-cholecystectomy diarrhea via bile acids stimulating colonic serotonin. Gut Microbes 2023; 15:2168101. [PMID: 36732497 PMCID: PMC9897804 DOI: 10.1080/19490976.2023.2168101] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Post-cholecystectomy diarrhea (PCD) is highly prevalent among outpatients with cholecystectomy, and gut microbiota alteration is correlated with it. However, how and to what extent changed fecal bacteria contributes to diarrhea are still unrevealed. Humanized gut microbiome mice model by fecal microbiota transplantation was established to explore the diarrhea-inducible effects of gut microbiota. The role of microbial bile acids (BAs) metabolites was identified by UPLC/MS and the underlying mechanisms were investigated with selective inhibitors and antagonists as probes. These mice transplanted with fecal microbiome of PCD patients (PCD mice) exhibited significantly enhanced gastrointestinal motility and elevated fecal water content, compared with these mice with fecal microbiome of NonPCD patients and HC. In analyzing gut microbiota, tryptophan metabolism was enriched in PCD microbiome. In addition, overabundant serotonin in serum and colon, along with elevated biosynthesis gene and reduced reuptake gene, and highly expressed 5-HT receptors (5-HTRs) in colon of PCD mice were found, but not in small intestine. Notably, diarrheal phenotypes in PCD mice were depleted by tryptophan hydroxylase 1 inhibitor (LX1606) and 5-HTRs selective antagonists (alosetron and GR113808). Furthermore, increased microbial secondary BAs metabolites of DCA, HDCA and LCA were revealed in feces of PCD mice and they were found responsible for stimulating 5-HT level in vitro and in vivo. Intriguingly, blocking BAs-conjugated TGR5/TRPA1 signaling pathway could significantly alleviate PCD. In conclusion, altered gut microbiota after cholecystectomy contributes to PCD by promoting secondary BAs in colon, which stimulates colonic 5-HT and increases colon motility.
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Affiliation(s)
- Yayun Xu
- Department of Hepatopancreatobiliary Surgery, Minhang Hospital, Fudan University, Shanghai, P.R. China,Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, P.R. China
| | - Jianfa Wang
- Department of Hepatopancreatobiliary Surgery, Minhang Hospital, Fudan University, Shanghai, P.R. China,Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, P.R. China
| | - Xubo Wu
- Department of Hepatopancreatobiliary Surgery, Minhang Hospital, Fudan University, Shanghai, P.R. China,Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, P.R. China
| | - Hui Jing
- Department of Hepatopancreatobiliary Surgery, Minhang Hospital, Fudan University, Shanghai, P.R. China,Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, P.R. China
| | - Shilong Zhang
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, P.R, China
| | - Zhiqiu Hu
- Department of Hepatopancreatobiliary Surgery, Minhang Hospital, Fudan University, Shanghai, P.R. China,Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, P.R. China
| | - Longhua Rao
- Department of Hepatopancreatobiliary Surgery, Minhang Hospital, Fudan University, Shanghai, P.R. China,Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, P.R. China
| | - Qimeng Chang
- Department of Hepatopancreatobiliary Surgery, Minhang Hospital, Fudan University, Shanghai, P.R. China,Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, P.R. China
| | - Lishun Wang
- Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, P.R. China,Center for Traditional Chinese Medicine and Gut Microbiota, Minhang Hospital, Fudan University, Shanghai, China
| | - Ziping Zhang
- Department of Hepatopancreatobiliary Surgery, Minhang Hospital, Fudan University, Shanghai, P.R. China,Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, Shanghai, P.R. China,CONTACT Ziping Zhang Department of Hepatopancreatobiliary Surgery, Minhang Hospital, Fudan University, Shanghai, 201100, P.R. China
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Lembo A, Sultan S, Chang L, Heidelbaugh JJ, Smalley W, Verne GN. AGA Clinical Practice Guideline on the Pharmacological Management of Irritable Bowel Syndrome With Diarrhea. Gastroenterology 2022; 163:137-151. [PMID: 35738725 DOI: 10.1053/j.gastro.2022.04.017] [Citation(s) in RCA: 71] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder associated with significant disease burden. This American Gastroenterological Association Guideline is intended to support practitioners in decisions about the use of medications for the pharmacological management of IBS with predominant diarrhea (IBS-D) and is an update of a prior technical review and guideline. METHODS The Grading of Recommendations Assessment, Development and Evaluation framework was used to assess evidence and make recommendations. The technical review panel prioritized clinical questions and outcomes according to their importance for clinicians and patients and conducted an evidence review of the following agents: eluxadoline, rifaximin, alosetron, loperamide, tricyclic antidepressants, selective serotonin reuptake inhibitors, and antispasmodics. The guideline panel reviewed the evidence and used the Evidence-to-Decision Framework to develop recommendations. CONCLUSIONS The panel agreed on 8 recommendations for the management of patients with IBS-D. The panel made conditional recommendations for eluxadoline, rifaximin, alosetron, (moderate certainty), loperamide (very low certainty), tricyclic antidepressants, and anstispasmodics (low certainty). The panel made a conditional recommendation against the use of selective serotonin reuptake inhibitors (low certainty).
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Affiliation(s)
- Anthony Lembo
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Shahnaz Sultan
- Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis, Minnesota; Veterans Affairs Healthcare System, Minneapolis, Minnesota
| | - Lin Chang
- Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, California
| | - Joel J Heidelbaugh
- Department of Family Medicine, University of Michigan Medical School, Ann Arbor, Michigan
| | - Walter Smalley
- Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - G Nicholas Verne
- Department of Medicine, University of Tennessee College of Medicine, Memphis, Tennessee
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Barberio B, Savarino EV, Black CJ, Ford AC. Adverse events in trials of licensed drugs for irritable bowel syndrome with constipation or diarrhea: Systematic review and meta-analysis. Neurogastroenterol Motil 2022; 34:e14279. [PMID: 34672052 DOI: 10.1111/nmo.14279] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 09/21/2021] [Accepted: 09/27/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND Nocebo effects occurring in patients receiving placebo frequently impact on adverse events reported in randomized controlled trials (RCTs) in irritable bowel syndrome (IBS). Therefore, we conducted a systematic review and meta-analysis to assess the proportion of patients randomized to placebo or active drug experiencing any adverse event in trials of licensed drugs for IBS with constipation (IBS-C) or diarrhea (IBS-D), and to estimate the risk of developing adverse events among patients randomized to placebo. METHODS We searched MEDLINE, EMBASE CLASSIC and EMBASE, and the Cochrane central register of controlled trials (through June 2021) to identify RCTs comparing licensed drugs with placebo in adults with IBS-C or IBS-D. We generated Forest plots of pooled adverse event rates in both active drug and placebo arms and pooled risk differences (RDs) with 95% confidence intervals (CIs). KEY RESULTS There were 21 RCTs of licensed drugs versus placebo in IBS-C (5953 patients placebo) and 17 in IBS-D (3854 patients placebo). Overall, 34.9% and 46.9% of placebo patients in IBS-C and IBS-D trials, respectively, developed at least one adverse event, with a statistically significantly higher risk of any adverse event and withdrawal due to an adverse event with active drug. In IBS-C and IBS-D trials, rates of each individual adverse event were generally higher with active drug. However, in IBS-C trials, only diarrhea or headache was significantly more common with active drug (RD 0.066 (95% CI 0.043-0.088) and RD 0.011 (95% CI 0.002-0.021), respectively), and in IBS-D trials only constipation, nausea, or abdominal pain (RD 0.096 (95% CI 0.054-0.138), 0.014 (95% CI 0.002-0.027), and 0.018 (95% CI 0.002-0.034), respectively). CONCLUSIONS & INFERENCES Patients with IBS randomized to placebo have a high risk of reporting adverse events, which might relate to both nocebo and non-nocebo factors. Although patients' expectations and psychosocial factors may be involved, further understanding of the mechanisms are important to control or optimize these effects in RCTs, as well as in clinical practice.
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Affiliation(s)
- Brigida Barberio
- Department of Surgery, Oncology and Gastroenterology (DISCOG), Gastroenterology Unit, University of Padova-Azienda Ospedaliera di Padova, Padova, Italy
| | - Edoardo V Savarino
- Department of Surgery, Oncology and Gastroenterology (DISCOG), Gastroenterology Unit, University of Padova-Azienda Ospedaliera di Padova, Padova, Italy
| | - Christopher J Black
- Leeds Gastroenterology Institute, St. James's University Hospital, Leeds, UK.,Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, UK
| | - Alexander C Ford
- Leeds Gastroenterology Institute, St. James's University Hospital, Leeds, UK.,Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, UK
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Barberio B, Savarino EV, Black CJ, Ford AC. Placebo Response Rates in Trials of Licensed Drugs for Irritable Bowel Syndrome With Constipation or Diarrhea: Meta-analysis. Clin Gastroenterol Hepatol 2022; 20:e923-e944. [PMID: 34425274 DOI: 10.1016/j.cgh.2021.08.025] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 08/11/2021] [Accepted: 08/13/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS There are several licensed drugs for irritable bowel syndrome (IBS) that have proven efficacy in randomized controlled trials (RCTs), but placebo response rates are high. We conducted a systematic review and meta-analysis of licensed drugs to estimate magnitude of placebo response rate according to Food and Drug Administration (FDA)-recommended endpoints and to assess how this varies with stringency of the endpoint used to define response. METHODS We searched MEDLINE, EMBASE CLASSIC and EMBASE, and the Cochrane central register of controlled trials (through January 2021) to identify RCTs comparing licensed drugs with placebo in adult IBS patients. Studies assessed efficacy according to at least one of composite response, abdominal pain response, or stool response. Data were extracted as intention-to-treat analyses, with dropouts assumed to be treatment failures and pooled using a random-effects model. RESULTS There were 17 RCTs of licensed drugs versus placebo in IBS with constipation (4603 patients placebo) and 17 trials in IBS with diarrhea (3908 patients placebo). In IBS with constipation, according to FDA criteria, pooled composite, abdominal pain, and stool response rates with placebo over ≥6 of 12 weeks were 18.9%, 34.6%, and 30.1%, respectively. Evaluating response rates over ≥9 of 12 weeks led to placebo response rates of 4.3% for the composite endpoint, 24.5% for abdominal pain, and 7.7% for stool. In IBS with diarrhea, pooled placebo response rates according to FDA criteria were 16.2% for the composite endpoint, 40.2% for abdominal pain, and 16.2% for stool. Increasing the threshold used to define abdominal pain response from ≥30% improvement to ≥40% or ≥50% led to lower placebo response rates of 34.5% and 23.4%. CONCLUSIONS Future RCTs should adhere to current FDA-recommended endpoints for IBS because these lead to lower placebo response rates. However, consideration should be given to further refining some of these to better differentiate between active drug and placebo.
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Affiliation(s)
- Brigida Barberio
- Department of Surgery, Oncology and Gastroenterology (DISCOG), Gastroenterology Unit, University of Padova-Azienda Ospedaliera di Padova, Padova, Italy
| | - Edoardo Vincenzo Savarino
- Department of Surgery, Oncology and Gastroenterology (DISCOG), Gastroenterology Unit, University of Padova-Azienda Ospedaliera di Padova, Padova, Italy
| | - Christopher J Black
- Leeds Gastroenterology Institute, St James's University Hospital, Leeds, United Kingdom; Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom
| | - Alexander C Ford
- Leeds Gastroenterology Institute, St James's University Hospital, Leeds, United Kingdom; Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom.
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Elwing JE, Atassi H, Rogers BD, Sayuk GS. Emerging therapies in the management of Irritable Bowel Syndrome (IBS). Expert Opin Emerg Drugs 2022; 27:55-73. [PMID: 35266839 DOI: 10.1080/14728214.2022.2052043] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Irritable bowel syndrome (IBS) is a common, symptom-based disorder of chronic abdominal pain and altered bowel habits. The pathogenesis of IBS is multifactorial, leading to the potential for the development of multiple, diverse treatment strategies. This mechanistic heterogeneity also leads to the realization that available therapies are only effective in a subset of IBS suffers. Current US Food and Drug Administration (FDA) approved therapies for IBS with diarrhea (IBS-D) and IBS with constipation (IBS-C) are reviewed. Limited symptom responses and side effect experiences lead to considerable patient dissatisfaction with currently available IBS treatments. Only a small percentage of IBS patients are on prescription therapies underscoring the potential market and need for additional therapeutic options. AREAS COVERED : Expanding on currently available therapies, the serotonergic and endogenous opioid receptor systems continue to be a focus of future IBS treatment development. Additional novel emerging therapies include the endogenous cannabinoid system, bile acid secretion and sequestration, and exploit our enhanced understanding of visceral sensory signaling and intestinal secretomotor function. EXPERT OPINION While challenges remain for the future development of IBS therapies, the diverse etiologies underlying the disorder present an opportunity for novel therapies. Hence, great potential is anticipated for future IBS treatment options.
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Affiliation(s)
- Jill E Elwing
- St. Louis Veterans Affairs Medical Center, St. Louis, MO, USA
| | - Hadi Atassi
- Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville School of Medicine, Louisville, KY, USA
| | - Benjamin D Rogers
- Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville School of Medicine, Louisville, KY, USA.,Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO, USA
| | - Gregory S Sayuk
- St. Louis Veterans Affairs Medical Center, St. Louis, MO, USA.,Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
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Nee J, Lembo A. Review Article: Current and future treatment approaches for IBS with diarrhoea (IBS-D) and IBS mixed pattern (IBS-M). Aliment Pharmacol Ther 2021; 54 Suppl 1:S63-S74. [PMID: 34927757 DOI: 10.1111/apt.16625] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/10/2021] [Accepted: 09/18/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Irritable bowel syndrome-diarrhoea (IBS-D) and IBS-mixed stool pattern (IBS-M) are disorders of gut-brain interaction characterised by abdominal pain associated with diarrhoea or both diarrhoea and constipation respectively. The pathophysiology of IBS-D/M is multifactorial and not completely understood; thus, treatment is aimed at multiple mechanisms such as altering gut microbiota, visceral hypersensitivity, intestinal permeability, gut-brain interaction and psychological strategies. AIM The goal of this article was to provide an up-to-date review of the current evidence for both non-pharmacological and pharmacological treatment options in IBS-D and IBS-M. Future treatments for IBS-D and IBS-M will also be discussed. METHODS Medline and Embase database searches (through April 30 2021) to identify clinical studies in subjects with IBS-D in which dietary modification, alternative treatments (probiotics, acupuncture, exercise) as well as FDA-approved medications were used. RESULTS Dietary modification is often the first line of therapy. Furthermore, lifestyle treatments include complementary alternative medications (CAM), probiotics and peppermint oil are useful adjuncts but have not specifically been described in IBS-D/M. Evidence strongly supports psychotherapy in the treatment of IBS. Beyond over-the counter anti-diarrhoeals, anti-spasmodics and anti-depressants, pharmacological treatment now includes treating for bile acid malabsorption and the FDA-approved medications rifaximin, eluxadoline and alosetron. CONCLUSIONS The treatment of IBS-D/M ideally involves a multidisciplinary approach of primary care, gastroenterologist and psychologist. Treatment often involves both non-pharmacological and pharmacological therapies. Future therapies may include faecal microbial transplant, Crofelemer and serotonin antagonists, but further studies are needed.
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Affiliation(s)
- Judy Nee
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | - Anthony Lembo
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
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Diarrhea-Predominant and Constipation-Predominant Irritable Bowel Syndrome: Current Prescription Drug Treatment Options. Drugs 2021; 81:1953-1968. [PMID: 34727333 DOI: 10.1007/s40265-021-01634-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/17/2021] [Indexed: 12/14/2022]
Abstract
Irritable bowel syndrome (IBS) is a heterogenous disease with a variety of therapeutic options, including eight prescription drugs approved for use in IBS in the USA. Choosing among the myriad treatment options requires attention to patient preferences both on clinical outcomes and costs associated with treatment. We performed a narrative review of the literature to summarize these important determinants of treatment choice including: labeled indications; clinical profiles of efficacy, safety, and tolerability of prescription drugs; and cost-effectiveness for diarrhea-predominant IBS drugs (IBS-D: alosetron, eluxadoline, and rifaximin) and constipation-predominant IBS drugs (IBS-C: linaclotide, lubiprostone, plecanatide, tegaserod, and tenapanor). We then review the standard model of shared decision-making aimed at guiding an informed, patient-centered discussion to integrate comparative clinical and cost outcomes toward choosing an IBS treatment in practice.
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Medical Therapies for Diarrhea-Predominant Irritable Bowel Syndrome. Gastroenterol Clin North Am 2021; 50:611-637. [PMID: 34304791 DOI: 10.1016/j.gtc.2021.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2023]
Abstract
Diarrhea-predominant irritable bowel syndrome is a common functional gastrointestinal disorder that manifests with abdominal pain and diarrheal bowel patterns, without structural explanation. Diarrhea-predominant irritable bowel syndrome is a heterogeneous condition resulting from diverse pathophysiologic processes. Treatment strategies with varied mechanisms of action are beneficial in its management. The clinician must become familiar with a multi-dimensional approach to irritable bowel syndrome. The 3 approved medications are central to disease management. Effective treatment uses off-label medications and emerging therapies and a growing number of over-the-counter and supplemental agents to optimize symptom improvement for the patient with diarrhea-predominant irritable bowel syndrome.
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Rokkas T, Ekmektzoglou K, Niv Y. Comparative effectiveness of 5-hydroxytryptamine 3 receptor antagonists in irritable bowel syndrome: a network meta-analysis of randomized controlled studies. Ann Gastroenterol 2021; 34:535-546. [PMID: 34276193 PMCID: PMC8276363 DOI: 10.20524/aog.2021.0619] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 02/18/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND There is evidence demonstrating the beneficial effects of 5-hydroxytryptamine 3 receptor antagonists (5-HT3) for the treatment of non-constipated irritable bowel syndrome (NC-IBS). We aimed to determine the comparative effectiveness of 5-HT3 antagonists in NC-IBS, as evidenced by the results of a network meta-analysis (NWM) of published relevant randomized controlled trials (RCTs). METHODS We searched the PubMed/Medline, EMBASE, and Cochrane Library databases for relevant RCTs through September 2020 and data from each selected RCT were extracted. A Bayesian NWM was then performed to investigate the efficacy of 5-HT3 antagonists and to explore the effectiveness rank order in treating NC-IBS patients. RESULTS Twenty-one eligible RCTs were identified and entered into this NWM. They included a total of 10,421 NC-IBS patients, randomized to alosetron, cilansetron, ondansetron, ramosetron, placebo, and mebeverine. The cumulative ranking probability for each intervention at the end of treatment period, was evaluated by means of surfaces under cumulative ranking (SUCRA) values. These results showed that alosetron had the best performance for global symptom improvement (SUCRA 0.82), cilansetron showed the best performance (SUCRA 0.90) for abdominal pain/discomfort improvement, while ondansetron (SUCRA 0.98) was by far the best choice concerning bowel habits/consistency improvement. The control regimens (mebeverine and placebo) represented the least efficacious interventions. CONCLUSIONS This NWM showed that 5-HT3 receptor antagonists performed better in comparison to control drugs. Consequently, this class of drugs may play an important role in improving the debilitating symptoms in NC-IBS patients, in particular those with diarrhea.
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Affiliation(s)
- Theodore Rokkas
- Gastroenterology Clinic, Henry Dunant Hospital, Athens, Greece (Theodore Rokkas)
- Medical School, European University of Cyprus, Nicosia, Cyprus (Theodore Rokkas, Konstantinos Ekmektzoglou)
| | - Konstantinos Ekmektzoglou
- Medical School, European University of Cyprus, Nicosia, Cyprus (Theodore Rokkas, Konstantinos Ekmektzoglou)
| | - Yaron Niv
- Tel Aviv University, Ministry of Health, Israel (Yaron Niv)
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Bosman M, Elsenbruch S, Corsetti M, Tack J, Simrén M, Winkens B, Boumans T, Masclee A, Keszthelyi D. The placebo response rate in pharmacological trials in patients with irritable bowel syndrome: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2021; 6:459-473. [PMID: 33765447 DOI: 10.1016/s2468-1253(21)00023-6] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/12/2021] [Accepted: 01/14/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND Clinical trials in irritable bowel syndrome are associated with high placebo response rates. We aimed to identify the magnitude of the placebo response and the contributing factors to this occurrence. METHODS We did a systematic review and meta-analysis with a search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials between April 1, 1959, and April 30, 2020. We included all randomised controlled trials that compared an active pharmacotherapeutic agent with placebo and had a dichotomous outcome of response to therapy (in terms of global improvement or improvement in abdominal pain) in adults (aged ≥18 years) with irritable bowel syndrome. Exclusion criteria were trials reporting on treatment satisfaction as a dichotomous outcome of response to therapy or clinician-reported outcomes and a treatment duration of less than 4 weeks. Our main outcome was identification of the magnitude of the pooled placebo response rate for the following endpoints: global improvement, abdominal pain, and US Food and Drug Administration (FDA) endpoints. We extracted information from published reports and pooled proportions through meta-analysis with random effects. The study was registered with PROSPERO, CRD42020170908. FINDINGS Of the 6863 publications identified, 70 articles describing 73 randomised controlled trials were included in our analysis. The pooled placebo response rate was 27·3% (95% CI 24·3-30·9) using the global improvement endpoint, 34·4% (31·2-37·8) using the abdominal pain endpoint, and 17·9% (15·2-21·0) using the composite FDA endpoint responder definition, all with substantial heterogeneity between the trials. Studies published before 2006, and those done in Europe, with a parallel design, a run-in period of 2 weeks or less, a dose schedule of three times a day or more, or a smaller sample size of the control group were significantly associated with an increased pooled placebo response rate. INTERPRETATION More than a quarter of patients with irritable bowel syndrome had a placebo response in terms of global improvement, with multiple associated moderators. We recommend future trials apply a run-in period of at least 2 weeks and dose once or twice a day to minimise the placebo response rate. FUNDING None.
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Affiliation(s)
- Michelle Bosman
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, Netherlands.
| | - Sigrid Elsenbruch
- Department of Medical Psychology and Medical Sociology, Faculty of Medicine, Ruhr University Bochum, Bochum, Germany; Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Maura Corsetti
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK; University of Nottingham and Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK
| | - Jan Tack
- Translational Research Center for Gastrointestinal Disorders, Catholic University of Leuven, Leuven, Belgium; Division of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Magnus Simrén
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Centre for Functional GI and Motility Disorders, University of North Carolina, Chapel Hill, NC, USA
| | - Bjorn Winkens
- Department of Methodology and Statistics, Care and Public Health Research Institute, Faculty of Health, Medicine, and Life Sciences, Maastricht University, Maastricht, Netherlands
| | - Thimo Boumans
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, Netherlands
| | - Ad Masclee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, Netherlands
| | - Daniel Keszthelyi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, Netherlands
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13
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Nickerson AJ, Rottgen TS, Rajendran VM. Activation of KCNQ (K V7) K + channels in enteric neurons inhibits epithelial Cl - secretion in mouse distal colon. Am J Physiol Cell Physiol 2021; 320:C1074-C1087. [PMID: 33852365 PMCID: PMC8285638 DOI: 10.1152/ajpcell.00536.2020] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 03/30/2021] [Accepted: 03/30/2021] [Indexed: 12/14/2022]
Abstract
Voltage-gated Kv7 (KCNQ family) K+ channels are expressed in many neuronal populations and play an important role in regulating membrane potential by generating a hyperpolarizing K+ current and decreasing cell excitability. However, the role of KV7 channels in the neural regulation of intestinal epithelial Cl- secretion is not known. Cl- secretion in mouse distal colon was measured as a function of short-circuit current (ISC), and pharmacological approaches were used to test the hypothesis that activation of KV7 channels in enteric neurons would inhibit epithelial Cl- secretion. Flupirtine, a nonselective KV7 activator, inhibited basal Cl- secretion in mouse distal colon and abolished or attenuated the effects of drugs that target various components of enteric neurotransmission, including tetrodotoxin (NaV channel blocker), veratridine (NaV channel activator), nicotine (nicotinic acetylcholine receptor agonist), and hexamethonium (nicotinic antagonist). In contrast, flupritine did not block the response to epithelium-targeted agents VIP (endogenous VPAC receptor ligand) or carbachol (nonselective cholinergic agonist). Flupirtine inhibited Cl- secretion in both full-thickness and seromuscular-stripped distal colon (containing the submucosal, but not myenteric plexus) but generated no response in epithelial T84 cell monolayers. KV7.2 and KV7.3 channel proteins were detected by immunofluorescence in whole mount preparations of the submucosa from mouse distal colon. ICA 110381 (KV7.2/7.3 specific activator) inhibited Cl- secretion comparably to flupirtine. We conclude that KV7 channel activators inhibit neurally driven Cl- secretion in the colonic epithelium and may therefore have therapeutic benefit in treating pathologies associated with hyperexcitable enteric nervous system, such as irritable bowel syndrome with diarrhea (IBS-D).
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Affiliation(s)
- Andrew J Nickerson
- Departments of Physiology, Pharmacology and Neuroscience, West Virginia University School of Medicine, Morgantown, West Virginia
- Department of Biochemistry, West Virginia University School of Medicine, Morgantown, West Virginia
| | - Trey S Rottgen
- Departments of Physiology, Pharmacology and Neuroscience, West Virginia University School of Medicine, Morgantown, West Virginia
- Department of Biochemistry, West Virginia University School of Medicine, Morgantown, West Virginia
| | - Vazhaikkurichi M Rajendran
- Department of Biochemistry, West Virginia University School of Medicine, Morgantown, West Virginia
- Department of Medicine, West Virginia University School of Medicine, Morgantown, West Virginia
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14
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Fukudo S, Okumura T, Inamori M, Okuyama Y, Kanazawa M, Kamiya T, Sato K, Shiotani A, Naito Y, Fujikawa Y, Hokari R, Masaoka T, Fujimoto K, Kaneko H, Torii A, Matsueda K, Miwa H, Enomoto N, Shimosegawa T, Koike K. Evidence-based clinical practice guidelines for irritable bowel syndrome 2020. J Gastroenterol 2021; 56:193-217. [PMID: 33538894 PMCID: PMC7932982 DOI: 10.1007/s00535-020-01746-z] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Accepted: 10/27/2020] [Indexed: 02/06/2023]
Abstract
Managing irritable bowel syndrome (IBS) has attracted international attention because single-agent therapy rarely relieves bothersome symptoms for all patients. The Japanese Society of Gastroenterology (JSGE) published the first edition of evidence-based clinical practice guidelines for IBS in 2015. Much more evidence has accumulated since then, and new pharmacological agents and non-pharmacological methods have been developed. Here, we report the second edition of the JSGE-IBS guidelines comprising 41 questions including 12 background questions on epidemiology, pathophysiology, and diagnostic criteria, 26 clinical questions on diagnosis and treatment, and 3 questions on future research. For each question, statements with or without recommendations and/or evidence level are given and updated diagnostic and therapeutic algorithms are provided based on new evidence. Algorithms for diagnosis are requisite for patients with chronic abdominal pain or associated symptoms and/or abnormal bowel movement. Colonoscopy is indicated for patients with one or more alarm symptoms/signs, risk factors, and/or abnormal routine examination results. The diagnosis is based on the Rome IV criteria. Step 1 therapy consists of diet therapy, behavioral modification, and gut-targeted pharmacotherapy for 4 weeks. For non-responders, management proceeds to step 2 therapy, which includes a combination of different mechanistic gut-targeted agents and/or psychopharmacological agents and basic psychotherapy for 4 weeks. Step 3 therapy is for non-responders to step 2 and comprises a combination of gut-targeted pharmacotherapy, psychopharmacological treatments, and/or specific psychotherapy. These updated JSGE-IBS guidelines present best practice strategies for IBS patients in Japan and we believe these core strategies can be useful for IBS diagnosis and treatment globally.
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Affiliation(s)
- Shin Fukudo
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan.
- Department of Behavioral Medicine Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.
| | - Toshikatsu Okumura
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Masahiko Inamori
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Yusuke Okuyama
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Motoyori Kanazawa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Takeshi Kamiya
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Ken Sato
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Akiko Shiotani
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Yuji Naito
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Yoshiko Fujikawa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Ryota Hokari
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Tastuhiro Masaoka
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Kazuma Fujimoto
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Hiroshi Kaneko
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Akira Torii
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Kei Matsueda
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Hiroto Miwa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Nobuyuki Enomoto
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Tooru Shimosegawa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Kazuhiko Koike
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
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15
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Colomier E, Algera J, Melchior C. Pharmacological Therapies and Their Clinical Targets in Irritable Bowel Syndrome With Diarrhea. Front Pharmacol 2021; 11:629026. [PMID: 33679391 PMCID: PMC7935509 DOI: 10.3389/fphar.2020.629026] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 12/24/2020] [Indexed: 12/15/2022] Open
Abstract
Irritable bowel syndrome (IBS) is one of the most common disorders of the gut-brain axis, which affects approximately 4% of the global population. The Rome IV criteria define IBS as chronic or recurrent abdominal pain associated with altered bowel habits. Patients can be categorized in four subtypes: IBS with predominant constipation (IBS-C), predominant diarrhea (IBS-D), mixed bowel habits (IBS-M), and unclassified (IBS-U). IBS is associated with a lower quality of life, reduced work productivity, and high healthcare costs. When comparing subtypes, patients with IBS-D report lower disease related quality of life. Due to the scope of this review, we have solely focused on patients with IBS-D. Choosing the right pharmacological treatment in these patients remains challenging due to the heterogeneous patient population, patients' expectation of the treatment outcome, unavailability of efficacious drugs, and the multifactorial and incompletely understood underlying pathophysiology. Currently, pharmacological treatment options target individual symptoms, such as abdominal pain, altered bowel habits, and bloating. In this review, we aimed to summarize the current and recent pharmacological treatment options in IBS-D, targeting the predominant gastrointestinal symptoms. Additionally, we proposed a pharmacological treatment algorithm which healthcare professionals could use when treating individual patients with IBS-D.
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Affiliation(s)
- Esther Colomier
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism and Aging (CHROMETA), KU Leuven, Leuven, Belgium
| | - Joost Algera
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Chloé Melchior
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Gastroenterology Department and INSERM CIC-CRB 1404, Rouen University Hospital, Rouen, France.,INSERM UMR 1073, Institute for Research and Innovation in Biomedicine, Normandy University, Rouen, France
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16
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ACG Clinical Guideline: Management of Irritable Bowel Syndrome. Am J Gastroenterol 2021; 116:17-44. [PMID: 33315591 DOI: 10.14309/ajg.0000000000001036] [Citation(s) in RCA: 426] [Impact Index Per Article: 106.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 10/08/2020] [Indexed: 02/07/2023]
Abstract
Irritable bowel syndrome (IBS) is a highly prevalent, chronic disorder that significantly reduces patients' quality of life. Advances in diagnostic testing and in therapeutic options for patients with IBS led to the development of this first-ever American College of Gastroenterology clinical guideline for the management of IBS using Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Twenty-five clinically important questions were assessed after a comprehensive literature search; 9 questions focused on diagnostic testing; 16 questions focused on therapeutic options. Consensus was obtained using a modified Delphi approach, and based on GRADE methodology, we endorse the following: We suggest that a positive diagnostic strategy as compared to a diagnostic strategy of exclusion be used to improve time to initiating appropriate therapy. We suggest that serologic testing be performed to rule out celiac disease in patients with IBS and diarrhea symptoms. We suggest that fecal calprotectin be checked in patients with suspected IBS and diarrhea symptoms to rule out inflammatory bowel disease. We recommend a limited trial of a low fermentable oligosaccharides, disacchardies, monosaccharides, polyols (FODMAP) diet in patients with IBS to improve global symptoms. We recommend the use of chloride channel activators and guanylate cyclase activators to treat global IBS with constipation symptoms. We recommend the use of rifaximin to treat global IBS with diarrhea symptoms. We suggest that gut-directed psychotherapy be used to treat global IBS symptoms. Additional statements and information regarding diagnostic strategies, specific drugs, doses, and duration of therapy can be found in the guideline.
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17
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Liu R, Staller K. Update on Eluxadoline for the Treatment of Irritable Bowel Syndrome with Diarrhea: Patient Selection and Perspectives. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:1391-1400. [PMID: 32308371 PMCID: PMC7153999 DOI: 10.2147/dddt.s216056] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Accepted: 02/09/2020] [Indexed: 12/15/2022]
Abstract
Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder characterized by chronic abdominal pain associated with changes in bowel habits. It is the most common GI problem seen by gastroenterologists. IBS is a heterogenous disorder encompassing a spectrum of underlying mechanisms and clinical presentations. The pathophysiology of diarrhea-predominant form of IBS (IBS-D) remains poorly understood, and current available therapeutic options for IBS-D are limited. Eluxadoline is a novel, locally acting mixed μ- and κ-opioid receptor agonist and δ-receptor antagonist approved by the Food and Drug Administration (FDA) for treatment of adults with IBS-D. Data from two phase III clinical trials showed that approximately 25–30% of the eluxadoline-treated patients achieved composite clinical response, defined by a reduction of abdominal pain and improvement in stool consistency. Patients who achieve composite response during the first month of therapy were significantly more likely to demonstrate sustained clinical response. The most common adverse events reported with eluxadoline use were constipation, nausea and abdominal pain. The risk of abuse, dependence, or withdrawal is low. Serious adverse events associated with eluxadoline include sphincter of Oddi spasm (SOS) and pancreatitis particularly in patients without a gallbladder. Development of pancreatitis is likely secondary to SOS, but it remains unclear why pancreatitis occurs so quickly after initial doses. This adverse event profile helps guide proper selection of IBS-D patients for eluxadoline use, with important contraindications including absence of a gallbladder, biliary duct obstruction or sphincter of Oddi dysfunction, alcoholism, history of pancreatitis, or structural diseases of the pancreas. With the recent clinical trials demonstrating its efficacy, eluxadoline provides an additional option to the few existing pharmacologic interventions available for IBS-D. In this review, we discuss the drug development, efficacy and safety of eluxadoline, as well as selection criteria for identifying appropriate candidates for this medication.
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Affiliation(s)
- Rebecca Liu
- Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Kyle Staller
- Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.,Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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18
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Black CJ, Burr NE, Camilleri M, Earnest DL, Quigley EM, Moayyedi P, Houghton LA, Ford AC. Efficacy of pharmacological therapies in patients with IBS with diarrhoea or mixed stool pattern: systematic review and network meta-analysis. Gut 2020; 69:74-82. [PMID: 30996042 DOI: 10.1136/gutjnl-2018-318160] [Citation(s) in RCA: 114] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Revised: 02/04/2019] [Accepted: 04/02/2019] [Indexed: 12/15/2022]
Abstract
OBJECTIVE Over half of patients with IBS have either diarrhoea (IBS-D) or a mixed stool pattern (IBS-M). The relative efficacy of licenced pharmacological therapies is unclear in the absence of head-to-head trials. We conducted a network meta-analysis to resolve this uncertainty. DESIGN We searched MEDLINE, Embase, Embase Classic, the Cochrane central register of controlled trials, and Clinicaltrials.gov through January 2019 to identify randomised controlled trials (RCTs) assessing the efficacy of licenced pharmacological therapies (alosetron, eluxadoline, ramosetron and rifaximin) in adults with IBS-D or IBS-M. Trials included in the analysis reported a dichotomous assessment of overall response to therapy, and data were pooled using a random effects model. Efficacy and safety of all pharmacological therapies were reported as a pooled relative risk with 95% CIs to summarise the effect of each comparison tested. Treatments were ranked according to their p score. RESULTS We identified 18 eligible RCTs (seven alosetron, five ramosetron, two rifaximin and four eluxadoline), containing 9844 patients. All were superior to placebo for the treatment of IBS-D or IBS-M at 12 weeks, according to the Food and Drug Administration (FDA)-recommended endpoint for trials in IBS. Alosetron 1 mg twice daily was ranked first for efficacy, based on the FDA-recommended composite endpoint of improvement in both abdominal pain and stool consistency, effect on global symptoms of IBS and effect on stool consistency. Ramosetron 2.5µg once daily was ranked first for effect on abdominal pain. Total numbers of adverse events were significantly greater with alosetron 1 mg twice daily and ramosetron 2.5µg once daily, compared with placebo. Rifaximin 550 mg three times daily ranked first for safety. Constipation was significantly more common with all drugs, except rifaximin 550 mg three times daily. CONCLUSION In a network meta-analysis of RCTs of pharmacological therapies for IBS-D and IBS-M, we found all drugs to be superior to placebo, but alosetron and ramosetron appeared to be the most effective.
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Affiliation(s)
- Christopher J Black
- Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, UK.,Leeds Gastroenterology Institute, St. James's University Hospital, Leeds, UK
| | - Nicholas E Burr
- Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, UK.,Leeds Gastroenterology Institute, St. James's University Hospital, Leeds, UK
| | | | - David L Earnest
- Division of Gastroenterology, The University of Arizona College of Medicine, Tucson, Arizona, USA
| | - Eamonn Mm Quigley
- Division of Gastroenterology and Hepatology, The Methodist Hospital, Weill Cornell Medical College, Houston, Texas, USA
| | - Paul Moayyedi
- Department of Gastroenterology, McMaster University, Hamilton, Ontario, Canada
| | - Lesley A Houghton
- Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, UK
| | - Alexander C Ford
- Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, UK.,Leeds Gastroenterology Institute, St. James's University Hospital, Leeds, UK
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19
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Current US Food and Drug Administration-Approved Pharmacologic Therapies for the Treatment of Irritable Bowel Syndrome with Diarrhea. Adv Ther 2020; 37:83-96. [PMID: 31707713 DOI: 10.1007/s12325-019-01116-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Indexed: 02/07/2023]
Abstract
Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by abdominal pain and alterations in stool form and/or frequency, leading to reduced quality of life. Pharmacologic agents currently approved by the US Food and Drug Administration for treatment of IBS with diarrhea (IBS-D) in adults are the nonsystemic antibiotic rifaximin, the mixed µ- and κ-opioid receptor agonist/δ-opioid antagonist eluxadoline, and the selective serotonin 5-HT3 antagonist alosetron (the last of which is indicated only in women with severe IBS-D refractory to conventional therapy). Both eluxadoline and alosetron are administered as chronic daily therapies; rifaximin is given as a 2-week course of treatment with repeat courses administered as needed for symptom recurrence. Presumed mechanisms of action of rifaximin include modulation of the gut microbiota, anti-inflammatory activity, normalization of visceral hypersensitivity, and reduction in intestinal permeability. Eluxadoline targets opioid receptors in the gastrointestinal (GI) tract, resulting in decreased GI motility, fluid secretion, and visceral pain perception. Alosetron antagonizes serotonergic afferent neural signals and also slows GI motility. The efficacy and safety of these agents have been investigated in several rigorous clinical trials, and it has been demonstrated that they improve global and individual IBS symptoms. This review highlights the pivotal efficacy and safety data of the three pharmacologic agents currently indicated in the USA for the management of IBS-D in adults.Funding: Salix Pharmaceuticals.
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20
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Cangemi DJ, Lacy BE. Management of irritable bowel syndrome with diarrhea: a review of nonpharmacological and pharmacological interventions. Therap Adv Gastroenterol 2019; 12:1756284819878950. [PMID: 31632456 PMCID: PMC6778998 DOI: 10.1177/1756284819878950] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Accepted: 08/26/2019] [Indexed: 02/04/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a common gastrointestinal (GI) condition involving numerous potential causative factors (e.g. alterations in gut microbiota, motility, brain-gut axis). Several interventions are available for the management of patients with IBS, but no universal management algorithm currently exists. The aim of this article is to review interventions that may be considered in the management of patients with IBS with diarrhea (IBS-D). Nonpharmacological interventions include dietary and lifestyle modification, which are generally used as first-line therapy. Probiotics have demonstrated efficacy and safety in patients with IBS, but studies are inconsistent in strains examined, dosing, and treatment duration. Psychological therapies (e.g. cognitive behavioral therapy, hypnotherapy) also may improve IBS symptoms. Pharmacological interventions for the management of IBS-D include the US Food and Drug Administration-approved agents eluxadoline, rifaximin, and alosetron, as well as loperamide, smooth muscle antispasmodics, bile acid sequestrants, and antidepressants (i.e. tricyclic antidepressants, selective serotonin reuptake inhibitors). Eluxadoline and rifaximin have been shown to improve abdominal pain and stool consistency in patients with IBS-D. In addition, data indicate that alosetron improves IBS symptoms; however, it is approved only for women with severe IBS-D. Of the three approved agents, rifaximin has the most favorable safety profile. The risk-benefit ratio is an important consideration with every medication, but is especially important in the treatment of functional GI disorders such as IBS-D. Thus, the most troublesome symptoms, quality of life, symptom intensity, and individual patient preferences should be considered when formulating a management plan for patients with IBS-D.
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Affiliation(s)
- David J. Cangemi
- Division of Gastroenterology and Hepatology, Section of Gastroenterology, Mayo Clinic, Jacksonville, FL, USA
| | - Brian E. Lacy
- Division of Gastroenterology and Hepatology, Section of Gastroenterology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA
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Olden KW, Chey WD, Shringarpure R, Paul Nicandro J, Chuang E, Earnest DL. Alosetron versus traditional pharmacotherapy in clinical practice: effects on resource use, health-related quality of life, safety and symptom improvement in women with severe diarrhea-predominant irritable bowel syndrome. Curr Med Res Opin 2019; 35:461-472. [PMID: 30293448 DOI: 10.1080/03007995.2018.1533456] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVE Severe diarrhea-predominant irritable bowel syndrome (IBS-D) is associated with decreased health-related quality of life (HRQOL) and increased health care costs. Treatment recommendations for IBS-D often start with traditional pharmacotherapy (TP), with escalation to alosetron, rifaximin or eluxadoline if there is no success. There has been no previous head-to-head clinical trial comparing IBS-D treatment outcome for alosetron versus TP. This study, GSK protocol S3B30020, evaluated resource use, work productivity, health-related quality of life and global symptom response in women with IBS-D who were treated with alosetron or TP. METHODS A total of 1956 patients who met criteria for severe IBS-D were randomized to treatment with alosetron 1 mg twice daily (BID) or only TP for up to 24 weeks. Work productivity and resource use were evaluated by standard questionnaires, HRQOL by the IBSQOL instrument and IBS symptoms by the Global Improvement Scale (GIS). RESULTS Compared to only TP, alosetron-treated patients reported: (1) fewer clinic/office visits for any health problem (p = .0181) or for IBS-D (p = .0004); (2) reduced use of over-the-counter medications for IBS-D (p < .0001); (3) fewer days of lost work productivity (p < .0001); (4) decreased restriction of social and outdoor activities (p < .0001); and (5) greater global improvement in IBS-D symptoms (p < .0001). Alosetron treatment improved HRQOL scores for all domains (p < .0001). Incidence of adverse events during alosetron use was not remarkable and was similar to that previously reported. CONCLUSIONS Alosetron 1 mg BID significantly reduced health care utilization and lost productivity, and significantly improved global IBS symptoms, HRQOL, and participation in outdoor and social activities compared with treatment response to TP.
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Affiliation(s)
- Kevin W Olden
- a Department of Medicine , St Joseph's Hospital and Medical Center , Phoenix , AZ , USA
| | - William D Chey
- b Division of Gastroenterology , University of Michigan Health System , Ann Arbor , MI , USA
| | | | | | - Emil Chuang
- c Prometheus Laboratories Inc. , San Diego , CA , USA
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Lacy BE. Review article: an analysis of safety profiles of treatments for diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther 2018; 48:817-830. [PMID: 30194692 PMCID: PMC6667996 DOI: 10.1111/apt.14948] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 04/27/2018] [Accepted: 07/28/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is multifactorial in nature, and a wide range of therapies is available to manage symptoms of this common disorder. AIM To provide an overview of the safety of interventions that may be used to manage patients with diarrhoea-predominant IBS (IBS-D). METHODS Medline and Embase database searches (through 02 May 2018) to identify clinical studies that evaluated treatment safety and/or efficacy in adults with IBS-D. RESULTS IBS-D treatments include dietary modification, probiotics, serotonin receptor antagonists, opioid receptor agonists and antagonists, nonsystemic antibiotics, bile acid sequestrants, antidepressants, and complementary and alternative therapies. These treatments vary in administration frequency (eg, daily; short-course therapy) and target various pathophysiologic factors. Safety profiles vary considerably by treatment among IBS-D therapies. The number needed to harm (defined as the number of patients treated to encounter an adverse event) was lowest (worse) for antidepressants (8.5) and highest (best) for probiotics (35), and the number needed to harm (defined as the number of patients who discontinued due to an adverse event) was lowest for tricyclic antidepressants (9) and highest for rifaximin (8971). Notable safety concerns with IBS-D treatments include pancreatitis with eluxadoline, ischaemic colitis and serious complications of constipation with alosetron, and cardiac adverse events with loperamide and tricyclic antidepressants. Treatment decisions need to account for medication risks and adverse events for each patient. CONCLUSIONS Multiple treatment options are now available for patients with IBS-D. However, the safety profiles of these agents vary widely by number needed to harm value. Providers should consider both safety and efficacy of a specific intervention when determining how best to manage patients' IBS-D symptoms.
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Affiliation(s)
- Brian E. Lacy
- Section of GastroenterologyMayo ClinicJacksonvilleFlorida
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23
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Chang C. Short-course therapy for diarrhea-predominant irritable bowel syndrome: understanding the mechanism, impact on gut microbiota, and safety and tolerability of rifaximin. Clin Exp Gastroenterol 2018; 11:335-345. [PMID: 30288076 PMCID: PMC6160288 DOI: 10.2147/ceg.s167031] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Irritable bowel syndrome (IBS) is a common gastrointestinal (GI) disorder characterized by abdominal pain that occurs with defecation or alterations in bowel habits. Further classification is based on the predominant bowel habit: constipation-predominant IBS, diarrhea-predominant IBS (IBS-D), or mixed IBS. The pathogenesis of IBS is unclear and is considered multifactorial in nature. GI dysbiosis, thought to play a role in IBS pathophysiology, has been observed in patients with IBS. Alterations in the gut microbiota are observed in patients with small intestinal bacterial overgrowth, and overgrowth may occur in a subset of patients with IBS. The management of IBS includes therapies targeting the putative factors involved in the pathogenesis of the condition. However, many of these interventions (eg, eluxadoline and alosetron) require long-term, daily administration and have important safety considerations. Agents thought to modulate the gut microbiota (eg, antibiotics and probiotics) have shown potential benefits in clinical studies. However, conventional antibiotics (eg, neomycin) are associated with several adverse events and/or the risk of bacterial antibiotic resistance, and probiotics lack uniformity in composition and consistency of response in patients. Rifaximin, a nonsystemic antibiotic administered as a 2-week course of therapy, has been shown to be safe and efficacious for the treatment of IBS-D. Rifaximin exhibits a favorable benefit-to-harm ratio when compared with daily therapies for IBS-D (eg, alosetron and tricyclic antidepressants), and rifaximin was not associated with the emergence of bacterial antibiotic resistance. Thus, short-course therapy with rifaximin is an appropriate treatment option for IBS-D.
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Affiliation(s)
- Christopher Chang
- New Mexico VA Health Care System, Division of Gastroenterology and Hepatology, Albuquerque, NM, USA,
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA,
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24
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Ford AC, Moayyedi P, Chey WD, Harris LA, Lacy BE, Saito YA, Quigley EMM. American College of Gastroenterology Monograph on Management of Irritable Bowel Syndrome. Am J Gastroenterol 2018; 113:1-18. [PMID: 29950604 DOI: 10.1038/s41395-018-0084-x] [Citation(s) in RCA: 232] [Impact Index Per Article: 33.1] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Alexander C Ford
- Leeds Institute of Biomedical and Clinical Sciences, University of Leeds and Leeds Gastroenterology Institute, Leeds Teaching Hospitals Trust, Leeds, UK
| | - Paul Moayyedi
- Division of Gastroenterology, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - William D Chey
- Division of Gastroenterology, Department of Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA
| | | | | | | | - Eamonn M M Quigley
- Division of Gastroenterology and Hepatology, Houston Methodist Hospital and Weill Cornell Medical College, Houston, TX, USA.
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Acupuncture for Diarrhoea-Predominant Irritable Bowel Syndrome: A Network Meta-Analysis. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2018; 2018:2890465. [PMID: 29977312 PMCID: PMC5994265 DOI: 10.1155/2018/2890465] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/24/2018] [Accepted: 04/30/2018] [Indexed: 12/15/2022]
Abstract
Background The objective of this study was to compare the efficacy and side effects of acupuncture, sham acupuncture, and drugs in the treatment of diarrhoea-predominant irritable bowel syndrome. Methods Randomized controlled trials (RCTs) assessing the effects of acupuncture and drugs were comprehensively retrieved from electronic databases (such as PubMed, Cochrane Library, Embase, CNKI, Wanfang Database, VIP Database, and CBM) up to December 2017. Additional references were obtained from review articles. With document quality evaluations and data extraction, Network Meta-Analysis was performed using a random-effects model under a frequentist framework. Results A total of 29 studies (n = 9369) were included; 19 were high-quality studies, and 10 were low-quality studies. NMA showed the following: (1) the ranking of treatments in terms of efficacy in diarrhoea-predominant irritable bowel syndrome is acupuncture, sham acupuncture, pinaverium bromide, alosetron = eluxadoline, ramosetron, and rifaximin; (2) the ranking of treatments in terms of severity of side effects in diarrhoea-predominant irritable bowel syndrome is rifaximin, alosetron, ramosetron = pinaverium bromide, sham acupuncture, and acupuncture; and (3) the treatment of diarrhoea-predominant irritable bowel syndrome includes common acupoints such as ST25, ST36, ST37, SP6, GV20, and EX-HN3. Conclusion Acupuncture may improve diarrhoea-predominant irritable bowel syndrome better than drugs and has the fewest side effects. Sham acupuncture may have curative effect except for placebo effect. In the future, it is necessary to perform highly qualified research to prove this result. Pinaverium bromide also has good curative effects with fewer side effects than other drugs.
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Lacy BE, Nicandro JP, Chuang E, Earnest DL. Alosetron use in clinical practice: significant improvement in irritable bowel syndrome symptoms evaluated using the US Food and Drug Administration composite endpoint. Therap Adv Gastroenterol 2018; 11:1756284818771674. [PMID: 29774051 PMCID: PMC5949923 DOI: 10.1177/1756284818771674] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Accepted: 03/21/2018] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Alosetron is approved to treat women with severe IBS and diarrhea (IBS-D) who have failed standard therapy. In our study, we aimed to evaluate alosetron efficacy using new US Food and Drug Administration (FDA) endpoints and utilization in clinical practice. METHODS This prospective, open-label, multicenter, observational 12-week study evaluated women with severe IBS-D enrolled in the alosetron prescribing program. The coprimary FDA endpoints were changes from baseline in stool consistency and abdominal pain severity. Responders achieved a 30% decrease compared with baseline in weekly average of the worst abdominal pain in the past 24 h, and a 50% or greater reduction from baseline in the number of days/week with at least one stool of type 6 (mushy) or type 7 (watery) consistency. Secondary endpoints included changes from baseline in stool frequency, fecal urgency and fecal incontinence. RESULTS Enrolled patients (n = 192) were primarily White (90.6%), with a mean age of 44.5 years. Patient and physician rating of IBS severity was between moderate and severe (85.9% concordance, Spearman coefficient 0.429, p < 0.0001). Alosetron 0.5 mg twice daily (82.8%) was the most common dosing regimen. A total of 152 alosetron-treated patients completed the study. Of 105 fully evaluable patients, 45% met the FDA composite endpoint responder criteria for ⩾50% of the study period. Improvements in all individual symptoms were statistically significant compared with baseline. There were no serious adverse events, cases of colonic ischemia, or complications of constipation. CONCLUSION In a clinical practice setting study, alosetron demonstrated treatment success using a rigorous FDA composite endpoint and also improved multiple other IBS symptoms, including fecal urgency and incontinence in women with severe IBS-D [ClinicalTrials.gov identifier: NCT01257477].
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Affiliation(s)
| | - Jean Paul Nicandro
- Clinical Development and Medical Affairs, Prometheus Laboratories Inc., San Diego, CA, USA
| | - Emil Chuang
- Clinical Development and Medical Affairs, Prometheus Laboratories Inc., San Diego, CA, USA
| | - David L. Earnest
- Clinical Development and Medical Affairs, Prometheus Laboratories Inc., San Diego, CA, USA
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Abstract
PURPOSE OF REVIEW Post-infectious irritable bowel syndrome (PI-IBS) is characterized by persistent abdominal pain and diarrhea, typically following an episode of infectious gastroenteritis. The mechanisms that underlie IBS-D remain elusive, but PI-IBS provides a mechanistic model of this disorder. This review provides an up-to-date appraisal of the pathophysiology, clinical features, and management approaches for PI-IBS. RECENT FINDINGS Disordered immune reactions and release of cytokines with resultant gut inflammation and dysfunction appear to be key features of PI-IBS. Disordered brain-gut-microbiota interactions, type of infecting agent, and host-genetic susceptibility are risk factors but also are reasons for the varying spectrum of clinical severity. Although prognosis is generally good, symptoms and inflammation may persist for a long time. Symptomatic relief with antidiarrheals, antispasmodics, 5HT3 antagonists, mesalamine, probiotics, and low-dose antidepressants remain the primary approaches, but in some difficult cases, a combination of drugs that target the pathophysiology may be helpful. PI-IBS has many overlapping features with IBS-D and shares similar pathophysiology and management approaches.
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Affiliation(s)
- Yeong Yeh Lee
- School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
| | | | - Satish S C Rao
- Section of Gastroenterology/Hepatology, Department of Internal Medicine, Medical College of Georgia, AD 2226, Digestive Health Center, Augusta University, 1481 Laney-Walker Blvd, Augusta, GA, 30912, USA.
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Levio S, Cash BD. The place of eluxadoline in the management of irritable bowel syndrome with diarrhea. Therap Adv Gastroenterol 2017; 10:715-725. [PMID: 28932272 PMCID: PMC5598810 DOI: 10.1177/1756283x17721152] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2017] [Accepted: 06/27/2017] [Indexed: 02/04/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder characterized by abdominal pain associated with defecation with altered stool frequency or stool form. The global prevalence of IBS ranges from 10% to 15% and total healthcare cost attributable to IBS is significant. Among individuals with IBS, the condition has dramatic effects on health-related quality of life, work and school productivity, and activities of daily living. It may be diagnosed with confidence, based on symptom-based diagnostic criteria, exclusion of alarm features and directed diagnostic testing. Management of IBS typically begins with dietary and lifestyle modifications, progressing to over-the-counter therapies, and then to prescription medications, both approved and nonapproved for IBS. This narrative summarizes the efficacy and safety of three US Food and Drug Administration (FDA)-approved prescription therapies for IBS with diarrhea (IBS-D), with a focus on the most recently marketed agent, eluxadoline, and its role in the treatment IBS-D.
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Affiliation(s)
- Sherry Levio
- Division of Gastroenterology, University of South Alabama, Mobile, AL, USA
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Zheng Y, Yu T, Tang Y, Xiong W, Shen X, Jiang L, Lin L. Efficacy and safety of 5-hydroxytryptamine 3 receptor antagonists in irritable bowel syndrome: A systematic review and meta-analysis of randomized controlled trials. PLoS One 2017; 12:e0172846. [PMID: 28291778 PMCID: PMC5349445 DOI: 10.1371/journal.pone.0172846] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Accepted: 02/10/2017] [Indexed: 02/06/2023] Open
Abstract
AIM We assessed the efficacy and safety of 5-hydroxytryptamine (5-HT3) receptor antagonists in adults with non-constipated irritable bowel syndrome (IBS) or diarrhea-predominant IBS (IBS-D). METHODS We searched PubMed, MEDLINE, EMBASE, and the Cochrane Controlled Trials Register for randomized controlled trials (RCTs) involving adults with non-constipated IBS or IBS-D that compared 5-HT3 receptor antagonists with placebo or other conventional treatment. Dichotomous symptom data were pooled to obtain the relative risk (RR) and 95% confidence intervals (CIs) for improving global IBS symptoms, abdominal pain and abnormal bowel habits, or stool consistency symptoms after therapy, and adverse events, including constipation. Meta- analysis was performed with Mantel Haenszel method using Revman 5.3 software. RESULTS We included 21 RCTs; 16 were high quality (Jadad score ≥ 4). The pooled RR of global IBS symptoms improved by 5-HT3 receptor antagonists versus placebo or mebeverine was 1.56 (95% CI: 1.43-1.71); alosetron, ramosetron, and cilansetron had similar treatment effects. The pooled RR of abdominal pain relieved by 5-HT3 receptor antagonists versus placebo was 1.33 (95% CI: 1.26-1.39). The pooled RR showed that 5-HT3 receptor antagonists improved abnormal bowel habits or stool consistency symptoms (RR = 1.63, 95% CI: 1.33, 1.99). The pooled RR of adverse events following 5-HT3 receptor antagonist treatment was 1.15 (95% CI: 1.08, 1.22). Subgroup analysis indicated that alosetron had a high rate of adverse effects (RR = 1.16, 95% CI: 1.08, 1.25); adverse events following ramosetron treatment were not statistically significantly different. 5-HT3 receptor antagonists were likelier to cause constipation: the pooled RR of constipation developing with 5-HT3 receptor antagonist versus placebo was 3.71 (95% CI: 2.98-4.61). However, constipation was likelier in patients with non-constipated IBS after taking 5-HT3 receptor antagonists than in patients with IBS-D only (non-constipated IBS and IBS-D: RR = 5.28 [95% CI: 3.93, 7.08] vs. IBS-D only 3.24 [2.54, 4.12]). CONCLUSIONS Ramosetron, cilansetron, ondansetron, and alosetron are effective for treating non-constipated IBS and IBS-D. Our systematic review found rare serious adverse events.
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Affiliation(s)
- Yongping Zheng
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Ting Yu
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Yurong Tang
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Wenjie Xiong
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Xiaoxue Shen
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Ling Jiang
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Lin Lin
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
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Lucak S, Chang L, Halpert A, Harris LA. Current and emergent pharmacologic treatments for irritable bowel syndrome with diarrhea: evidence-based treatment in practice. Therap Adv Gastroenterol 2017; 10:253-275. [PMID: 28203283 PMCID: PMC5298476 DOI: 10.1177/1756283x16663396] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Irritable bowel syndrome with diarrhea (IBS-D) is a common, chronic functional gastrointestinal disorder with symptoms that can be distressing for patients and often result in substantially impaired quality of life. This review focuses on providing clinicians with information on practical, evidence-based treatment for IBS-D. Current therapies commonly used for the treatment of IBS-D, including pharmacologic and nonpharmacologic interventions, are briefly reviewed, followed by discussion of the emergent pharmacologic treatments (rifaximin and eluxadoline) and medical foods (IBgard® and EnteraGam®). Given the lack of a standard treatment algorithm for IBS-D and the emergence of new pharmacologic therapies, treatment needs to be tailored to the individual patient and take into account the severity of disease. In this context, the latter part of this manuscript examines how treatments for IBS-D can be used in clinical practice by presenting three patient case scenarios with varying degrees of IBS-D severity. For each case, the patient's medical history and clinical presentation are related to the Rome Foundation multidimensional clinical profile (MDCP) and potential treatment options with current and emergent therapies are reviewed. The interplay of gastrointestinal symptoms and their psychosocial impact, as well as the importance of a patient-centered approach to therapy, are discussed. Consideration is given to the potential need for combination therapies and how emergent treatments could fit into the treatment pathway for mild, moderate, and severe cases of IBS-D in clinical practice.
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Affiliation(s)
- Susan Lucak
- Division of Digestive and Liver Diseases, Department of Medicine, Weill Cornell Medicine, 903 Park Avenue, First Floor, New York, NY 10075, USA
| | - Lin Chang
- Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Albena Halpert
- Section of Gastroenterology & Hepatology, Boston Medical Center, Boston, MA, USA
| | - Lucinda A. Harris
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo College of Medicine, Scottsdale, AZ, USA
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Simrén M, Törnblom H, Palsson OS, Whitehead WE. Management of the multiple symptoms of irritable bowel syndrome. Lancet Gastroenterol Hepatol 2017; 2:112-122. [PMID: 28403981 DOI: 10.1016/s2468-1253(16)30116-9] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Revised: 08/19/2016] [Accepted: 08/22/2016] [Indexed: 12/14/2022]
Abstract
Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders. A stepwise management approach is advocated for patients with IBS. For a substantial proportion of patients with mild symptoms, general management principles, including making a confident diagnosis and offering explanation, reassurance, and dietary and lifestyle advice, are sufficient. However, many patients continue to have moderate-to-severe symptoms and are not satisfied solely with this approach. In these patients, use of pharmacotherapy on the basis of the predominant symptom (constipation, diarrhoea, pain, or bloating) or combination of symptoms is the next step. For patients with symptoms that are refractory to these initial treatment options and those who have comorbid conditions or psychological symptoms, a combination of therapies should be used, and the use of psychotropic drugs and psychological treatment alternatives is often effective. Finally, the key to successful treatment of patients with IBS is a good physician-patient relationship and use of person-centred care principles.
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Affiliation(s)
- Magnus Simrén
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Center for Functional Gastrointestinal and Motility Disorders, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
| | - Hans Törnblom
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Olafur S Palsson
- Center for Functional Gastrointestinal and Motility Disorders, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - William E Whitehead
- Center for Functional Gastrointestinal and Motility Disorders, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Whitehead WE, Duffy K, Sharpe J, Nabata T, Bruce M. Randomised clinical trial: exploratory phase 2 study of ONO-2952 in diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther 2017; 45:14-26. [PMID: 27910150 PMCID: PMC5157770 DOI: 10.1111/apt.13839] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Revised: 07/17/2016] [Accepted: 10/04/2016] [Indexed: 12/15/2022]
Abstract
BACKGROUND ONO-2952 is a novel and selective inhibitor of translocator protein 18 kDa that reduces stress-induced defecation and visceral hyperalgesia in rat models. AIM To evaluate the efficacy and safety of ONO-2952 in females with irritable bowel syndrome with diarrhoea in an exploratory proof-of-concept study. METHODS A randomised, double-blind, placebo-controlled study was conducted at 49 US centres. Two hundred subjects with irritable bowel syndrome with diarrhoea (Rome III criteria) were randomised to ONO-2952 20 mg, or 60 mg, or placebo. Subjects recorded irritable bowel syndrome symptoms daily during a 2-week baseline period, the 4-week treatment period and for 4 weeks post-treatment. The co-primary endpoints were change from baseline to week 4 in abdominal pain, stool consistency and stool frequency. RESULTS Improvements in irritable bowel syndrome symptoms were seen with ONO-2952 over placebo in per-protocol analyses for all three co-primary endpoints, but these did not reach statistical significance at the 5% level. The largest improvement was seen with ONO-2952 60 mg. ONO-2952 was well tolerated with a safety profile similar to that of placebo. Most adverse events were mild or moderate in severity and not treatment related. CONCLUSION ONO-2952 showed evidence of clinical efficacy in reducing irritable bowel syndrome-related symptoms in female subjects with irritable bowel syndrome with diarrhoea, and further evaluation is, therefore, warranted to assess its potential as a treatment for irritable bowel syndrome with diarrhoea (NCT01844180).
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Affiliation(s)
- W. E. Whitehead
- Division of Gastroenterology and HepatologyDepartment of MedicineUniversity of North Carolina at Chapel HillChapel HillNCUSA
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Abstract
Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders worldwide. The economic impact of IBS on the health care system is substantial, as is the personal impact on patients. Patients with diarrhea-predominant IBS (IBS-D) comprise a substantial proportion of the overall IBS population. Primary care providers are often the first point of contact for patients with IBS-D and can accurately diagnose IBS after a careful history and examination without extensive diagnostic tests. Several pharmacologic treatments (eg, loperamide, alosetron, and antidepressants) and non-pharmacologic treatments (eg, dietary modification and probiotics) are available for IBS-D, but restrictions on use (eg, alosetron) or the lack of controlled trial data showing reductions in both global and individual IBS-D symptoms (eg, bloating, pain and stool frequency) emphasize the need for alternative treatment options. Two newer medications (eluxadoline and rifaximin) were approved in May 2015 for the treatment of IBS-D, and represent new treatment options for this common gastrointestinal condition.
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Affiliation(s)
- Brian E Lacy
- Division of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA
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34
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Abstract
Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders worldwide. The economic impact of IBS on the health care system is substantial, as is the personal impact on patients. Patients with diarrhea-predominant IBS (IBS-D) comprise a substantial proportion of the overall IBS population. Primary care providers are often the first point of contact for patients with IBS-D and can accurately diagnose IBS after a careful history and examination without extensive diagnostic tests. Several pharmacologic treatments (eg, loperamide, alosetron, and antidepressants) and non-pharmacologic treatments (eg, dietary modification and probiotics) are available for IBS-D, but restrictions on use (eg, alosetron) or the lack of controlled trial data showing reductions in both global and individual IBS-D symptoms (eg, bloating, pain and stool frequency) emphasize the need for alternative treatment options. Two newer medications (eluxadoline and rifaximin) were approved in May 2015 for the treatment of IBS-D, and represent new treatment options for this common gastrointestinal condition.
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Affiliation(s)
- Brian E Lacy
- Division of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA
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Cash BD, Lacy BE, Rao T, Earnest DL. Rifaximin and eluxadoline - newly approved treatments for diarrhea-predominant irritable bowel syndrome: what is their role in clinical practice alongside alosetron? Expert Opin Pharmacother 2015; 17:311-22. [PMID: 26559529 DOI: 10.1517/14656566.2016.1118052] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Diarrhea-predominant irritable bowel syndrome (IBS-D) is a common functional gastrointestinal condition in which patients experience abdominal pain, diarrhea, bloating, cramps, flatulence, fecal urgency, and incontinence. AREAS COVERED We review two recently approved therapies that focus on treating underlying pathogenic mechanisms of IBS-D: (1) the non-absorbable antibiotic rifaximin, and (2) the opioid receptor agonist/antagonist eluxadoline. We compare the safety and efficacy data emerging from rifaximin and eluxadoline registration trials with safety and efficacy data from the alosetron clinical development program. EXPERT OPINION The rifaximin and eluxadoline clinical development programs for IBS-D have demonstrated significant improvement in IBS-D endpoints compared to placebo. Direct comparison of primary endpoint results from the alosetron, rifaximin, and eluxadoline pivotal trials is not possible; however, general estimates of efficacy can be made, and these demonstrate similar and significantly greater responses to 'adequate relief' and a composite endpoint of abdominal pain/stool form for each agent compared to placebo. With the recent approval in the United States of rifaximin and eluxadoline for IBS-D, how should clinicians employ these agents? We suggest that they be utilized sequentially, taking into consideration patient symptoms and severity, prior medical history, mode of action, cost, availability, managed care coverage, and adverse event profiles.
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Affiliation(s)
- Brooks D Cash
- a Gastroenterology Division , University of South Alabama , Mobile , AL , USA
| | - Brian E Lacy
- b Division of Gastroenterology & Hepatology , Dartmouth-Hitchcock Medical Center , Lebanon , NH , USA
| | - Tharaknath Rao
- c Clinical Development & Medical Affairs , Prometheus Laboratories Inc ., San Diego , CA , USA
| | - David L Earnest
- c Clinical Development & Medical Affairs , Prometheus Laboratories Inc ., San Diego , CA , USA
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Abstract
OPINION STATEMENT Irritable bowel syndrome (IBS) is a common gastrointestinal disease characterized by abdominal pain and change in bowel habits. IBS diarrhea predominant (IBS-D), which is arguably the most common subset of IBS, is also associated with rectal urgency, increased frequency, abdominal bloating, and loose to watery stools. Current treatments for diarrhea include mu-opioid agonists (i.e., loperamide, lomotil) and bile acid sequestrants (i.e., cholestyramine) while treatments for abdominal pain include antispasmodics (i.e., hyoscyamine, dicyclomine) and tricyclic antidepressants (i.e., amitriptyline). There are currently 3 FDA-approved treatments for IBS-D, which have been shown to improve both abdominal pain and diarrhea. Alosetron was initially approved by FDA 2000; however, its use is now limited to women with severe IBS-D symptoms refractory to other treatment. Eluxadoline, a mixed mu-opioid agonist, and rifaximin, a broad spectrum gut specific antibiotic, were both FDA approved in 2015. Eluxadoline has been shown to relieve abdominal pain and stool consistency in appropriate candidates. While large trials already showed the efficacy of rifaximin in treating non-constipated IBS for bloating, stool consistency, and abdominal pain, the recent TARGET 3 trial demonstrates that retreatment is also effective. While these new treatments significantly expand options for patients suffering from IBS-D, there is likely to remain a need for additional safe and effective therapies.
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A comprehensive review of randomized placebo-controlled pharmacological clinical trials in children with functional abdominal pain disorders. J Pediatr Gastroenterol Nutr 2015; 60:645-53. [PMID: 25906454 DOI: 10.1097/mpg.0000000000000718] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVES Abdominal pain-predominant functional gastrointestinal disorders (AP-FGIDs) are the most common cause of consultation to pediatric gastroenterology; however, no medications have been approved to treat this group of disorders in children. The Food and Drug Administration have published recommendations for clinical trials on AP-FGIDs in adults but not in children. The lack of methodological guidelines and accepted primary endpoints for clinical trials in children hampers the progress of the field, making the approval of new medications difficult. A necessary first step to determine the feasibility of clinical trials in children and provide recommendations on the best design for future trials is to review the methods, ability to recruit, attrition rate, and results of previous clinical trials. We designed a comprehensive review of pharmacological clinical trials in AP-FGIDs in children focused on study design. METHODS Study eligibility was randomized controlled trials (RCTs) evaluating the efficacy of pharmacological interventions compared with that of placebo in children and adolescents with AP-FGIDs. RESULTS There is no evidence to support the use of most commonly used drugs in children. Only 7 pharmacological RCTs on AP-FGIDs in children were found. Most studies were single center based and had a small sample size. The methods and outcomes were heterogeneous. Primary endpoints varied widely among studies. Many of the RCTs did not show a consistently significant benefit of the drug over placebo in some or all of the outcomes. We found a considerable risk of bias in most studies. None of the studies have considered minimal clinically important differences in their selection of primary endpoints. CONCLUSIONS Few randomized clinical trials have been conducted. Most studies have methodological limitations and small sample size. There is an urgent need for well-designed randomized clinical trials using age-appropriate validated outcome measures.
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Choi CH, Kwon JG, Kim SK, Myung SJ, Park KS, Sohn CI, Rhee PL, Lee KJ, Lee OY, Jung HK, Jee SR, Jeen YT, Choi MG, Choi SC, Huh KC, Park H. Efficacy of combination therapy with probiotics and mosapride in patients with IBS without diarrhea: a randomized, double-blind, placebo-controlled, multicenter, phase II trial. Neurogastroenterol Motil 2015; 27:705-16. [PMID: 25809913 DOI: 10.1111/nmo.12544] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Accepted: 02/17/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Probiotics can be beneficial in irritable bowel syndrome (IBS). Mosapride citrate, a selective 5-HT4 receptor agonist, stimulates gastrointestinal motility. We investigated the efficacy of combination therapy with probiotics and mosapride for non-diarrheal-type IBS. METHODS Two hundred and eighty-five IBS patients were randomly assigned to either a combination of probiotics (Bacillus subtilis and Streptococcus faecium) and mosapride at one of four different doses or a placebo for 4 weeks. The primary outcome was the proportion of patients experiencing adequate relief (AR) of global IBS symptoms at week 4. The secondary outcomes included subject's global assessment (SGA) of IBS symptom relief, individual symptoms, stool parameters, and IBS-quality of life. KEY RESULTS The proportion of AR at week 4 was significantly higher in all treatment groups compared to the placebo group (53.7% in group 1, 55.0% in group 2, 55.2% in group 3, 53.6% in group 4 [the highest dose], and 35.1% in placebo group, respectively, p < 0.05). The proportion of patients reporting 'completely or considerably relieved' in the SGA was higher in the treatment groups than in the placebo group. The abdominal pain/discomfort score in the treatment group 4 was more prominently improved compared with that of the placebo group. In patients with constipation-predominant IBS, the improvements in stool frequency and consistency were significantly higher in the treatment groups 4 and 1, respectively, than those in the placebo group. CONCLUSIONS & INFERENCES Combination therapy with probiotics and mosapride is effective for relief of symptoms in patients with non-diarrheal-type IBS. The study has been registered in the US National Library of Medicine (http://www.clinicaltrials.gov, NCT01505777).
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Affiliation(s)
- C H Choi
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
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Good L, Rosario R, Panas R. New therapeutic option for irritable bowel syndrome: Serum-derived bovine immunoglobulin. World J Gastroenterol 2015; 21:3361-3366. [PMID: 25805945 PMCID: PMC4363768 DOI: 10.3748/wjg.v21.i11.3361] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Revised: 10/17/2014] [Accepted: 12/16/2014] [Indexed: 02/06/2023] Open
Abstract
Oral prescription medical foods have long been used in hospital settings but are also appropriate therapies for gastrointestinal disorders in outpatient medical practice. Oral serum-derived bovine immunoglobulin/protein isolate (SBI) has been shown in clinical studies to reduce loose stools and improve stool consistency as well as other symptoms (i.e., abdominal pain, bloating, and urgency) in patients with irritable bowel syndrome with diarrhea (IBS-D) and human immunodeficiency virus-associated enteropathy. This case series reports the outcomes of 14 IBS patients who received SBI as an addition to standard of care at an individual physician’s clinical practice. The patients: 2 IBS with constipation (IBS-C), 7 IBS-D, 2 mixed diarrhea and constipation IBS (IBS-M) and 3 undefined IBS (IBS-U; also described by some physicians as IBS-Bloating), ranged in age from 22-87 years. SBI (5 g or 10 g daily dose) was added to the patient’s current standard care and followed for several weeks to determine if symptoms were improved with the addition of SBI. Overall, 12 of the 14 patients indicated some level of improvement through direct questioning of the patients regarding changes from the prior visit. One IBS-Bloating patient had a resolution of symptoms and two patients (1 IBS-Bloating and 1 IBS-C) discontinued therapy because of insufficient relief. The 12 patients who continued on therapy reported an overall improvement in symptoms with better stool consistency, decreased frequency as well as reductions in abdominal pain, bloating, distention, and incontinence. In most cases, therapeutic effects of SBI were seen within the first four weeks of therapy with continued improvements at subsequent visits. SBI has a multifaceted mechanism of action and may help to manage IBS by providing a distinct protein source required to normalize bowel function, gastrointestinal microbiota, and nutritionally enhance tight junction protein expression between intestinal epithelial cells. SBI as a medical food provides a safe option for patients with IBS-D but may have application in other forms of IBS.
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Fukudo S, Kaneko H, Akiho H, Inamori M, Endo Y, Okumura T, Kanazawa M, Kamiya T, Sato K, Chiba T, Furuta K, Yamato S, Arakawa T, Fujiyama Y, Azuma T, Fujimoto K, Mine T, Miura S, Kinoshita Y, Sugano K, Shimosegawa T. Evidence-based clinical practice guidelines for irritable bowel syndrome. J Gastroenterol 2015; 50:11-30. [PMID: 25500976 DOI: 10.1007/s00535-014-1017-0] [Citation(s) in RCA: 93] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Accepted: 11/06/2014] [Indexed: 02/05/2023]
Abstract
New strategies for the care of irritable bowel syndrome (IBS) are developing and several novel treatments have been globally produced. New methods of care should be customized geographically because each country has a specific medical system, life style, eating habit, gut microbiota, genes and so on. Several clinical guidelines for IBS have been proposed and the Japanese Society of Gastroenterology (JSGE) subsequently developed evidence-based clinical practice guidelines for IBS. Sixty-two clinical questions (CQs) comprising 1 definition, 6 epidemiology, 6 pathophysiology, 10 diagnosis, 30 treatment, 4 prognosis, and 5 complications were proposed and statements were made to answer to CQs. A diagnosis algorithm and a three-step treatment was provided for patients with chronic abdominal pain or abdominal discomfort and/or abnormal bowel movement. If more than one alarm symptom/sign, risk factor and/or routine examination is positive, colonoscopy is indicated. If all of them, or the subsequent colonoscopy, are/is negative, Rome III or compatible criteria is applied. After IBS diagnosis, step 1 therapy consisting of diet therapy, behavioral modification and gut-targeted pharmacotherapy is indicated for four weeks. Non-responders to step 1 therapy proceed to the second step that includes psychopharmacological agents and simple psychotherapy for four weeks. In the third step, for patients non-responsive to step 2 therapy, a combination of gut-targeted pharmacotherapy, psychopharmacological treatments and/or specific psychotherapy is/are indicated. Clinical guidelines and consensus for IBS treatment in Japan are well suited for Japanese IBS patients; as such, they may provide useful insight for IBS treatment in other countries around the world.
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Affiliation(s)
- Shin Fukudo
- Guidelines Committee for creating and evaluating the "Evidence-based clinical practice guidelines for irritable bowel syndrome", the Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13 Ginza, Chuo, Tokyo, 104-0061, Japan,
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Nee J, Zakari M, Lembo AJ. Current and emerging drug options in the treatment of diarrhea predominant irritable bowel syndrome. Expert Opin Pharmacother 2015; 16:2781-92. [PMID: 26558923 DOI: 10.1517/14656566.2015.1101449] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Irritable bowel syndrome diarrhea predominant (IBS-D) is a highly prevalent GI disease, affecting nearly a third of all patients diagnosed with irritable bowel syndrome. Current treatment options are limited. AREAS COVERED This review discusses the pharmacotherapeutic options for IBS-D including currently used medications, the two newly FDA approved medications, as well as emerging therapies with potential benefit in IBS-D. Particular emphasis is placed on rifaximin and eluxadoline and their possible use in IBS-D. EXPERT OPINION Current pharmacological treatment of IBS-D includes loperamide, bile acid sequestrants, antispasmodics, tricyclic antidepressants, alosetron, eluxadoline and rifaximin. The latter two treatments have significantly added to the pharmacotherapeutic options for patients suffering from IBS-D.
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Affiliation(s)
- Judy Nee
- a Harvard Medical School, Beth Israel Deaconess Medical Center , Boston , MA , USA
| | - Mohammed Zakari
- a Harvard Medical School, Beth Israel Deaconess Medical Center , Boston , MA , USA
| | - Anthony J Lembo
- a Harvard Medical School, Beth Israel Deaconess Medical Center , Boston , MA , USA
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Chang L, Lembo A, Sultan S. American Gastroenterological Association Institute Technical Review on the pharmacological management of irritable bowel syndrome. Gastroenterology 2014; 147:1149-72.e2. [PMID: 25224525 DOI: 10.1053/j.gastro.2014.09.002] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Lin Chang
- Division of Digestive Diseases, David Geffen School of Medicine University of California, Los Angeles, Los Angeles, California
| | - Anthony Lembo
- Harvard Medical School, Beth Israel Deaconess, Boston, Massachusetts
| | - Shahnaz Sultan
- Department of Veterans Affairs Medical Center, Gastroenterology Section, North Florida/South Georgia Veterans Health System, Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, Gainesville, Florida; Minneapolis Veterans Affairs Health System, University of Minnesota, Minneapolis, Minnesota
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Garsed K, Chernova J, Hastings M, Lam C, Marciani L, Singh G, Henry A, Hall I, Whorwell P, Spiller R. A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea. Gut 2014; 63:1617-25. [PMID: 24334242 PMCID: PMC4173656 DOI: 10.1136/gutjnl-2013-305989] [Citation(s) in RCA: 164] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Irritable bowel syndrome with diarrhoea (IBS-D) is particularly debilitating due to urgency and episodic incontinence. Some 5-hydroxytryptamine 3 (5-HT3) receptor antagonists (5-HT3RAs) have proven effective but have serious side effects. Ondansetron, also a 5-HT3RA, has been widely used as an antiemetic with an excellent safety record for over two decades. Our aim was to assess its effectiveness in IBS-D. METHODS 120 patients meeting Rome III criteria for IBS-D entered a randomised, double-blind, placebo-controlled crossover study of 5 weeks of ondansetron 4 mg versus placebo with dose titration allowed, up to two tablets three times daily in the first 3 weeks. Patients completed daily diaries documenting stool consistency using the Bristol Stool Form score. Gut transit was measured in the last week of each treatment. The primary endpoint was average stool consistency in the last 2 weeks of treatment. RESULTS Ondansetron significantly improved stool consistency (mean difference in stool form between ondansetron and placebo -0.9, 95% CI -1.1 to -0.6, p<0.001). Compared with placebo, patients on ondansetron experienced fewer days with urgency (p<0.001), lower urgency scores (p<0.001), reduced frequency of defaecation (p=0.002) and less bloating (p=0.002), although pain scores did not change significantly. IBS symptom severity score fell more with ondansetron than placebo (83±9.8 vs 37±9.7, p=0.001). 65% reported adequate relief with ondansetron but not placebo compared with 14% reporting relief with placebo but not ondansetron, relative risk 4.7, 95% CI 2.6 to 8.5, p<0.001. CONCLUSIONS Ondansetron relieves some of the most intrusive symptoms of IBS-D, namely loose stools, frequency and urgency.
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Affiliation(s)
- Klara Garsed
- Nottingham Digestive Diseases Biomedical Research Unit, Queens Medical Centre, Nottingham, UK
| | - Julia Chernova
- Nottingham Digestive Diseases Biomedical Research Unit, Queens Medical Centre, Nottingham, UK
| | | | - Ching Lam
- Nottingham Digestive Diseases Biomedical Research Unit, Queens Medical Centre, Nottingham, UK
| | - Luca Marciani
- Sir Peter Mansfield Magnetic Resonance Imaging Centre, University of Nottingham, Nottingham, UK
| | - Gulzar Singh
- Nottingham Digestive Diseases Biomedical Research Unit, Queens Medical Centre, Nottingham, UK
| | - Amanda Henry
- Department of Molecular Medicine, School of Surgical and Medical Sciences, University of Nottingham, Nottingham, UK
| | - Ian Hall
- Department of Molecular Medicine, School of Surgical and Medical Sciences, University of Nottingham, Nottingham, UK
| | - Peter Whorwell
- Neurogastroenterology Unit, Wythenshawe Hospital, Manchester, UK
| | - Robin Spiller
- Nottingham Digestive Diseases Biomedical Research Unit, Queens Medical Centre, Nottingham, UK
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Ford AC, Moayyedi P, Lacy BE, Lembo AJ, Saito YA, Schiller LR, Soffer EE, Spiegel BMR, Quigley EMM. American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol 2014; 109 Suppl 1:S2-26; quiz S27. [PMID: 25091148 DOI: 10.1038/ajg.2014.187] [Citation(s) in RCA: 391] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Alexander C Ford
- 1] Leeds Gastroenterology Institute, St James's University Hospital, Leeds, UK [2] First author on the monograph, but is not a member of the Task Force
| | - Paul Moayyedi
- 1] Farncombe Family Digestive Health Research Institute, Division of Gastroenterology, McMaster University, Hamilton, Ontario, Canada [2] Conducted systematic reviews with the support of A.C. Ford, and carried out the technical analyses of the data independent of the Task Force
| | - Brian E Lacy
- Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - Anthony J Lembo
- Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
| | | | - Lawrence R Schiller
- Baylor University Medical Center, Digestive Health Associates of Texas, Dallas, Texas, USA
| | - Edy E Soffer
- Division of Gastroenterology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Brennan M R Spiegel
- UCLA School of Medicine, UCLA/VA Center for Outcomes Research and Education (CORE), Los Angeles, California, USA
| | - Eamonn M M Quigley
- Division of Gastroenterology and Hepatology, Houston Methodist Hospital and Weill Cornell Medical College, Houston, Texas, USA
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Shah E, Pimentel M. Evaluating the functional net value of pharmacologic agents in treating irritable bowel syndrome. Aliment Pharmacol Ther 2014; 39:973-83. [PMID: 24612075 DOI: 10.1111/apt.12692] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Revised: 12/02/2013] [Accepted: 02/16/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND The recent FDA provisional endpoint incorporates a one-tailed measure of improvement for IBS based on the underlying motility complaint. However, motility exists along a spectrum. Patients may experience diarrhoea resulting from therapy for their constipation-predominant IBS (IBS-C) or constipation during treatment for diarrhoea-predominant IBS (IBS-D), but still meet a unidirectional motility-based FDA endpoint. AIM To weigh the reported efficacy of existing therapies based on patient-reported outcomes with negative intestinal side effects in controlled clinical trial data. METHODS We analysed the difference between 'attributable risk' of efficacy based on number needed to treat (NNT) in the literature and percentage of adverse events (AE) of opposite intestinal complaints in placebo-controlled trials identified through a literature search of IBS trials. This calculation was coined 'functional net value' (FNV) or net benefit of the given drug. RESULTS For treating IBS-C, lubiprostone caused diarrhoea in excess of placebo in 3.9% of patients, leading to a FNV of 3.9 percentage units. Linaclotide caused diarrhoea in 15.3% resulting in negative FNV (-1.0 percentage unit). For IBS-D, alosetron and tricyclic anti-depressants caused constipation among a respective 16.9% and 13.0% resulting in a FNV of -3.6 and -0.5 percentage units. Among all therapies, only rifaximin did not cause the adverse event opposite the underlying motility complaint and the drug only had benefit, not detriment. CONCLUSIONS Functional net value (FNV) offers a method of evaluating the net benefit of a drug in IBS. Most IBS treatments have a negative effect on IBS that exceeds the benefits.
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Affiliation(s)
- E Shah
- GI Motility Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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Shah E, Triantafyllou K, Hana AA, Pimentel M. Adverse events appear to unblind clinical trials in irritable bowel syndrome. Neurogastroenterol Motil 2014; 26:482-8. [PMID: 24350975 DOI: 10.1111/nmo.12289] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2013] [Accepted: 11/23/2013] [Indexed: 12/15/2022]
Abstract
BACKGROUND Clinical trial design is challenging in irritable bowel syndrome (IBS) due in part to a high placebo effect. We postulated that the mere presence of an adverse event (AE) may unmask patients in clinical trials who are assigned to the active agent, and this may lead to higher reported efficacy. METHODS We evaluated therapies receiving at least a Grade 1B from the American College of Gastroenterology Task Force for IBS or which passed recent phase III clinical trials. Therapies with AE data derived from less than 50 patients in each study arm were excluded. Statistically significant excess AE were identified, risk difference was calculated for each AE, and incidence of AE in the treatment arm was reported. We examined the relationship of attributable drug benefit, defined as the reciprocal of number-needed-to-treat found in literature, with various measures of AE incidence. KEY RESULTS Attributable drug benefit correlated significantly with average AE risk difference, calculated as treatment arm AE incidence minus placebo arm AE incidence (R(2) = 0.70, p = 0.039), and also with highest treatment arm AE incidence (R(2) = 0.70, p = 0.038) for each therapy. There were also trends toward correlation with average treatment arm AE incidence (R(2) = 0.54, p = 0.096) and highest AE risk difference (R(2) = 0.63, p = 0.059) for each therapy. CONCLUSIONS & INFERENCES Our study suggests that higher AE incidence on active therapy is associated with more beneficial patient-reported outcomes in IBS clinical trials. This raises the issue of spontaneous unblinding.
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Affiliation(s)
- E Shah
- GI Motility Program, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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Tong K, Nicandro JP, Shringarpure R, Chuang E, Chang L. A 9-year evaluation of temporal trends in alosetron postmarketing safety under the risk management program. Therap Adv Gastroenterol 2013; 6:344-57. [PMID: 24003335 PMCID: PMC3756634 DOI: 10.1177/1756283x13491798] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
OBJECTIVES Adverse events (AEs) of ischemic colitis (IC) and complications of constipation (CoC) associated with alosetron are rare and have been adjudicated during the first 5.5 years of the risk management program (RMP); however, changes in incidence rates relative to reductions in AE reports and increases in alosetron prescriptions over the 9-year RMP have not been evaluated. The authors aim to evaluate temporal trends in alosetron postmarketing safety over the 9-year RMP. METHODS The alosetron safety database was searched to identify cases of IC, CoC, and related AEs from 20 November 2002 to 31 December 2011. Adjudication of IC and CoC cases were based on US Food and Drug Administration-defined criteria. Incidence rates were calculated using the number of AEs and alosetron prescriptions (expressed as cases/1000 patient-years exposure). RESULTS A total of 29 cases were adjudicated as probable/possible IC and 7 cases were adjudicated as CoC. Cumulative adjudicated incidence rate of IC (1.03 cases/1000 patient-years) is low and stable, while that of CoC (0.25 cases/1000 patient-years) is low, declining progressively over time. Decreases in the incidence rates of potential symptoms of IC (abdominal pain with bloody diarrhea/hematochezia) and CoC (constipation) were also observed. CONCLUSIONS Over the 9-year RMP period, incidence rates of IC and CoC remain rare. Substantial reductions over time were observed in the incidence of CoC and in symptoms suggestive of IC or CoC, while IC incidence has been stable at approximately 1.0 case/1000 patient-years. Decreases in AEs and serious outcomes associated with IC and CoC since the reintroduction of alosetron are likely attributable to the RMP.
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Abstract
Irritable bowel syndrome (IBS), characterized by abdominal pain or discomfort associated with a change in bowel patterns, is one of the most common functional gastrointestinal disorders. Because no single drug effectively relieves all IBS symptoms, management relies on dietary and lifestyle modifications, as well as pharmacologic and nonpharmacologic therapies. The authors review current approaches to treatment and discuss nursing implications.
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Abstract
INTRODUCTION Awareness of the seriousness of irritable bowel disorder (IBS) remains low among clinicians. In this review, we summarize the current knowledge of IBS and highlight the major personal, economic, and social burden of the disease, and the importance of adequate treatment of what is still often viewed as a trivial disorder. In fact, IBS is a major reason for referral. PATHOPHYSIOLOGY It is crucial that the varied pathophysiologies of this complex heterogeneous disease are understood in order to be able to treat both the presenting symptoms (pain, bloating, flatulence, abnormal defecation, diarrhea, constipation) and the underlying disorder effectively. Low-grade inflammatory and immune activation has been observed, but the precise triggers and mechanisms, and the relevance to symptom generation, remain to be established. TREATMENT IBS patients require different treatment strategies according to the pattern, severity, frequency, and symptoms. While initial therapy traditionally targets the most bothersome symptom, long-term therapy aims at maintaining symptom control and preventing recurrence. In addition to dietary/lifestyle interventions and psychosocial strategies, a wide range of pharmacologic therapies are approved for use in IBS depending on the symptoms reported. Musculotropic spasmolytics, which act directly on intestinal smooth muscle contractility, such as otilonium bromide, are effective, particularly in the relief of abdominal pain and bloating, and are well tolerated in IBS. THE OBIS TRIAL: The recent large placebo-controlled Otilonium Bromide in Irritable Bowel Syndrome study demonstrated the superiority of otilonium bromide versus placebo not only in the reduction of pain and bloating, but also in protection from relapse due to the long-lasting effect.
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Affiliation(s)
- Guy Boeckxstaens
- Department of Gastroenterology, Translational Research Center for Gastrointestinal Disorders, University Hospital Leuven, Catholic University of Leuven, Herestraat 49, 3000 Leuven, Belgium
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