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1
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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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2
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Chuy DS, Wi RS, Tadros M. Irritable Bowel Syndrome: Current Landscape of Diagnostic Guidelines and Therapeutic Strategies. GASTROENTEROLOGY INSIGHTS 2024; 15:786-809. [DOI: 10.3390/gastroent15030056] [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] [Indexed: 01/30/2025] Open
Abstract
Irritable bowel syndrome (IBS) is a disorder of the gut–brain axis with pronounced adverse effects on physical health, psychological health, and overall quality of life. Diagnostic strategies can vary, highlighting a need to synthesize best-practice guidelines. Particularly, the American College of Gastroenterology and the British Society of Gastroenterology both support a positive diagnostic strategy; evaluation with C-reactive protein, fecal calprotectin, and fecal lactoferrin; and evaluation with celiac disease serology. Both guidelines do not support routine colonoscopy, and both differ in recommendations for anorectal physiology testing. Given there is currently no curative treatment available, IBS management focuses on symptomatic relief, and challenges exist in achieving and maintaining this relief. Many treatments, both pharmacologic and nonpharmacologic, exist to alleviate the uncomfortable, painful symptoms of the disorder; however, stratifying the quality of evidence behind each option is critical for application to clinical management and for tailoring this management to each patient. Lifestyle adjustments, especially in relation to diet, can be effective first-line therapies and supplements to pharmacologic therapy. Pharmacologic treatment is broadly categorized in accordance with the subtypes of IBS, with indications for different populations and mechanisms that work to target components of IBS pathophysiology. The aim of this article is to comprehensively compare updated diagnostic guidelines, review standard treatments, and outline recent pharmacologic advancements.
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Affiliation(s)
| | - Ryan S. Wi
- Albany Medical College, Albany, NY 12208, USA
| | - Micheal Tadros
- Department of Gastroenterology, Albany Medical Center, Albany, NY 12208, USA
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3
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Dahlgren D, Hellström PM. Medicinal grade opium tincture for severe diarrhea: effect revisited in observational study. Curr Opin Gastroenterol 2024; 40:196-202. [PMID: 37903075 DOI: 10.1097/mog.0000000000000985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/01/2023]
Abstract
PURPOSE OF REVIEW Chronic diarrhea is a common disorder that interferes with normal daily activities and results in poor quality of life. Fecal urgency and incontinence often necessitate clinical consultation, but the pathophysiological mechanisms are difficult to differentiate in a clinical setting. Therefore, drugs targeting the opioid receptors, such as diphenoxylate and loperamide, are typically used, as they reduce both gut motility and secretion. RECENT FINDINGS For severe diarrhea, morphine-containing extemporaneous opium tincture drops have recently been reprofiled to a pharmaceutical. The drug is indicated for severe diarrhea in adults when other antidiarrheals do not give sufficient fecal emptying control. The pronounced effect is due to the liquid formulation with rapid onset as a drug dissolution step is avoided. A recent prospective, noninterventional study (CLARIFY) of patients treated with opioid drops demonstrates a rapid and sustained therapeutic effect. Tolerance does not develop for the antidiarrheal effect and no dependence was observed after discontinuation. SUMMARY This mini-review discusses the use of opium derivates for treatment of diarrhea, with an emphasis on opium drops as a new medicinal grade opium for the use as additional treatment of severe diarrhea, emphasizing its mechanism of action and evaluation of the risk-benefit ratio in the clinical setting.
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Affiliation(s)
- David Dahlgren
- Department of Pharmaceutical Biosciences Uppsala University
| | - Per M Hellström
- Department of Medical Sciences, Gastroenterology/Hepatology Uppsala University, Uppsala, Sweden
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4
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Marasco G, Cremon C, Barbaro MR, Stanghellini V, Barbara G. Journal of Clinical Gastroenterology Lectureship Dubai 2022 : Management of Irritable Bowel Syndrome With Diarrhea. J Clin Gastroenterol 2024; 58:221-231. [PMID: 38227850 DOI: 10.1097/mcg.0000000000001964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 12/13/2023] [Indexed: 01/18/2024]
Abstract
Irritable bowel syndrome (IBS) with diarrhea (IBS-D) affects ~1% of the general population and is characterized by abdominal pain associated with diarrhea. IBS-D symptoms significantly impact the quality of life of patients. Major uncertainties remain regarding the optimal management of these patients. Several therapies have been investigated over the years for the treatment of IBS-D. In the initial management, commonly prescribed approaches with an effect on global IBS symptoms include a low Fermentable Oligo-, Di-, Mono-Saccharides and Polyols diet and probiotics, while antispasmodics are used for targeting abdominal pain and loperamide for diarrhea only. Additional therapeutic options for the relief of global IBS symptoms include rifaximin, 5-HT 3 antagonists, gut-directed psychological therapies, and eluxadoline, while tricyclic antidepressants can target abdominal pain and bile acid sequestrants diarrhea. Promising evidence exists for the use of mesalazine and fecal microbiota transplantation in IBS-D, although further evidence is needed for definitive conclusions regarding their efficacy.
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Affiliation(s)
- Giovanni Marasco
- IRCCS Azienda Ospedaliero Universitaria di Bologna
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Cesare Cremon
- IRCCS Azienda Ospedaliero Universitaria di Bologna
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | | | - Vincenzo Stanghellini
- IRCCS Azienda Ospedaliero Universitaria di Bologna
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Giovanni Barbara
- IRCCS Azienda Ospedaliero Universitaria di Bologna
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
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5
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Wal A, Wal P, Verma N, Pandey SS, Krishnan K, Bhowmick M. Children and Adolescents with Irritable Bowel Syndrome: Treatment and Management. Curr Pediatr Rev 2024; 20:166-177. [PMID: 36443973 DOI: 10.2174/1573396319666221128094843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 08/13/2022] [Accepted: 09/02/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is a disorder that causes stomach pain in children and adolescents. It may also impact one's quality of life. IBS is linked to gastrointestinal issues such as diarrhoea and constipation. Despite the identification of several potential pathophysiological pathways, the aetiology of IBS remained unknown. OBJECTIVE The aim of this paper is to discuss the diagnosis, pathogenesis, case studies and treatment of Irritable bowel syndrome in children and adolescents. METHODS This systematic review covered relevant papers from the previous ten years that were accessible in Science Direct, Elsevier, NCBI, and Web of Science related to the pathophysiology and function of pharmacological drugs such as antidepressants, antispasmodics, prokinetics, and antibiotics in children with irritable bowel syndrome. RESULTS Only a few prospective therapy techniques have been investigated in children, and even fewer of those have been demonstrated to be effective. This article presents case studies including 50-59 children, which demonstrate a favourable acceptable impact that is more effective than a placebo in terms of reducing symptoms and improving the overall quality of life in children who have irritable bowel syndrome. Furthermore, the majority of the pathophysiological explanations and treatment options discussed are based on adult studies. These major issues arose when treating paediatric IBS, and they must be addressed in order to properly treat children with IBS. Trials that focus on many combinations of pharmacological and non-pharmacological therapies seem to be more helpful. DISCUSSION In recent years, a number of systematic reviews have been conducted to evaluate the efficacy of medication treatments in children for IBS; however, the dependability of these systematic reviews needs to be further investigated owing to the various experimental designs and levels of evidence used. This article highlights paediatric therapy options, including pharmaceutical medications such as antidepressants, antispasmodics, prokinetics, and antibiotics. The goal is to alleviate IBS symptoms while also enhancing the quality of life for children with this illness.
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Affiliation(s)
- Ankita Wal
- Department of Pharmacy, Pranveer Singh Institute of Technology, Nh2 Kanpur Agra Highway Bhaunti, Kanpur, UP, India
| | - Pranay Wal
- Department of Pharmacy, Pranveer Singh Institute of Technology, Nh2 Kanpur Agra Highway Bhaunti, Kanpur, UP, India
| | - Neha Verma
- Department of Pharmacy, Pranveer Singh Institute of Technology, Nh2 Kanpur Agra Highway Bhaunti, Kanpur, UP, India
| | | | - Karthickeyan Krishnan
- Institute of Science Technology & Advanced Studies Pallavaram, Chennai, 600117, Tamil Nadu, 600117, India
| | - Mithun Bhowmick
- D101 Shikshak Niketan, Campus of Bengal College of Pharmaceutical Sciences and Research, Bidhananagar Durgapur, West Bengal, 713212, India
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6
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Qu Y, Park SH, Dallas DC. The Role of Bovine Kappa-Casein Glycomacropeptide in Modulating the Microbiome and Inflammatory Responses of Irritable Bowel Syndrome. Nutrients 2023; 15:3991. [PMID: 37764775 PMCID: PMC10538225 DOI: 10.3390/nu15183991] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 09/10/2023] [Accepted: 09/12/2023] [Indexed: 09/29/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a common gastrointestinal disorder marked by chronic abdominal pain, bloating, and irregular bowel habits. Effective treatments are still actively sought. Kappa-casein glycomacropeptide (GMP), a milk-derived peptide, holds promise because it can modulate the gut microbiome, immune responses, gut motility, and barrier functions, as well as binding toxins. These properties align with the recognized pathophysiological aspects of IBS, including gut microbiota imbalances, immune system dysregulation, and altered gut barrier functions. This review delves into GMP's role in regulating the gut microbiome, accentuating its influence on bacterial populations and its potential to promote beneficial bacteria while inhibiting pathogenic varieties. It further investigates the gut microbial shifts observed in IBS patients and contemplates GMP's potential for restoring microbial equilibrium and overall gut health. The anti-inflammatory attributes of GMP, especially its impact on vital inflammatory markers and capacity to temper the low-grade inflammation present in IBS are also discussed. In addition, this review delves into current research on GMP's effects on gut motility and barrier integrity and examines the changes in gut motility and barrier function observed in IBS sufferers. The overarching goal is to assess the potential clinical utility of GMP in IBS management.
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Affiliation(s)
- Yunyao Qu
- Department of Food Science & Technology, Oregon State University, Corvallis, OR 97331, USA; (Y.Q.); (S.H.P.)
- Nutrition Program, College of Health, Oregon State University, Corvallis, OR 97331, USA
| | - Si Hong Park
- Department of Food Science & Technology, Oregon State University, Corvallis, OR 97331, USA; (Y.Q.); (S.H.P.)
| | - David C. Dallas
- Department of Food Science & Technology, Oregon State University, Corvallis, OR 97331, USA; (Y.Q.); (S.H.P.)
- Nutrition Program, College of Health, Oregon State University, Corvallis, OR 97331, USA
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7
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Ghoshal UC, Sachdeva S, Pratap N, Karyampudi A, Mustafa U, Abraham P, Bhatt CB, Chakravartty K, Chaudhuri S, Goyal O, Makharia GK, Panigrahi MK, Parida PK, Patwari S, Sainani R, Sadasivan S, Srinivas M, Upadhyay R, Venkataraman J. Indian consensus statements on irritable bowel syndrome in adults: A guideline by the Indian Neurogastroenterology and Motility Association and jointly supported by the Indian Society of Gastroenterology. Indian J Gastroenterol 2023; 42:249-273. [PMID: 36961659 PMCID: PMC10036984 DOI: 10.1007/s12664-022-01333-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 12/20/2022] [Indexed: 03/25/2023]
Abstract
The Indian Neurogastroenterology and Motility Association (INMA), earlier named the Indian Motility and Functional Diseases Association developed this evidence-based practice guidelines for the management of irritable bowel syndrome (IBS). A modified Delphi process was used to develop this consensus containing 28 statements, which were concerning diagnostic criteria, epidemiology, etiopathogenesis and comorbidities, investigations, lifestyle modifications and treatments. Owing to the Coronavirus disease-19 (COVID-19) pandemic, lockdowns and mobility restrictions, web-based meetings and electronic voting were the major tools used to develop this consensus. A statement was regarded as accepted when the sum of "completely accepted" and "accepted with minor reservation" voted responses were 80% or higher. Finally, the consensus was achieved on all 28 statements. The consensus team members are of the view that this work may find use in teaching, patient care, and research on IBS in India and other nations.
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Affiliation(s)
- Uday C Ghoshal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226 014, India.
| | - Sanjeev Sachdeva
- Department of Gastroenterology, GB Pant Hospital, New Delhi, 110 002, India
| | - Nitesh Pratap
- Department of Gastroenterology, KIMS Hospital, Secunderabad, 500 003, India
| | - Arun Karyampudi
- Department of Gastroenterology, GSL Medical College and General Hospital, Rajahmundry , 533 296, India
| | - Uzma Mustafa
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226 014, India
| | - Philip Abraham
- Department of Gastroenterology, P. D. Hinduja Hospital, Mumbai, 400 016, India
| | - Chetan B Bhatt
- Sir HN Reliance Foundation Hospital, Mumbai, 400 004, India
| | - Karmabir Chakravartty
- Department of Gastroenterology, Woodland Multispeciality Hospital, Kolkata, 700 027, India
| | - Sujit Chaudhuri
- Department of Gastroenterology, AMRI Hospitals, Salt Lake, Kolkata, 700 098, India
| | - Omesh Goyal
- Department of Gastroenterology, Dayanand Medical College and Hospital, Ludhiana, 141 001, India
| | - Govind K Makharia
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, 110 029, India
| | - Manas Kumar Panigrahi
- Department of Gastroenterology, All India Institute of Medical Sciences, Bhubaneswar, 751 019, India
| | - Prasanta Kumar Parida
- Department of Gastroenterology, SCB Medical College and Hospital, Cuttack, 753 001, India
| | | | - Rajesh Sainani
- Department of Gastroenterology, Jaslok Hospital, Mumbai, 400 026, India
| | - Shine Sadasivan
- Department of Gastroenterology, Amrita Institute of Medical Sciences, Kochi, 682 041, India
| | - M Srinivas
- Department of Gastroenterology, Gleneagles Global Health City, Chennai, 600 100, India
| | - Rajesh Upadhyay
- Department of Gastroenterology, Max Superspeciality Hospital, New Delhi, 110 017, India
| | - Jayanthi Venkataraman
- Department of Gastroenterology, Sri Ramachandra Institute of Higher Education and Research, Chennai, 600 116, India
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8
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Graven-Nielsen CS, Knoph CS, Okdahl T, Høyer KL, Krogh K, Hellström PM, Drewes AM. Opioids in the Treatment of Chronic Idiopathic Diarrhea in Humans—A Systematic Review and Treatment Guideline. J Clin Med 2023; 12:jcm12072488. [PMID: 37048572 PMCID: PMC10094889 DOI: 10.3390/jcm12072488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/14/2023] [Accepted: 03/20/2023] [Indexed: 03/29/2023] Open
Abstract
In patients with chronic idiopathic diarrhea resistant to standard treatment, opioids are often used as rescue therapy. This systematic review investigated opioid effects on gut function in chronic diarrhea. PubMed and Embase were searched regarding effects of opioid agonists on the gastrointestinal tract in humans with chronic or experimentally induced diarrhea. A total of 1472 relevant articles were identified and, after thorough evaluation, 11 clinical trials were included. Generally, studies reported a reduction in stool frequency and an increase in transit time during treatment with the opioid receptor agonists loperamide, asimadoline, casokefamide, and codeine compared with placebo. Loperamide and diphenoxylate significantly improved stool consistency compared with placebo, whereas asimadoline showed no such effects. Compared with placebo, loperamide treatment caused less abdominal pain and urgency. Asimadoline showed no significant subjective improvements, but fedotozine was superior to placebo in reducing abdominal pain and bloating in selected patients. Only two relevant studies were published within the last 20 years, and standardized endpoint measures are lacking. Most trials included few participants, and further evidence is needed from larger, prospective studies. Likewise, consensus is needed to standardize endpoints for stool frequency, transit time, and consistency to conduct future meta-analyses on opioids in management of chronic idiopathic diarrhea.
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9
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Camilleri M, Dilmaghani S. Update on treatment of abdominal pain in irritable bowel syndrome: A narrative review. Pharmacol Ther 2023; 245:108400. [PMID: 37001737 DOI: 10.1016/j.pharmthera.2023.108400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/22/2023] [Accepted: 03/27/2023] [Indexed: 03/31/2023]
Abstract
The objectives of this narrative review are to update readers on the current state-of-the-art regarding diverse approaches for the treatment of pain, global symptoms, or adequate relief in irritable bowel syndrome (IBS). The article appraises medications, dietary interventions including low fermentable oligosaccharides, disaccharides, and monosaccharides and polyols (FODMAP) diet, fecal microbial transplantation (FMT), electrical approaches, and behavioral therapies including cognitive behavioral therapy (CBT), gut-directed hypnotherapy (GDH), mindfulness, and open-label placebo. Current evidence demonstrates only modest benefit in global IBS symptoms and pain relief. A future approach that identifies pathophysiological mechanisms of IBS through validated biomarkers has the potential to individualize treatment of patients rather than sequential therapeutic trial and error approaches.
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10
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Okdahl T, Mark EB, Nedergaard RB, Knoph CS, Cook ME, Krogh K, Drewes AM. Effects of opium tincture on the enteric and central nervous systems: A randomized controlled trial. Basic Clin Pharmacol Toxicol 2023; 132:434-448. [PMID: 36851814 DOI: 10.1111/bcpt.13850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 02/16/2023] [Accepted: 02/23/2023] [Indexed: 03/01/2023]
Abstract
Opioids change gut motility, and opium tincture has been used for treatment of chronic diarrhoea for centuries. However, the effects have never been documented in controlled trials. We aimed to investigate the effects of opium tincture on gastrointestinal transit and motility, frequency of bowel movements, stool consistency, gastrointestinal symptoms and sedation. Twenty healthy subjects were included in this randomized controlled trial. Opium tincture or placebo was each applied for 9 days. Gastrointestinal transit and motility were investigated with the 3D-transit system. Bowel movements and gastrointestinal symptoms were recorded daily. General cognition, reaction time, memory and electroencephalography were used to assess effects on the central nervous system. Opium tincture doubled colonic transit (49 vs. 23 h, p < 0.001), decreased antegrade colonic movements (p < 0.05), reduced daily bowel movements (0.7 vs. 1.2, p < 0.001) and increased stool consistency (Type 3 vs. Type 4, p < 0.001). No changes in general cognition, reaction time or memory were observed, and minor changes of power observed by electroencephalography did not indicate sedation. This study is the first to show that opium tincture has anti-propulsive properties in the healthy gut, while no sedative effects were seen. This indicates that opium tincture is a relevant and safe treatment option in chronic diarrhoea.
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Affiliation(s)
- Tina Okdahl
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Esben Bolvig Mark
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark.,Clinical Institute, Aalborg University, Aalborg, Denmark
| | - Rasmus Bach Nedergaard
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Cecilie Siggaard Knoph
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark.,Clinical Institute, Aalborg University, Aalborg, Denmark
| | - Mathias Ellgaard Cook
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark.,Clinical Institute, Aalborg University, Aalborg, Denmark
| | - Klaus Krogh
- Neurogastroenterology Unit, Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Asbjørn Mohr Drewes
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark.,Clinical Institute, Aalborg University, Aalborg, Denmark
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11
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Barbara G, Cremon C, Bellini M, Corsetti M, Di Nardo G, Falangone F, Fuccio L, Galeazzi F, Iovino P, Sarnelli G, Savarino EV, Stanghellini V, Staiano A, Stasi C, Tosetti C, Turco R, Ubaldi E, Zagari RM, Zenzeri L, Marasco G. Italian guidelines for the management of irritable bowel syndrome: Joint Consensus from the Italian Societies of: Gastroenterology and Endoscopy (SIGE), Neurogastroenterology and Motility (SINGEM), Hospital Gastroenterologists and Endoscopists (AIGO), Digestive Endoscopy (SIED), General Medicine (SIMG), Gastroenterology, Hepatology and Pediatric Nutrition (SIGENP) and Pediatrics (SIP). Dig Liver Dis 2023; 55:187-207. [PMID: 36517261 DOI: 10.1016/j.dld.2022.11.015] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 11/21/2022] [Accepted: 11/24/2022] [Indexed: 01/29/2023]
Abstract
The irritable bowel syndrome (IBS) is a chronic disorder of gut-brain interaction. IBS is still associated with areas of uncertainties, especially regarding the optimal diagnostic work-up and the more appropriate management. Experts from 7 Italian Societies conducted a Delphi consensus with literature summary and voting process on 27 statements. Recommendations and quality of evidence were evaluated using the grading of recommendations, assessment, development, and evaluation (GRADE) criteria. Consensus was defined as >80% agreement and reached for all statements. In terms of diagnosis, the consensus supports a positive diagnostic strategy with a symptom-based approach, including the psychological comorbidities assessment and the exclusion of alarm symptoms, together with the digital rectal examination, full blood count, C-reactive protein, serology for coeliac disease, and fecal calprotectin assessment. Colonoscopy should be recommended in patients with alarm features. Regarding treatment, the consensus strongly supports a dietary approach for patients with IBS, the use of soluble fiber, secretagogues, tricyclic antidepressants, psychologically directed therapies and, only in specific IBS subtypes, rifaximin. A conditional recommendation was achieved for probiotics, polyethylene glycol, antispasmodics, selective serotonin reuptake inhibitors and, only in specific IBS subtypes, 5-HT3 antagonists, 5-HT4 agonists, bile acid sequestrants.
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Affiliation(s)
- Giovanni Barbara
- IRCCS Azienda Ospedaliero Universitaria di Bologna, 40126 Bologna, Italy; Department of Medical and Surgical Sciences, University of Bologna, 40126 Bologna, Italy.
| | - Cesare Cremon
- IRCCS Azienda Ospedaliero Universitaria di Bologna, 40126 Bologna, Italy; Department of Medical and Surgical Sciences, University of Bologna, 40126 Bologna, Italy
| | - Massimo Bellini
- Gastrointestinal Unit, Department of Translational Sciences and New Technologies in Medicine and Surgery, University of Pisa, 56010 Pisa, Italy
| | - Maura Corsetti
- NIHR Nottingham Biomedical Research Centre (BRC), Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham Digestive Diseases Biomedical Research Centre, Nottingham, United Kingdom
| | - Giovanni Di Nardo
- NESMOS Department, Faculty of Medicine and Psychology, Sapienza University of Rome, Sant'Andrea University Hospital, Rome, Italy
| | - Francesca Falangone
- Medical-Surgical Department of Clinical Sciences and Translational Medicine, University Sapienza, Rome, Italy
| | - Lorenzo Fuccio
- Department of Medical and Surgical Sciences, University of Bologna, 40126 Bologna, Italy; Gastroenterology Unit, IRCCS Azienda Ospedaliero Universitaria di Bologna, 40126 Bologna, Italy
| | - Francesca Galeazzi
- Gastroenterology Unit, Azienda Ospedale Università di Padova, 35128 Padua, Italy
| | - Paola Iovino
- Gastrointestinal Unit Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081 Baronissi, Italy
| | - Giovanni Sarnelli
- Department of Clinical Medicine and Surgery, University of Naples "Federico II", 80131 Naples, Italy
| | | | - Vincenzo Stanghellini
- IRCCS Azienda Ospedaliero Universitaria di Bologna, 40126 Bologna, Italy; Department of Medical and Surgical Sciences, University of Bologna, 40126 Bologna, Italy
| | - Annamaria Staiano
- Department of Translational Medical Sciences-Section of Pediatric, University Federico II, 80100 Naples, Italy
| | - Cristina Stasi
- Internal Medicine and Liver Unit, Department of Experimental and Clinical Medicine, Careggi University Hospital, Florence, Italy
| | | | - Rossella Turco
- Department of Translational Medical Sciences-Section of Pediatric, University Federico II, 80100 Naples, Italy
| | - Enzo Ubaldi
- Primary Care, Health Care Agency of Ascoli Piceno, Ascoli Piceno, Italy
| | - Rocco Maurizio Zagari
- Department of Medical and Surgical Sciences, University of Bologna, 40126 Bologna, Italy; Gastroenterology Unit, IRCCS Azienda Ospedaliero Universitaria di Bologna, 40126 Bologna, Italy
| | - Letizia Zenzeri
- NESMOS Department, Faculty of Medicine and Psychology, Sapienza University of Rome, Sant'Andrea University Hospital, Rome, Italy
| | - Giovanni Marasco
- IRCCS Azienda Ospedaliero Universitaria di Bologna, 40126 Bologna, Italy; Department of Medical and Surgical Sciences, University of Bologna, 40126 Bologna, Italy
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12
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Anderle K, Wolzt M, Moser G, Keip B, Peter J, Meisslitzer C, Gouya G, Freissmuth M, Tschegg C. Safety and efficacy of purified clinoptilolite-tuff treatment in patients with irritable bowel syndrome with diarrhea: Randomized controlled trial. World J Gastroenterol 2022; 28:6573-6588. [PMID: 36569277 PMCID: PMC9782844 DOI: 10.3748/wjg.v28.i46.6573] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 09/09/2022] [Accepted: 11/16/2022] [Indexed: 12/08/2022] Open
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is a highly prevalent gastrointestinal disorder with poor response to treatment. IBS with predominant diarrhea (IBS-D) is accompanied by abdominal pain as well as high stool frequency and urgency. Purified clinoptilolite-tuff (PCT), which is approved by the Food and Drug Administration for use as a dietary supplement with the brand name G-PUR®, has previously shown therapeutic potential in other indications based on its physical adsorption capacity.
AIM To assess whether symptoms of IBS-D can be ameliorated by oral treatment with PCT.
METHODS In this randomized, placebo-controlled, double-blind pilot study, 30 patients with IBS-D diagnosis based on Rome IV criteria were enrolled. Following a 4-wk run-in phase, 14 patients were randomized to receive a 12-wk treatment with G-PUR® (2 g three times daily), and 16 patients received placebo. The relief from IBS-D symptoms as measured by the proportion of responders according to the Subject’s Global Assessment (SGA) of Relief was assessed as the primary outcome. For the secondary outcomes, validated IBS-D associated symptom questionnaires, exploratory biomarkers and microbiome data were collected.
RESULTS The proportions of SGA of Relief responders after 12 wk were comparable in both groups, namely 21% in the G-PUR® group and 25% in the placebo group. After 4 wk of treatment, 36% of patients in the G-PUR® group vs 0% in the placebo group reported complete or considerable relief. An improvement in daily abdominal pain was noted in 94% vs 83% (P = 0.0353), and the median number of days with diarrhea per week decreased by 2.4 d vs 0.3 d in the G-PUR® and placebo groups, respectively. Positive trends were observed for 50% of responders in the Bristol Stool Form Scale. Positive trends were also noted for combined abdominal pain and stool consistency response and the Perceived Stress Questionnaire score. Only 64% in the G-PUR® group compared to 86% in the placebo group required rescue medication intake during the study. Stool microbiome studies showed a minor increase in diversity in the G-PUR® group but not in the placebo group. No PCT-related serious adverse events were reported.
CONCLUSION In this randomized, double-blind, placebo-controlled study, the PCT product, G-PUR®, demonstrated safety and clinical benefit towards some symptoms of IBS-D, representing a promising novel treatment option for these patients.
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Affiliation(s)
- Karolina Anderle
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna 1090, Austria
| | - Michael Wolzt
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna 1090, Austria
| | - Gabriele Moser
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna 1090, Austria
| | - Bettina Keip
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna 1090, Austria
| | - Johannes Peter
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna 1090, Austria
| | - Claudia Meisslitzer
- Glock Health, Science and Research GmbH, Deutsch-Wagram 2232, Lower Austria, Austria
| | | | - Michael Freissmuth
- Institute of Pharmacology and the Gaston H. Glock Research Laboratories for Exploratory Drug Development, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna 1090, Austria
| | - Cornelius Tschegg
- Glock Health, Science and Research GmbH, Deutsch-Wagram 2232, Lower Austria, Austria
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Savarino E, Zingone F, Barberio B, Marasco G, Akyuz F, Akpinar H, Barboi O, Bodini G, Bor S, Chiarioni G, Cristian G, Corsetti M, Di Sabatino A, Dimitriu AM, Drug V, Dumitrascu DL, Ford AC, Hauser G, Nakov R, Patel N, Pohl D, Sfarti C, Serra J, Simrén M, Suciu A, Tack J, Toruner M, Walters J, Cremon C, Barbara G. Functional bowel disorders with diarrhoea: Clinical guidelines of the United European Gastroenterology and European Society for Neurogastroenterology and Motility. United European Gastroenterol J 2022; 10:556-584. [PMID: 35695704 PMCID: PMC9278595 DOI: 10.1002/ueg2.12259] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 05/20/2022] [Indexed: 11/23/2022] Open
Abstract
Irritable bowel syndrome with diarrhoea (IBS‐D) and functional diarrhoea (FDr) are the two major functional bowel disorders characterized by diarrhoea. In spite of their high prevalence, IBS‐D and FDr are associated with major uncertainties, especially regarding their optimal diagnostic work‐up and management. A Delphi consensus was performed with experts from 10 European countries who conducted a literature summary and voting process on 31 statements. Quality of evidence was evaluated using the grading of recommendations, assessment, development, and evaluation criteria. Consensus (defined as >80% agreement) was reached for all the statements. The panel agreed with the potential overlapping of IBS‐D and FDr. In terms of diagnosis, the consensus supports a symptom‐based approach also with the exclusion of alarm symptoms, recommending the evaluation of full blood count, C‐reactive protein, serology for coeliac disease, and faecal calprotectin, and consideration of diagnosing bile acid diarrhoea. Colonoscopy with random biopsies in both the right and left colon is recommended in patients older than 50 years and in presence of alarm features. Regarding treatment, a strong consensus was achieved for the use of a diet low fermentable oligo‐, di‐, monosaccharides and polyols, gut‐directed psychological therapies, rifaximin, loperamide, and eluxadoline. A weak or conditional recommendation was achieved for antispasmodics, probiotics, tryciclic antidepressants, bile acid sequestrants, 5‐hydroxytryptamine‐3 antagonists (i.e. alosetron, ondansetron, or ramosetron). A multinational group of European experts summarized the current state of consensus on the definition, diagnosis, and management of IBS‐D and FDr.
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Affiliation(s)
- Edoardo Savarino
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Fabiana Zingone
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Brigida Barberio
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Giovanni Marasco
- Division of Internal Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Filiz Akyuz
- Department of Gastroenterology, İstanbul University İstanbul School of Medicine, İstanbul, Turkey
| | - Hale Akpinar
- Department of Internal Medicine, Dokuz Eylül University School of Medicine, Izmir, Turkey
| | - Oana Barboi
- Department of Gastroenterology, 'Grigore T. Popa' University of Medicine and Pharmacy, Iasi, Romania.,Institute of Gastroenterology and Hepatology, 'Saint Spiridon' Hospital, Iasi, Romania
| | - Giorgia Bodini
- Gastrointestinal Unit, Department of Internal Medicine, University of Genoa, Genoa, Italy
| | - Serhat Bor
- Division of Gastroenterology, Ege University School of Medicine, Izmir, Turkey
| | | | - Gheorghe Cristian
- Fundeni Clinical Institute Center of Gastroenterology and Hepatology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Maura Corsetti
- National Institute for Health Research, Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK.,Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK
| | - Antonio Di Sabatino
- First Department of Internal Medicine, IRCCS San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Anca Mirela Dimitriu
- Center of Gastroenterology and Hepatology, Fundeni Clinical Institute, University of Medicine and Pharmacy, Bucharest, Romania
| | - Vasile Drug
- Department of Gastroenterology, 'Grigore T. Popa' University of Medicine and Pharmacy, Iasi, Romania.,Institute of Gastroenterology and Hepatology, 'Saint Spiridon' Hospital, Iasi, Romania
| | - Dan L Dumitrascu
- 2nd Department of Internal Medicine, 'Iuliu Hatieganu' University of Medicine and Farmacy, Cluj-Napoca, Romania
| | - Alexander C Ford
- Leeds Gastroenterology Institute, Leeds Teaching Hospitals NHS Trust, Leeds, UK.,Leeds Institute of Medical Research at St. James's Sciences, University of Leeds, Leeds, UK
| | - Goran Hauser
- Department of Gastroenterology, Clinical Hospital Center Rijeka, Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | - Radislav Nakov
- Department of Gastroenterology, Tsaritsa Yoanna University Hospital, Medical University of Sofia, Sofia, Bulgaria
| | - Nisha Patel
- Imperial College Healthcare NHS Trust, Institute of Global Health Innovation, St Mary's Hospital Campus, London, UK
| | - Daniel Pohl
- Department of Gastroenterology, University Hospital Zurich, Zurich, Switzerland
| | - Cătălin Sfarti
- Department of Gastroenterology, 'Grigore T. Popa' University of Medicine and Pharmacy, Iasi, Romania.,Institute of Gastroenterology and Hepatology, 'Saint Spiridon' Hospital, Iasi, Romania
| | - Jordi Serra
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Badalona, Spain.,Digestive System Research Unit, University Hospital Vall d'Hebron, Barcelona, Spain.,Department of Medicine, Autonomous University of Barcelona, Badalona, Spain
| | - Magnus Simrén
- Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Alina Suciu
- Center of Gastroenterology and Hepatology, Fundeni Clinical Institute, University of Medicine and Pharmacy, Bucharest, Romania
| | - Jan Tack
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
| | - Murat Toruner
- Department of Gastroenterology, Ankara University School of Medicine, Ankara, Turkey
| | - Julian Walters
- Division of Digestive Diseases, Department of Metabolism, Digestion, and Reproduction, Faculty of Medicine, Imperial College London, London, UK.,Department of Gastroenterology, Division of Medicine and Integrated Care, Imperial College Healthcare NHS Trust, London, UK
| | - Cesare Cremon
- Division of Internal Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Giovanni Barbara
- Division of Internal Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
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14
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Huang H, Lu L, Chen Y, Zeng Y, Xu C. The efficacy of vitamin D supplementation for irritable bowel syndrome: a systematic review with meta-analysis. Nutr J 2022; 21:24. [PMID: 35509010 PMCID: PMC9069731 DOI: 10.1186/s12937-022-00777-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 04/14/2022] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder involving gut-brain interactions with limited effective treatment options. Vitamin D deficiency is commonly observed in patients with IBS, but whether vitamin D supplementation ameliorates IBS is controversial in randomized controlled trials. The present systematic review and meta-analysis explored the efficacy of vitamin D supplementation in patients with IBS. METHODS We performed a systematic search of potentially relevant publications from PubMed, EMBASE, the Cochrane Central Register of Controlled Studies and the Web of Science up until January 2022. We assessed the weighted mean difference (WMD) and 95% confidence interval (95% CI) of the IBS severity scoring system (IBS-SSS), IBS quality of life (IBS-QoL) and IBS total score (IBS-TS) before and after vitamin D supplementation intervention. RESULTS We included four randomized, placebo-controlled trials involving 335 participants. The differences in IBS-SSS score between participants in the intervention group and the placebo group increased after intervention (WMD: -55.55, 95% CI: -70.22 to -40.87, I2 = 53.7%, after intervention; WMD: -3.17, 95% CI: -18.15 to 11.81, I2 = 0.0%, before intervention). Participants receiving vitamin D supplementation showed greater improvement in IBS-SSS after intervention than participants receiving placebo treatment (WMD: -84.21, 95% CI: -111.38 to -57.05, I2 = 73.2%; WMD: -28.29, 95% CI: -49.95 to -6.62, I2 = 46.6%, respectively). Vitamin D supplementation was also superior to placebo in IBS-QoL improvement (WMD: 14.98, 95% CI: 12.06 to 17.90, I2 = 0.0%; WMD: 6.55, 95% CI: -2.23 to 15.33, I2 = 82.7%, respectively). Sensitivity analyses revealed an unstable pooled effect on IBS-TS in participants receiving vitamin D supplementation. Therefore, we did not evaluate the efficacy of vitamin D intervention in IBS-TS. CONCLUSIONS This systematic review and meta-analysis suggested that vitamin D supplementation was superior to placebo for IBS treatment.
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Affiliation(s)
- Hangkai Huang
- Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, 310003, Hangzhou, China
| | - Linjie Lu
- Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, 310003, Hangzhou, China
- Department of Gastroenterology, Haining Branch of the First Affiliated Hospital, Zhejiang University School of Medicine, 314499, Haining, China
| | - Yishu Chen
- Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, 310003, Hangzhou, China
| | - Yan Zeng
- Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, 310003, Hangzhou, China
| | - Chengfu Xu
- Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, 310003, Hangzhou, China.
- Department of Gastroenterology, Haining Branch of the First Affiliated Hospital, Zhejiang University School of Medicine, 314499, Haining, China.
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15
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Kindt S, Louis H, De Schepper H, Arts J, Caenepeel P, De Looze D, Gerkens A, Holvoet T, Latour P, Mahler T, Mokaddem F, Nullens S, Piessevaux H, Poortmans P, Rasschaert G, Surmont M, Vafa H, Van Malderen K, Vanuytsel T, Wuestenberghs F, Tack J. Belgian consensus on irritable bowel syndrome. Acta Gastroenterol Belg 2022; 85:360-382. [PMID: 35709780 DOI: 10.51821/85.2.10100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is characterised by recurrent abdominal pain related to defaecation or associated with altered stool frequency or consistency. Despite its prevalence, major uncertainties in the diagnostic and therapeutic management persist in clinical practice. METHODS A Delphi consensus was conducted by 20 experts from Belgium, and consisted of literature review and voting process on 78 statements. Grading of recommendations, assessment, development and evaluation criteria were applied to evaluate the quality of evidence. Consensus was defined as > 80 % agreement. RESULTS Consensus was reached for 50 statements. The Belgian consensus agreed as to the multifactorial aetiology of IBS. According to the consensus abdominal discomfort also represents a cardinal symptom, while bloating and abdominal distension often coexist. IBS needs subtyping based on stool pattern. The importance of a positive diagnosis, relying on history and clinical examination is underlined, while additional testing should remain limited, except when alarm features are present. Explanation of IBS represents a crucial part of patient management. Lifestyle modification, spasmolytics and water-solube fibres are considered first-line agents. The low FODMAP diet, selected probiotics, cognitive behavioural therapy and specific treatments targeting diarrhoea and constipation are considered appropriate. There is a consensus to restrict faecal microbiota transplantation and gluten-free diet, while other treatments are strongly discouraged. CONCLUSIONS A panel of Belgian gastroenterologists summarised the current evidence on the aetiology, symptoms, diagnosis and treatment of IBS with attention for the specificities of the Belgian healthcare system.
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Affiliation(s)
- S Kindt
- Department of gastroenterology and Hepatology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussel, Belgium
| | - H Louis
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme University Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070 Brussels, Belgium
| | - H De Schepper
- Department of Gastroenterology and Hepatology, University Hospital Antwerp, Antwerp, Belgium
| | - J Arts
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
- Department of Gastroenterology, AZ Sint-Lucas, Brugge, Belgium
| | - P Caenepeel
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
- Department of Gastroenterology, Ziekenhuis Oost-Limburg, Campus Sint-Jan, Genk, Belgium
- UHasselt, Hasselt, Belgium
| | - D De Looze
- Department of Gastroenterology and Hepatology, University Hospital Ghent, Gent, Belgium
| | - A Gerkens
- Boitsfort Medical Center, Brussels, Belgium
| | - T Holvoet
- Department of Gastroenterology and Hepatology, University Hospital Ghent, Gent, Belgium
- Department of Gastroenterology, AZ Nikolaas, Sint Niklaas, Belgium
| | - P Latour
- Department of Gastroenterology, Hepatology and Digestive Oncology, Centre Hospitalier Universitaire de Liège, Liège, Belgium
| | - T Mahler
- Department of Pediatrics, Universitair Ziekenuis Brussel, Brussel, Belgium
| | - F Mokaddem
- Department of Gastroenterology and Hepatology, Vivalia-Centre Sud Luxembourg, Arlon, Belgium
| | - S Nullens
- Department of Gastroenterology and Hepatology, University Hospital Antwerp, Antwerp, Belgium
| | - H Piessevaux
- Department of Hepato-gastroenterology, Cliniques universitaires St-Luc, Université catholique de Louvain, Brussels, Belgium
| | - P Poortmans
- Department of gastroenterology and Hepatology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussel, Belgium
| | - G Rasschaert
- Department of gastroenterology and Hepatology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussel, Belgium
| | - M Surmont
- Department of gastroenterology and Hepatology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussel, Belgium
| | - H Vafa
- Department of Gastroenterology and Hepatology, Chirec-Site Delta, Brussels, Belgium
| | - K Van Malderen
- Department of Gastroenterology and Hepatology, University Hospital Antwerp, Antwerp, Belgium
| | - T Vanuytsel
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - F Wuestenberghs
- Department of Gastroenterology and Hepatology, CHU UCL Namur, Université catholique de Louvain, Yvoir, Belgium
| | - J Tack
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
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16
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Layer P, Andresen V, Allescher H, Bischoff SC, Claßen M, Elsenbruch S, Freitag M, Frieling T, Gebhard M, Goebel-Stengel M, Häuser W, Holtmann G, Keller J, Kreis ME, Kruis W, Langhorst J, Jansen PL, Madisch A, Mönnikes H, Müller-Lissner S, Niesler B, Pehl C, Pohl D, Raithel M, Röhrig-Herzog G, Schemann M, Schmiedel S, Schwille-Kiuntke J, Storr M, Preiß JC, Andus T, Buderus S, Ehlert U, Engel M, Enninger A, Fischbach W, Gillessen A, Gschossmann J, Gundling F, Haag S, Helwig U, Hollerbach S, Karaus M, Katschinski M, Krammer H, Kuhlbusch-Zicklam R, Matthes H, Menge D, Miehlke S, Posovszky MC, Schaefert R, Schmidt-Choudhury A, Schwandner O, Schweinlin A, Seidl H, Stengel A, Tesarz J, van der Voort I, Voderholzer W, von Boyen G, von Schönfeld J, Wedel T. Update S3-Leitlinie Reizdarmsyndrom: Definition, Pathophysiologie, Diagnostik und Therapie. Gemeinsame Leitlinie der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) und der Deutschen Gesellschaft für Neurogastroenterologie und Motilität (DGNM) – Juni 2021 – AWMF-Registriernummer: 021/016. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2021; 59:1323-1415. [PMID: 34891206 DOI: 10.1055/a-1591-4794] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- P Layer
- Medizinische Klinik, Israelitisches Krankenhaus, Hamburg, Deutschland
| | - V Andresen
- Medizinische Klinik, Israelitisches Krankenhaus, Hamburg, Deutschland
| | - H Allescher
- Zentrum für Innere Medizin, Gastroent., Hepatologie u. Stoffwechsel, Klinikum Garmisch-Partenkirchen, Garmisch-Partenkirchen, Deutschland
| | - S C Bischoff
- Institut für Ernährungsmedizin, Universität Hohenheim, Stuttgart, Deutschland
| | - M Claßen
- Klinik für Kinder- und Jugendmedizin, Klinikum Links der Weser, Bremen, Deutschland
| | - S Elsenbruch
- Klinik für Neurologie, Translational Pain Research Unit, Universitätsklinikum Essen, Essen, Deutschland.,Abteilung für Medizinische Psychologie und Medizinische Soziologie, Ruhr-Universität Bochum, Bochum, Deutschland
| | - M Freitag
- Abteilung Allgemeinmedizin Department für Versorgungsforschung, Universität Oldenburg, Oldenburg, Deutschland
| | - T Frieling
- Medizinische Klinik II, Helios Klinikum Krefeld, Krefeld, Deutschland
| | - M Gebhard
- Gemeinschaftspraxis Pathologie-Hamburg, Hamburg, Deutschland
| | - M Goebel-Stengel
- Innere Medizin II, Helios Klinik Rottweil, Rottweil, und Innere Medizin VI, Psychosomat. Medizin u. Psychotherapie, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | - W Häuser
- Innere Medizin I mit Schwerpunkt Gastroenterologie, Klinikum Saarbrücken, Saarbrücken, Deutschland
| | - G Holtmann
- Faculty of Medicine & Faculty of Health & Behavioural Sciences, Princess Alexandra Hospital, Brisbane, Australien
| | - J Keller
- Medizinische Klinik, Israelitisches Krankenhaus, Hamburg, Deutschland
| | - M E Kreis
- Klinik für Allgemein-, Viszeral- und Gefäßchirurgie, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Deutschland
| | | | - J Langhorst
- Klinik für Integrative Medizin und Naturheilkunde, Sozialstiftung Bamberg, Klinikum am Bruderwald, Bamberg, Deutschland
| | - P Lynen Jansen
- Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten, Berlin, Deutschland
| | - A Madisch
- Klinik für Gastroenterologie, interventionelle Endoskopie und Diabetologie, Klinikum Siloah, Klinikum Region Hannover, Hannover, Deutschland
| | - H Mönnikes
- Klinik für Innere Medizin, Martin-Luther-Krankenhaus, Berlin, Deutschland
| | | | - B Niesler
- Abteilung Molekulare Humangenetik Institut für Humangenetik, Universitätsklinikum Heidelberg, Heidelberg, Deutschland
| | - C Pehl
- Medizinische Klinik, Krankenhaus Vilsbiburg, Vilsbiburg, Deutschland
| | - D Pohl
- Klinik für Gastroenterologie und Hepatologie, Universitätsspital Zürich, Zürich, Schweiz
| | - M Raithel
- Medizinische Klinik II m.S. Gastroenterologie und Onkologie, Waldkrankenhaus St. Marien, Erlangen, Deutschland
| | | | - M Schemann
- Lehrstuhl für Humanbiologie, TU München, Deutschland
| | - S Schmiedel
- I. Medizinische Klinik und Poliklinik Gastroenterologie, Universitätsklinikum Hamburg-Eppendorf, Deutschland
| | - J Schwille-Kiuntke
- Abteilung für Psychosomatische Medizin und Psychotherapie, Medizinische Universitätsklinik Tübingen, Tübingen, Deutschland.,Institut für Arbeitsmedizin, Sozialmedizin und Versorgungsforschung, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | - M Storr
- Zentrum für Endoskopie, Gesundheitszentrum Starnberger See, Starnberg, Deutschland
| | - J C Preiß
- Klinik für Innere Medizin - Gastroenterologie, Diabetologie und Hepatologie, Vivantes Klinikum Neukölln, Berlin, Deutschland
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17
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Pesce M, Puoti MG, Rybak A, Andreozzi M, Bruzzese E, Sarnelli G, Borrelli O. Pharmacological interventions for pediatric irritable bowel syndrome. Expert Opin Pharmacother 2021; 23:91-103. [PMID: 34523358 DOI: 10.1080/14656566.2021.1976753] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Irritable bowel syndrome is a common functional gastrointestinal disorder in children, characterized by recurrent abdominal pain associated with altered bowel habits in terms of both frequency and consistency. According to change in stool consistency it is categorized into 4 subtypes. From the etiological perspective, it is a combination of factors takes part in symptoms' generation, the overall treatment response rate is often unsatisfactory if a multidisciplinary is not pursued. AREAS COVERED The aim of this manuscript is to summarize the current pharmacotherapy in pediatric irritable bowel syndrome in order to aid clinicians in treating this challenging disorder. EXPERT OPINION Most evidence involving pediatric populations rely on open label or retrospective studies and/or are not specifically designed for irritable bowel syndrome but tend to generalize their results to mixed populations of children with functional gastrointestinal disorders. A high placebo response rate combined with poor patients' selection could account for the overall weak evidence supporting the use of pharmacological agents in pediatric irritable bowel syndrome. Given the multifaceted nature of the disorder, multidisciplinary approaches combining pharmacotherapy with alternative treatments is highly recommendable.
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Affiliation(s)
- Marcella Pesce
- Department of Clinical Medicine and Surgery, University "Federico Ii" of Naples, Naples, Italy
| | - Maria Giovanna Puoti
- Division of Neurogastroenterology & Motility, Department of Paediatric Gastroenterology, Great Ormond Street Hospital for children, London, UK
| | - Anna Rybak
- Division of Neurogastroenterology & Motility, Department of Paediatric Gastroenterology, Great Ormond Street Hospital for children, London, UK
| | - Marta Andreozzi
- Department of Clinical Medicine and Surgery, University "Federico Ii" of Naples, Naples, Italy
| | - Eugenia Bruzzese
- Department of Translational Medical Science, University "Federico Ii" of Naples, Naples, Italy
| | - Giovanni Sarnelli
- Department of Clinical Medicine and Surgery, University "Federico Ii" of Naples, Naples, Italy
| | - Osvaldo Borrelli
- Division of Neurogastroenterology & Motility, Department of Paediatric Gastroenterology, Great Ormond Street Hospital for children, London, UK
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18
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Malinky CA, Lindsley CW, Han C. DARK Classics in Chemical Neuroscience: Loperamide. ACS Chem Neurosci 2021; 12:2964-2973. [PMID: 34346690 DOI: 10.1021/acschemneuro.1c00382] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Loperamide, a popular and inexpensive over-the-counter antidiarrheal medicine, is a potent μ-opioid receptor agonist approved by the U.S. Food and Drug Administration (FDA). It has been on the market since 1976 and is relatively safe with no central nervous system-related side effects when used for a short period of time at the recommended therapeutic dose (2-8 mg/day). In recent years, loperamide has become notoriously known as the "poor man's methadone" for people with substance dependence due to the increase in loperamide overdoses from self-administered medication to treat opioid withdrawal symptoms. As a result, in 2018, the FDA decided to limit the available packaged dose of loperamide to stop prominent abuse. This review provides the synthesis and chemical properties of loperamide as well as the pharmacology and adverse effects of its use and the social effects of such abuse.
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Affiliation(s)
- Cori A. Malinky
- Warren Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
| | - Craig W. Lindsley
- Warren Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
- Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
- Department of Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232, United States
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
| | - Changho Han
- Warren Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
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19
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Narayanan SP, Anderson B, Bharucha AE. Sex- and Gender-Related Differences in Common Functional Gastroenterologic Disorders. Mayo Clin Proc 2021; 96:1071-1089. [PMID: 33814075 PMCID: PMC8075061 DOI: 10.1016/j.mayocp.2020.10.004] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 09/07/2020] [Accepted: 10/02/2020] [Indexed: 12/11/2022]
Abstract
Functional gastrointestinal (GI) disorders (FGIDs) result from central and peripheral mechanisms, cause chronic remitting-relapsing symptoms, and are associated with comorbid conditions and impaired quality of life. This article reviews sex- and gender-based differences in the prevalence, pathophysiologic factors, clinical characteristics, and management of functional dyspepsia (FD) and irritable bowel syndrome (IBS) that together affect approximately 1 in 4 people in the United States. These conditions are more common in women. Among patients with IBS, women are more likely to have severe symptoms and coexistent anxiety or depression; constipation or bloating and diarrhea are more common in women and men, respectively, perhaps partly because defecatory disorders, which cause constipation, are more common in women. Current concepts suggest that biological disturbances (eg, persistent mucosal inflammation after acute gastroenteritis) interact with other environmental factors (eg, abuse) and psychological stressors, which influence the brain and gut to alter GI tract motility or sensation, thereby causing symptoms. By comparison to a considerable understanding of sex-based differences in the pathogenesis of visceral hypersensitivity in animal models, we know less about the contribution of these differences to FGID in humans. Slow gastric emptying and colon transit are more common in healthy women than in men, but effects of gonadal hormones on colon transit are less important than in rodents. Although increased visceral sensation partly explains symptoms, the effects of sex on visceral sensation, colonic permeability, and the gut microbiome are less prominent in humans than rodents. Whether sex or gender affects response to medications or behavioral therapy in FD or IBS is unclear because most patients in these studies are women.
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Affiliation(s)
| | | | - Adil E Bharucha
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.
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20
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Li X, Li B, Zhang J, Chen T, Wu H, Shi X, Ma J, Qin J, Tang X, Wang F. Efficacy of opioid receptor modulators in patients with irritable bowel syndrome: A systematic review and meta-analysis. Medicine (Baltimore) 2021; 100:e24361. [PMID: 33530231 PMCID: PMC7850711 DOI: 10.1097/md.0000000000024361] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 10/03/2020] [Accepted: 12/21/2020] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND While irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal diseases in clinical practice, it has diverse pathogenesis. Because of its sudden and lingering intractable symptoms, it seriously affects patients work and life. Opioid receptors are G protein-coupled receptors distributed across the brain, spinal cord, skin, and gastrointestinal tract, and each of the subtypes has a unique role and specific distribution. They play a role in regulating gastrointestinal motility, secretion, and visceral sensations in the gastrointestinal tract. Therefore, this meta-analysis aims to evaluate the effects of opioid receptor modulators on improving the symptoms of IBS. METHODS Searching the key words (Irritable Bowel Syndromes or Syndrome, Irritable Bowel OR Syndromes, Irritable Bowel OR Colon, Irritable OR Irritable Colon OR Colitis, Mucous OR Colitides, Mucous OR Mucous Colitides OR Mucous Colitis) AND (opioid receptor modulators OR eluxadoline OR Viberzi OR asimadoline OR loperamide), a preliminary search on PubMed (English), EMBASE (English), Cochrane Library (English), China National Knowledge Infrastructure Database (CNKI, Chinese), WanFang (Chinese), VIP citation databases (Chinese) and SinoMed (Chinese) databases yielded 1023 papers published in English and Chinese from inception to July 1, 2019. Nine studies were included in the final meta-analysis. Because this is a systematic review and meta-analysis, ethical approval is not necessary. RESULTS The random-effects meta-analysis based on these 9 studies and their 4156 patients found that opioid receptor modulators have a statistically significant beneficial effect on IBS global symptoms (RR = 0.85, 95%CI = 0.79-0.92, P < .01) and bowel movement frequency (SMD = -1.26, 95%CI = -2.49--0.04, P < .05), and while there was an improvement trend in stool consistency and quality of life, these findings were not statistically significant. CONCLUSIONS This is the first meta-analysis to examine the use of opioid receptor modulators in IBS, and few adverse events were reported in the available trials. Compared with the control group, eluxadolin has a better effect in improving IBS global symptoms and abdominal pain and has statistical significance and showed a low rate of constipation development in IBS patients in comparison with known effects of other opioid receptor modulators. However, current findings are based on a considerably limited evidence base with marked heterogeneity. Future studies should aim to identify subpopulations of patients with IBS and need to evaluate the long-term safety of these therapies.PROSPERO registration number: CRD42020141597.
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Affiliation(s)
- Xia Li
- Graduate School of Beijing University of Chinese Medicine
| | - Bo Li
- Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing Institute of Traditional Chinese Medicine
| | - Jiaqi Zhang
- Xiyuan Hospital Affiliated to China Academy of Traditional Chinese Sciences, Beijing Institute of Spleen and Stomach Disease of Traditional Chinese Medicine
| | - Ting Chen
- Xiyuan Hospital Affiliated to China Academy of Traditional Chinese Sciences, Beijing Institute of Spleen and Stomach Disease of Traditional Chinese Medicine
| | - Haomeng Wu
- Xiyuan Hospital Affiliated to China Academy of Traditional Chinese Sciences, Beijing Institute of Spleen and Stomach Disease of Traditional Chinese Medicine
| | - Xiaoshuang Shi
- Institute of Acupuncture and Moxibustion, Center for Post-doctoral Studies, China Academy of Chinese Medical Sciences
| | - Jinxin Ma
- Department of Gastroenterology, Peking University Traditional Chinese Medicine Clinical Medical School (Xiyuan), Beijing, China
| | - Jinyan Qin
- Graduate School of Beijing University of Chinese Medicine
| | - Xudong Tang
- Xiyuan Hospital Affiliated to China Academy of Traditional Chinese Sciences, Beijing Institute of Spleen and Stomach Disease of Traditional Chinese Medicine
| | - Fengyun Wang
- Xiyuan Hospital Affiliated to China Academy of Traditional Chinese Sciences, Beijing Institute of Spleen and Stomach Disease of Traditional Chinese Medicine
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21
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Quitadamo P, Isoldi S, Mallardo S, Zenzeri L, Di Nardo G. Scientific Evidence for the Treatment of Children with Irritable Bowel Syndrome. Curr Pediatr Rev 2021; 17:92-102. [PMID: 33504308 DOI: 10.2174/1573396317666210127123330] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 10/20/2020] [Accepted: 11/05/2020] [Indexed: 11/22/2022]
Abstract
Irritable bowel syndrome (IBS) is one of the most common functional gastro-intestinal disorders which significantly impacts the quality of life of affected children. Abdominal pain improved by defecation, associated with a change in stool form and frequency, represents its specific clinical marker. Even if a number of potential patho-physiological mechanisms have been described, the exact underlying etiology of IBS is so far unclear. Likewise, no optimal treatment has ever been found neither for adult nor for pediatric patients. Current therapeutic options include drugs, dietary interventions and biopsychosocial therapies. The present review aims at evaluating the scientific evidence supporting the efficacy of these treatments for children with IBS.
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Affiliation(s)
- Paolo Quitadamo
- Department of Pediatrics, A.O.R.N. Santobono-Pausilipon, Naples, Italy
| | - Sara Isoldi
- Maternal and Child Health Department, Sapienza - University of Rome, Santa Maria Goretti Hospital, Polo Pontino, Latina, Italy
| | - Saverio Mallardo
- Maternal and Child Health Department, Sapienza - University of Rome, Santa Maria Goretti Hospital, Polo Pontino, Latina, Italy
| | - Letizia Zenzeri
- Pediatric Emergency Unit, Santobono-Pausilipon Children's Hospital, Naples, Italy
| | - Giovanni Di Nardo
- Chair of Pediatrics, Pediatric Gastroenterology and Endoscopy Unit, NESMOS Department, Faculty School of Medicine and Psychology, Sapienza University of Rome, Sant'Andrea University Hospital, Rome, Italy
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22
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Masuy I, Pannemans J, Tack J. Irritable bowel syndrome: diagnosis and management. MINERVA GASTROENTERO 2020; 66:136-150. [DOI: 10.23736/s1121-421x.19.02640-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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23
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Roudsari NM, Lashgari NA, Momtaz S, Farzaei MH, Marques AM, Abdolghaffari AH. Natural polyphenols for the prevention of irritable bowel syndrome: molecular mechanisms and targets; a comprehensive review. Daru 2019; 27:755-780. [PMID: 31273572 PMCID: PMC6895345 DOI: 10.1007/s40199-019-00284-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Accepted: 06/14/2019] [Indexed: 12/12/2022] Open
Abstract
Irritable bowel syndrome (IBS) is a well diagnosed disease, thoroughly attributed to series of symptoms criteria that embrace a broad range of abdominal complainers. Such criteria help to diagnosis the disease and can guide controlled clinical trials to seek new therapeutic agents. Accordingly, a verity of mechanisms and pathophysiological conditions including inflammation, oxidative stress, lipid peroxidation and different life styles are involved in IBS. Predictably, diverse therapeutic approaches are available and prescribed by clinicians due to major manifestations (i.e., diarrhea-predominance, constipation-predominance, abdominal pain and visceral hypersensitivity), psychological disturbances, and patient preferences between herbal treatments versus pharmacological therapies, dietary or microbiological approaches. Herein, we gathered the latest scientific data between 1973 and 2019 from databases such as PubMed, Google Scholar, Scopus and Cochrane library on relevant studies concerning beneficial effects of herbal treatments for IBS, in particular polyphenols. This is concluded that polyphenols might be applicable for preventing IBS and improving the IBS symptoms, mainly through suppressing the inflammatory signaling pathways, which nowadays are known as novel platform for the IBS management. Graphical abstract.
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Affiliation(s)
- Nazanin Momeni Roudsari
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran
| | - Naser-Aldin Lashgari
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran
| | - Saeideh Momtaz
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, Iran
- Toxicology and Diseases Group, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
- Department of Toxicology and Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hosein Farzaei
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| | - André M Marques
- Oswaldo Cruz Foundation (FIOCRUZ), Institute of Technology in Pharmaceuticals (Farmanguinhos), Rio de Janeiro, RJ, Brazil
| | - Amir Hossein Abdolghaffari
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran.
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, Iran.
- Toxicology and Diseases Group, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran.
- Department of Toxicology and Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.
- Gastrointestinal Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
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24
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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: 50] [Impact Index Per Article: 8.3] [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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25
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Gwee KA, Gonlachanvit S, Ghoshal UC, Chua ASB, Miwa H, Wu J, Bak YT, Lee OY, Lu CL, Park H, Chen M, Syam AF, Abraham P, Sollano J, Chang CS, Suzuki H, Fang X, Fukudo S, Choi MG, Hou X, Hongo M. Second Asian Consensus on Irritable Bowel Syndrome. J Neurogastroenterol Motil 2019; 25:343-362. [PMID: 31327218 PMCID: PMC6657923 DOI: 10.5056/jnm19041] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 05/13/2019] [Accepted: 06/24/2019] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND/AIMS There has been major progress in our understanding of the irritable bowel syndrome (IBS), and novel treatment classes have emerged. The Rome IV guidelines were published in 2016 and together with the growing body of Asian data on IBS, we felt it is timely to update the Asian IBS Consensus. METHODS Key opinion leaders from Asian countries were organized into 4 teams to review 4 themes: symptoms and epidemiology, pathophysiology, diagnosis and investigations, and lifestyle modifications and treatments. The consensus development process was carried out by using a modified Delphi method. RESULTS Thirty-seven statements were developed. Asian data substantiate the current global viewpoint that IBS is a disorder of gut-brain interaction. Socio-cultural and environmental factors in Asia appear to influence the greater overlap between IBS and upper gastrointestinal symptoms. New classes of treatments comprising low fermentable oligo-, di-, monosacharides, and polyols diet, probiotics, non-absorbable antibiotics, and secretagogues have good evidence base for their efficacy. CONCLUSIONS Our consensus is that all patients with functional gastrointestinal disorders should be evaluated comprehensively with a view to holistic management. Physicians should be encouraged to take a positive attitude to the treatment outcomes for IBS patients.
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Affiliation(s)
- Kok Ann Gwee
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, and Gleneagles Hospital,
Singapore
| | - Sutep Gonlachanvit
- Center of Excellence on Neurogastroenterology and Motility, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok,
Thailand
- Correspondence: Sutep Gonlachanvit, MD, Center of Excellence on Neurogastroenterology and Motility, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand, Tel: +66-2-256-4265, Fax: +66-2-252-7839, E-mail:
| | - Uday C Ghoshal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow,
India
| | | | - Hiroto Miwa
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Mukogawa-cho, Nishinomiya, Hyogo,
Japan
| | - Justin Wu
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, New Territories,
Hong Kong
| | - Young-Tae Bak
- Department of Internal Medicine, Korea University College of Medicine, Seoul,
Korea
| | - Oh Young Lee
- Department of Gastroenterology, College of Medicine, Hanyang University, Seoul,
Korea
| | - Ching-Liang Lu
- Endoscopy Center for Diagnosis and Treatment, Taipei Veterans General Hospital, Taipei,
Taiwan
| | - Hyojin Park
- Division of Gastroenterology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul,
Korea
| | - Minhu Chen
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou,
China
| | - Ari F Syam
- Division of Gastroenterology, Departement of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta,
Indonesia
| | - Philip Abraham
- Division of Gastroenterology, P D Hinduja Hospital, Mumbai,
India
| | - Jose Sollano
- Department of Internal Medicine, Division of Gastroenterology, University of Santo Tomas, Manila,
Philippine
| | - Chi-Sen Chang
- Taichung Veterans General Hospital, Taiwan Boulevard, Taichung City,
Taiwan
| | - Hidekazu Suzuki
- Department of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Kanagawa,
Japan
| | - Xiucai Fang
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing,
China
| | - Shin Fukudo
- Department of Behavioral Medicine, Tohoku University Graduate School of Medicine, Aoba Sendai,
Japan
| | - Myung-Gyu Choi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Catholic University of Korea, Seoul,
Korea
| | - Xiaohua Hou
- Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan,
China
| | - Michio Hongo
- Department of Medicine, Kurokawa General Hospital, Kurokawa, Miyagi,
Japan
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26
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Moayyedi P, Andrews CN, MacQueen G, Korownyk C, Marsiglio M, Graff L, Kvern B, Lazarescu A, Liu L, Paterson WG, Sidani S, Vanner S. Canadian Association of Gastroenterology Clinical Practice Guideline for the Management of Irritable Bowel Syndrome (IBS). J Can Assoc Gastroenterol 2019; 2:6-29. [PMID: 31294724 PMCID: PMC6507291 DOI: 10.1093/jcag/gwy071] [Citation(s) in RCA: 111] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Accepted: 11/04/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND & AIMS Irritable bowel syndrome (IBS) is one of the most common gastrointestinal (GI) disorders, affecting about 10% of the general population globally. The aim of this consensus was to develop guidelines for the management of IBS. METHODS A systematic literature search identified studies on the management of IBS. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an iterative online platform and then finalized and voted on by a multidisciplinary group of clinicians and a patient. RESULTS Consensus was reached on 28 of 31 statements. Irritable bowel syndrome is diagnosed based on symptoms; serological testing is suggested to exclude celiac disease, but routine testing for C-reactive protein (CRP), fecal calprotectin or food allergies is not recommended. A trial of a low fermentable oligosaccharides, disaccharides, monosaccharides, polyols (FODMAP) diet is suggested, while a gluten-free diet is not. Psyllium, but not wheat bran, supplementation may help reduce symptoms. Alternative therapies such as peppermint oil and probiotics are suggested, while herbal therapies and acupuncture are not. Cognitive behavioural therapy and hypnotherapy are suggested psychological therapies. Among the suggested or recommended pharmacological therapies are antispasmodics, certain antidepressants, eluxadoline, lubiprostone, and linaclotide. Loperamide, cholestyramine and osmotic laxatives are not recommended for overall IBS symptoms. The nature of the IBS symptoms (diarrhea-predominant or constipation-predominant) should be considered in the choice of pharmacological treatments. CONCLUSIONS Patients with IBS may benefit from a multipronged, individualized approach to treatment, including dietary modifications, psychological and pharmacological therapies.
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Affiliation(s)
- Paul Moayyedi
- Division of Gastroenterology, McMaster University, Hamilton, Ontario, Canada
| | | | - Glenda MacQueen
- Department of Psychiatry, University of Calgary, Calgary, Alberta, Canada
| | - Christina Korownyk
- Department of Family Medicine, University of Alberta, Edmonton, Alberta, Canada
| | | | - Lesley Graff
- Department of Clinical Health Psychology, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Brent Kvern
- Department of Family Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Adriana Lazarescu
- Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada
| | - Louis Liu
- Division of Gastroenterology, University of Toronto, Toronto, Ontario, Canada
| | - William G Paterson
- Division of Gastroenterology, Queen’s University, Kingston, Ontario, Canada
| | - Sacha Sidani
- Division of Gastroenterology, McMaster University, Hamilton, Ontario, Canada
| | - Stephen Vanner
- Division of Gastroenterology, Queen’s University, Kingston, Ontario, Canada
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27
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Kim JH, Jee SR. Irritable Bowel Syndrome. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2019; 73:84-91. [DOI: 10.4166/kjg.2019.73.2.84] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 01/28/2019] [Accepted: 02/01/2019] [Indexed: 12/13/2022]
Affiliation(s)
- Jae Hak Kim
- Department of Internal Medicine, Dongguk University College of Medicine, Goyang, Korea
| | - Sam Ryong Jee
- Department of Internal Medicine, Inje University College of Medicine, Busan, Korea
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28
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Simrén M, Tack J. New treatments and therapeutic targets for IBS and other functional bowel disorders. Nat Rev Gastroenterol Hepatol 2018; 15:589-605. [PMID: 29930260 DOI: 10.1038/s41575-018-0034-5] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Functional bowel disorders (FBDs) are a spectrum of disorders characterized by combinations of symptoms attributable to the lower gastrointestinal tract. Most current first-line therapies for IBS and other FBDs target the predominant symptom and mainly affect one symptom in the symptom complex. Additional broadly effective treatment alternatives targeting the entire symptom complex are needed. New drugs for FBDs (such as lubiprostone, linaclotide, plecanatide, prucalopride, eluxadoline and rifaximin) target key mechanisms in the pathophysiology of these disorders and improve both the abnormal bowel habit and other key symptoms, such as abdominal pain and bloating. The current development of new treatment alternatives is focusing on different aspects of the complex pathophysiology of IBS and other FBDs: gut microenvironment (via diet and modulation of gut microbiota), enterohepatic circulation of bile acids, gastrointestinal secretion, motility and sensation, gut-brain interactions, gut barrier function and the immune system within the gastrointestinal tract. Studies also suggest that personalized treatment of IBS and other FBDs is possible using various diagnostic markers.
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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, Chapel Hill, NC, USA.
| | - Jan Tack
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
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29
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Pannemans J, Corsetti M. Opioid receptors in the GI tract: targets for treatment of both diarrhea and constipation in functional bowel disorders? Curr Opin Pharmacol 2018; 43:53-58. [PMID: 30189347 DOI: 10.1016/j.coph.2018.08.008] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 08/11/2018] [Accepted: 08/13/2018] [Indexed: 02/08/2023]
Abstract
Opioids have been used for centuries, mostly as a sedative and to treat pain. Currently, they are used on a global scale for the treatment of acute and chronic pain in diseases as osteoarthritis, fibromyalgia, and low back pain. Binding of opioids on opioid receptors can cause a range of different effects such as changes in stress response, analgesia, motor activity and autonomic functions. This review provide a synthetic summary of the most recent literature on the use of drugs acting on mu-receptors to treat two prevalent functional bowel disorders, presenting with opposite bowel habit. Eluxadoline and naloxegol, methylnaltrexone and naldemedine are recently FDA and/or EMA approved drugs demonstrated to be effective and safe for treatment respectively of irritable bowel syndrome subtype diarrhea and opioid induced constipation.
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Affiliation(s)
- J Pannemans
- Catholic University of Leuven, KU Leuven, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium
| | - M Corsetti
- NIHR Nottingham Biomedical Research Centre (BRC), Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK; Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK.
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Song KH, Jung HK, Kim HJ, Koo HS, Kwon YH, Shin HD, Lim HC, Shin JE, Kim SE, Cho DH, Kim JH, Kim HJ. Clinical Practice Guidelines for Irritable Bowel Syndrome in Korea, 2017 Revised Edition. J Neurogastroenterol Motil 2018; 24:197-215. [PMID: 29605976 PMCID: PMC5885719 DOI: 10.5056/jnm17145] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Revised: 02/11/2018] [Accepted: 02/27/2018] [Indexed: 12/12/2022] Open
Abstract
In 2011, the Korean Society of Neurogastroenterology and Motility (KSNM) published clinical practice guidelines on the management of irritable bowel syndrome (IBS) based on a systematic review of the literature. The KSNM planned to update the clinical practice guidelines to support primary physicians, reduce the socioeconomic burden of IBS, and reflect advances in the pathophysiology and management of IBS. The present revised version of the guidelines is in continuity with the previous version and targets adults diagnosed with, or suspected to have, IBS. A librarian created a literature search query, and a systematic review was conducted to identify candidate guidelines. Feasible documents were verified based on predetermined inclusion and exclusion criteria. The candidate seed guidelines were fully evaluated by the Guidelines Development Committee using the Appraisal of Guidelines for Research and Evaluation II quality assessment tool. After selecting 7 seed guidelines, the committee prepared evidence summaries to generate data exaction tables. These summaries comprised the 4 main themes of this version of the guidelines: colonoscopy; a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols; probiotics; and rifaximin. To adopt the core recommendations of the guidelines, the Delphi technique (ie, a panel of experts on IBS) was used. To enhance dissemination of the clinical practice guidelines, a Korean version will be made available, and a food calendar for patients with IBS is produced.
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Affiliation(s)
- Kyung Ho Song
- Department of Internal Medicine, Konyang University College of Medicine, Daejeon,
Korea
- Konyang University Myunggok Medical Research Institute Daejeon,
Korea
| | - Hye-Kyung Jung
- Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul,
Korea
- Correspondence: Hye-Kyung Jung, MD, PhD Department of Internal Medicine, Ewha Womans University Medical Center, 1071 Anyangcheon-ro, Yangcheon-gu, Seoul 07985, Korea, Tel: +82-2-2650-2874, Fax: +82-2-2655-2874, E-mail:
| | - Hyun Jin Kim
- Department of Internal Medicine, Gyeongsang National University, College of Medicine, Jinju,
Korea
| | - Hoon Sup Koo
- Department of Internal Medicine, Konyang University College of Medicine, Daejeon,
Korea
| | - Yong Hwan Kwon
- Department of Internal Medicine, Kyungpook National University, School of Medicine, Daegu,
Korea
| | - Hyun Duk Shin
- Department of Internal Medicine, Dankook University College of Medicine, Cheonan,
Korea
| | - Hyun Chul Lim
- Department of Internal Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin,
Korea
| | - Jeong Eun Shin
- Department of Internal Medicine, Dankook University College of Medicine, Cheonan,
Korea
| | - Sung Eun Kim
- Department of Internal Medicine, Kosin University College of Medicine, Busan,
Korea
| | - Dae Hyeon Cho
- Department of Internal Medicine, Sungkyunkwan University School of Medicine, Changwon,
Korea
| | - Jeong Hwan Kim
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul,
Korea
| | - Hyun Jung Kim
- Department of Preventive Medicine, Korea University College of Medicine, Seoul,
Korea
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Wasilewski A, Misicka A, Sacharczuk M, Fichna J. Prosecretory effect of loperamide in ileal and colonic mucosae of mice displaying high or low swim stress-induced analgesia associated with high and low endogenous opioid system activity. Neurogastroenterol Motil 2018; 30. [PMID: 28745837 DOI: 10.1111/nmo.13166] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Accepted: 06/23/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is characterized by abdominal pain, bloating, and changes in bowel habit. The aim of this study was to characterize the effect of loperamide hydrochloride (LOP) and naloxone hydrochloride (NLX), an opioid agonist and antagonist, respectively, on electrolyte equilibrium in ileal and colonic mucosae and to estimate the possible influence of divergent activity of the endogenous opioid system (EOS) on IBS therapy. METHODS Two mouse lines bidirectionally selected for high (HA) and low (LA) swim stress-induced analgesia associated with high and low EOS activity were used in this study. To assess the effect of LOP and NLX on HA/LA lines in vivo, we used the castor oil-induced diarrhea model. Changes in electrolyte equilibrium were determined on the basis of short-circuit current (ΔIsc ) in isolated mouse ileum and colon exposed to LOP and NLX and stimulated by forskolin (FSK), veratridine (VER), and bethanechol (BET). KEY RESULTS In vivo, we found that LOP significantly prolonged time to appearance of diarrhea in HA and LA lines. In vitro, LOP and NLX increased ΔIsc in FSK- and VER-stimulated colonic tissue, respectively, in HA line. In the ileum, LOP increased ΔIsc in FSK- and VER-stimulated tissue and decreased ΔIsc in BET-stimulated tissues in HA line. CONCLUSIONS & INFERENCES Individual differences in EOS activity may play a crucial role in the response to the IBS-D therapy, thus some patients may be at an increased risk of side effects such as constipation or diarrhea.
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Affiliation(s)
- A Wasilewski
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - A Misicka
- Department of Neuropeptides, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
| | - M Sacharczuk
- Laboratory of Neurogenomics, Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Magdalenka, Poland.,Department of Pharmacodynamics, Centre for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland.,Department of Internal Medicine, Hypertension and Vascular Diseases, Medical University of Warsaw, Warsaw, Poland
| | - J Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
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Barshop K, Staller K. Eluxadoline in irritable bowel syndrome with diarrhea: rationale, evidence and place in therapy. Ther Adv Chronic Dis 2017; 8:153-160. [PMID: 29090081 PMCID: PMC5638229 DOI: 10.1177/2040622317714389] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Accepted: 05/17/2017] [Indexed: 12/31/2022] Open
Abstract
Irritable bowel syndrome (IBS) is the most common gastrointestinal (GI) disorder worldwide, however treatment options for diarrhea-predominant IBS (IBS-D) remain limited. Eluxadoline, a µ- and κ-opioid receptor agonist and δ-opioid receptor antagonist, was recently approved for the treatment of IBS-D. A novel compound first described in 2008, eluxadoline was shown to normalize GI transit, with a subsequent phase I demonstrating its safety and tolerability in healthy adults. In 2016, two randomized, double-blind, placebo-controlled phase III trials studying eluxadoline use at 75 mg and 100 mg twice daily over 26 weeks demonstrated a significant improvement in stool consistency and many global symptoms of IBS. However, the data did not demonstrate a significant advantage over placebo using the United States Food and Drug Administration (US FDA) and European Medicines Agency (EMA) endpoints for abdominal pain. Safety and tolerability data, pooled from both phase II and III studies, suggest that eluxadoline is generally well tolerated with the most common adverse events (AEs) occurring in approximately 3-8% of patients and included nausea, constipation, and abdominal pain. The most common serious adverse event (SAE) is pancreatitis, which had a 0.4% incidence. Recent US FDA reports reporting severe pancreatitis and sphincter of Oddi dysfunction after short-term use of eluxadoline in patients without a gallbladder has added a history of cholecystectomy as an important contraindication. Eluxadoline is also contraindicated in patients with a history of biliary duct obstruction, sphincter of Oddi dysfunction, active alcohol abuse, history of pancreatitis or known pancreatic duct obstruction, severe hepatic impairment, severe or chronic constipation, or known mechanical gastrointestinal obstruction. As a new drug to enter the IBS-D market, the place of eluxadoline in the hierarchy of IBS treatments is still to be determined. In this article, we review the development and clinical trial data behind the approval of eluxadoline with a focus on safety data and its use in clinical practice.
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Affiliation(s)
- Kenneth Barshop
- Department of Internal Medicine, Brigham and Women’s Hospital, Boston, MA, USA
| | - Kyle Staller
- Division of Gastroenterology, Center for Neurointestinal Health, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA
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Camilleri M, Lembo A, Katzka DA. Opioids in Gastroenterology: Treating Adverse Effects and Creating Therapeutic Benefits. Clin Gastroenterol Hepatol 2017; 15:1338-1349. [PMID: 28529168 PMCID: PMC5565678 DOI: 10.1016/j.cgh.2017.05.014] [Citation(s) in RCA: 103] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Accepted: 05/02/2017] [Indexed: 02/07/2023]
Abstract
The use of opioid medications on both an acute and chronic basis is ubiquitous in the United States. As opioid receptors densely populate the gastrointestinal tract, symptoms and side effects can be expected in these patients. In the esophagus, dysmotility may result, manifesting with dysphagia and a syndrome indistinguishable from primary achalasia. In the stomach, a marked delay in gastric emptying may occur with postprandial nausea and early satiety. Postoperatively, particularly with abdominal surgery, opioid-induced ileus may ensue. In the colon, opioid-induced constipation is common. A unique syndrome termed narcotic bowel syndrome is characterized by chronic abdominal pain often accompanied by nausea and vomiting in the absence of other identifiable causes. With the recognition of the important role of opioids on gastrointestinal function, novel drugs have been developed that use this physiology. These medications include peripheral acting opioid agonists to treat opioid-induced constipation and combination agonist and antagonists used for diarrhea-predominant irritable bowel syndrome. This review summarizes the most recent data in these areas.
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Affiliation(s)
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Anthony Lembo
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - David A Katzka
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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Eluxadoline Efficacy in IBS-D Patients Who Report Prior Loperamide Use. Am J Gastroenterol 2017; 112:924-932. [PMID: 28417992 PMCID: PMC5465428 DOI: 10.1038/ajg.2017.72] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Accepted: 02/08/2017] [Indexed: 02/08/2023]
Abstract
OBJECTIVES Irritable bowel syndrome with diarrhea (IBS-D) is often managed with over-the-counter therapies such as loperamide, though with limited success. This analysis evaluated the efficacy of eluxadoline in patients previously treated with loperamide in two phase 3 studies. METHODS Adults with IBS-D (Rome III criteria) were enrolled and randomized to placebo or eluxadoline (75 or 100 mg) twice daily for 26 (IBS-3002) or 52 (IBS-3001) weeks. Patients reported loperamide use over the previous year and recorded their rescue loperamide use during the studies. The primary efficacy end point was the proportion of patients with a composite response of simultaneous improvement in abdominal pain and reduction in diarrhea. RESULTS A total of 2,428 patients were enrolled; 36.0% reported prior loperamide use, of whom 61.8% reported prior inadequate IBS-D symptom control with loperamide. Among patients with prior loperamide use, a greater proportion treated with eluxadoline (75 and 100 mg) were composite responders vs. those treated with placebo with inadequate prior symptom control, over weeks 1-12 (26.3% (P=0.001) and 27.0% (P<0.001) vs. 12.7%, respectively); similar results were observed over weeks 1-26. When daily rescue loperamide use was imputed as a nonresponse day, the composite responder rate was still higher in patients receiving eluxadoline (75 and 100 mg) vs. placebo over weeks 1-12 (P<0.001) and weeks 1-26 (P<0.001). Adverse events included nausea and abdominal pain. CONCLUSIONS Eluxadoline effectively and safely treats IBS-D symptoms of abdominal pain and diarrhea in patients who self-report either adequate or inadequate control of their symptoms with prior loperamide treatment, with comparable efficacy and safety irrespective of the use of loperamide as a rescue medication during eluxadoline treatment.
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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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36
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Chen L, Ilham SJ, Feng B. Pharmacological Approach for Managing Pain in Irritable Bowel Syndrome: A Review Article. Anesth Pain Med 2017; 7:e42747. [PMID: 28824858 PMCID: PMC5556397 DOI: 10.5812/aapm.42747] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Revised: 12/02/2016] [Accepted: 12/24/2016] [Indexed: 12/13/2022] Open
Abstract
Context Visceral pain is a leading symptom for patients with irritable bowel syndrome (IBS) that affects 10% - 20 % of the world population. Conventional pharmacological treatments to manage IBS-related visceral pain is unsatisfactory. Recently, medications have emerged to treat IBS patients by targeting the gastrointestinal (GI) tract and peripheral nerves to alleviate visceral pain while avoiding adverse effects on the central nervous system (CNS). Several investigational drugs for IBS also target the periphery with minimal CNS effects. Evidence of Acquisition In this paper, reputable internet databases from 1960 - 2016 were searched including Pubmed and ClinicalTrials.org, and 97 original articles analyzed. Search was performed based on the following keywords and combinations: irritable bowel syndrome, clinical trial, pain, visceral pain, narcotics, opioid, chloride channel, neuropathy, primary afferent, intestine, microbiota, gut barrier, inflammation, diarrhea, constipation, serotonin, visceral hypersensitivity, nociceptor, sensitization, hyperalgesia. Results Certain conventional pain managing drugs do not effectively improve IBS symptoms, including NSAIDs, acetaminophen, aspirin, and various narcotics. Anxiolytic and antidepressant drugs (Benzodiazepines, TCAs, SSRI and SNRI) can attenuate pain in IBS patients with relevant comorbidities. Clonidine, gabapentin and pregabalin can moderately improve IBS symptoms. Lubiprostone relieves constipation predominant IBS (IBS-C) while loperamide improves diarrhea predominant IBS (IBS-D). Alosetron, granisetron and ondansetron can generally treat pain in IBS-D patients, of which alosetron needs to be used with caution due to cardiovascular toxicity. The optimal drugs for managing pain in IBS-D and IBS-C appear to be eluxadoline and linaclotide, respectively, both of which target peripheral GI tract. Conclusions Conventional pain managing drugs are in general not suitable for treating IBS pain. Medications that target the GI tract and peripheral nerves have better therapeutic profiles by limiting adverse CNS effects.
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Affiliation(s)
- Longtu Chen
- Department of Biomedical Engineering, University of Connecticut, Storrs, CT 06269, USA
| | - Sheikh J. Ilham
- Department of Biomedical Engineering, University of Connecticut, Storrs, CT 06269, USA
| | - Bin Feng
- Department of Biomedical Engineering, University of Connecticut, Storrs, CT 06269, USA
- Corresponding author: Bin Feng, Ph.D., Department of Biomedical Engineering, University of Connecticut, 260 Glenbrook Road, Unit 3247, Storrs, CT 06269-3247, USA. Tel: +1-8604866435, Fax: +1-8604862500, E-mail:
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37
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Park CH, Han DS. Pharmacotherapy of irritable bowel syndrome. JOURNAL OF THE KOREAN MEDICAL ASSOCIATION 2017. [DOI: 10.5124/jkma.2017.60.1.57] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Affiliation(s)
- Chan Hyuk Park
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Dong Soo Han
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
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Abstract
UNLABELLED There is little evidence for most of the medications currently used to treat functional abdominal pain disorders (FAPDs) in children. Not only are there very few clinical trials, but also most have significant variability in the methods used and outcomes measured. Thus, the decision on the most appropriate pharmacological treatment is frequently based on adult studies or empirical data. In children, peppermint oil, trimebutine, and drotaverine have shown significant benefit compared with placebo, each of them in a single randomized clinical trial. A small study found that cyproheptadine was beneficial in the treatment of FAPDs in children. There are conflicting data regarding amitriptyline. While one small study found a significant benefit in quality of life compared with placebo, a large multicenter study found no benefit compared with placebo. The antidepressant, citalopram, failed to meet the primary outcomes in intention-to-treat and per-protocol analysis. Rifaximin has been shown to be efficacious in the treatment of adults with IBS. Those findings differ from studies in children where no benefit was found compared to placebo. To date, there are no placebo-controlled trials published on the use of linaclotide or lubiprostone in children. Alpha 2 delta ligands such as gabapentin and pregabalin are sometimes used in the care of this group of children, but no clinical trials are available in children with FAPDs. Similarly, novel drugs that have been approved for the care of irritable bowel with diarrhea in adults such as eluxadoline have yet to be studied in children. CONCLUSIONS Little data support the use of most medications commonly used to treat FAPDs in children. More randomized, placebo-controlled studies are needed to assess the efficacy of pharmacological interventions in the treatment of FAPDs in children.
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Affiliation(s)
- Miguel Saps
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Nationwide Children's Hospital, Columbus, OH, USA.
| | - Adrian Miranda
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital of Wisconsin, Milwaukee, WI, USA
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Camilleri M, Bueno L, Andresen V, De Ponti F, Choi MG, Lembo A. Pharmacological, Pharmacokinetic, and Pharmacogenomic Aspects of Functional Gastrointestinal Disorders. Gastroenterology 2016; 150:S0016-5085(16)00220-1. [PMID: 27144621 DOI: 10.1053/j.gastro.2016.02.029] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Accepted: 02/09/2016] [Indexed: 02/08/2023]
Abstract
This article reviews medications commonly used for the treatment of patients with functional gastrointestinal disorders. Specifically, we review the animal models that have been validated for the study of drug effects on sensation and motility; the preclinical pharmacology, pharmacokinetics, and toxicology usually required for introduction of new drugs; the biomarkers that are validated for studies of sensation and motility endpoints with experimental medications in humans; the pharmacogenomics applied to these medications and their relevance to the FGIDs; and the pharmacology of agents that are applied or have potential for the treatment of FGIDs, including psychopharmacologic drugs.
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Affiliation(s)
- Michael Camilleri
- Professor of Medicine, Pharmacology, and Physiology, Mayo Clinic College of Medicine, Consultant in Gastroenterology, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Viola Andresen
- Israelitic Hospital, University of Hamburg, Orchideenstieg 14, Hamburg, Germany
| | - Fabrizio De Ponti
- Professor of Pharmacology, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Myung-Gyu Choi
- Professor of Gastroenterology, The Catholic University of Korea College of Medicine Internal Medicine , President, Korean Society of Neurogastroenterology and Motility , Seoul, Korea
| | - Anthony Lembo
- Associate Professor, Harvard Medical School, Director of the GI Motility Laboratory at the Beth Israel Deaconess Medical Center's (BIDMC) Division of Gastroenterology, Boston, MA, USA
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40
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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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41
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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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42
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Asrani VM, Yoon HD, Megill RD, Windsor JA, Petrov MS. Interventions That Affect Gastrointestinal Motility in Hospitalized Adult Patients: A Systematic Review and Meta-Analysis of Double-Blind Placebo-Controlled Randomized Trials. Medicine (Baltimore) 2016; 95:e2463. [PMID: 26844455 PMCID: PMC4748872 DOI: 10.1097/md.0000000000002463] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Gastrointestinal (GI) dysmotility is a common complication in acute, critically ill, postoperative, and chronic patients that may lead to impaired nutrient delivery, poor clinical, and patient-reported outcomes. Several pharmacological and nonpharmacological interventions to treat GI dysmotility were investigated in dozens of clinical studies. However, they often yielded conflicting results, at least in part, because various (nonstandardized) definitions of GI dysmotility were used and methodological quality of studies was poor. While a universally accepted definition of GI dysmotility is yet to be developed, a systematic analysis of data derived from double-blind placebo-controlled randomized trials may provide robust data on absolute and relative effectiveness of various interventions as the study outcome (GI motility) was assessed in the least biased manner.To systematically review data from double-blind placebo-controlled randomized trials to determine and compare the effectiveness of interventions that affect GI motility.Three electronic databases (MEDLINE, SCOPUS, and EMBASE) were searched. A random effects model was used for meta-analysis. The summary estimates were reported as mean difference (MD) with the corresponding 95% confidence interval (CI).A total of 38 double-blind placebo-controlled randomized trials involving 2371 patients were eligible for inclusion in the systematic review. These studies investigated a total of 20 different interventions, of which 6 interventions were meta-analyzed. Of them, the use of dopamine receptor antagonists (MD, -8.99; 95% CI, -17.72 to -0.27; P = 0.04) and macrolides (MD, -26.04; 95% CI, -51.25 to -0.82; P = 0.04) significantly improved GI motility compared with the placebo group. The use of botulism toxin significantly impaired GI motility compared with the placebo group (MD, 5.31; 95% CI, -0.04 to 10.67; P = 0.05). Other interventions (dietary factors, probiotics, hormones) did not affect GI motility.Based on the best available data and taking into account the safety profile of each class of intervention, dopamine receptor antagonists and macrolides significantly improve GI motility and are medications of choice in treating GI dysmotility.
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Affiliation(s)
- Varsha M Asrani
- From the Department of Surgery, University of Auckland (VMA, HDY, RDM, JAW, MSP); and Nutrition and Dietetics, Auckland City Hospital, Auckland, New Zealand (VMA)
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Lembo AJ, Lacy BE, Zuckerman MJ, Schey R, Dove LS, Andrae DA, Davenport JM, McIntyre G, Lopez R, Turner L, Covington PS. Eluxadoline for Irritable Bowel Syndrome with Diarrhea. N Engl J Med 2016; 374:242-53. [PMID: 26789872 DOI: 10.1056/nejmoa1505180] [Citation(s) in RCA: 221] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Background Effective and safe treatments are needed for patients who have irritable bowel syndrome (IBS) with diarrhea. We conducted two phase 3 trials to assess the efficacy and safety of eluxadoline, a new oral agent with mixed opioid effects (μ- and κ-opioid receptor agonist and δ-opioid receptor antagonist), in patients with IBS with diarrhea. Methods We randomly assigned 2427 adults who had IBS with diarrhea to eluxadoline (at a dose of 75 mg or 100 mg) or placebo twice daily for 26 weeks (IBS-3002 trial) or 52 weeks (IBS-3001 trial). The primary end point was the proportion of patients who had a composite response of decrease in abdominal pain and improvement in stool consistency on the same day for at least 50% of the days from weeks 1 through 12 and from weeks 1 through 26. Results For weeks 1 through 12, more patients in the eluxadoline groups (75 mg and 100 mg) than in the placebo group reached the primary end point (IBS-3001 trial, 23.9% with the 75-mg dose and 25.1% with the 100-mg dose vs. 17.1% with placebo; P=0.01 and P=0.004, respectively; IBS-3002 trial, 28.9% and 29.6%, respectively, vs. 16.2%; P<0.001 for both comparisons). For weeks 1 through 26, the corresponding rates in IBS-3001 were 23.4% and 29.3% versus 19.0% (P=0.11 and P<0.001, respectively), and the corresponding rates in IBS-3002 were 30.4% and 32.7% versus 20.2% (P=0.001 and P<0.001, respectively). The most common adverse events associated with 75 mg of eluxadoline and 100 mg of eluxadoline, as compared with placebo, were nausea (8.1% and 7.5% vs. 5.1%), constipation (7.4% and 8.6% vs. 2.5%), and abdominal pain (5.8% and 7.2% vs. 4.1%). Pancreatitis developed in 5 (2 in the 75-mg group and 3 in the 100-mg group) of the 1666 patients in the safety population (0.3%). Conclusions Eluxadoline is a new therapeutic agent that reduced symptoms of IBS with diarrhea in men and women, with sustained efficacy over 6 months in patients who received the 100-mg dose twice daily. (Funded by Furiex Pharmaceuticals, an affiliate of Allergan; IBS-3001 and IBS-3002 ClinicalTrials.gov numbers, NCT01553591 and NCT01553747 , respectively.).
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Affiliation(s)
- Anthony J Lembo
- From Harvard Medical School, Boston (A.J.L.); Geisel School of Medicine at Dartmouth, Hanover, NH (B.E.L.); Texas Tech University Health Sciences Center, El Paso (M.J.Z.); School of Medicine, Temple University, Philadelphia (R.S.); and Furiex Pharmaceuticals, Morrisville, NC (L.S.D., D.A.A., J.M.D., G.M., R.L., L.T., P.S.C.)
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Bokic T, Storr M, Schicho R. Potential Causes and Present Pharmacotherapy of Irritable Bowel Syndrome: An Overview. Pharmacology 2015; 96:76-85. [PMID: 26139425 DOI: 10.1159/000435816] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Accepted: 06/08/2015] [Indexed: 12/14/2022]
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is currently one of the most common disorders of the digestive system in the Western society. Almost 2 out of 10 people suffer from IBS with women being more affected than men. IBS is associated with abdominal pain, bloating and altered stool consistency and imposes a heavy burden for the affected patients. SUMMARY The pathophysiology of IBS remains elusive although potential causes have been suggested, such as a deranged brain-gut signaling, hypersensitivity of visceral sensory afferent fibers, bacterial gastroenteritis, small intestinal bacterial overgrowth (SIBO), genetic alterations and food sensitivity. Targets for the pharmacotherapy of IBS include the serotonergic and opioidergic system, and the microbial population of the gut. Alternative therapies like traditional Chinese medicine have shown some success in the combat against IBS. Key Messages: Many therapeutics for the treatment of IBS have emerged in the past; however, only a few have met up with the expectations in larger clinical trials. Additionally, the multifactorial etiology of IBS and its variety of cardinal symptoms requires an individual set of therapeutics. This review provides a short overview of potential causes and current pharmacological therapeutics and of additional and alternative therapies for IBS.
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Affiliation(s)
- Theodor Bokic
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
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Deiana S, Gabbani T, Bagnoli S, Annese V. Emerging drug for diarrhea predominant irritable bowel syndrome. Expert Opin Emerg Drugs 2015; 20:247-61. [PMID: 25732091 DOI: 10.1517/14728214.2015.1013935] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders with a 9 - 23% prevalence estimated in the general population. Patients can be subdivided into those who tend to have predominant diarrhea (IBS-D) or predominant constipation (IBS-C). Total annual productivity loss related to IBS in US is estimated at $205 million, with a significant impairment of health-related quality of life. A gold standard for the treatment of IBS is not established. Symptoms might improve with the use of few drugs and behavioral therapy, however, data concerning efficacy, safety and tolerability are limited. Therefore, development and validation of new therapies targeting at the molecular level are widely awaited. AREAS COVERED We will specifically describe in this review Phase II and Phase III trials, with specific focus on treatment of IBS-D patients. Unfortunately, it is difficult to draw definite conclusions from Phase II and Phase III trials, because of the known high placebo effect. EXPERT OPINION Drugs active on opioid receptor subtypes and neurokinin (NK) receptors seem to be the most promising, but substantial progress of information in this field is still needed. The achievement of more insights on the pathogenesis of IBS could surely better drive and target the therapy, but still strong efforts are awaited.
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Affiliation(s)
- Simona Deiana
- Emergency Department, Gastroenterology SOD2, AOU Careggi , Florence , Italy +39 55 7946035 ;
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Chronic Pain Syndromes, Mechanisms, and Current Treatments. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2015; 131:565-611. [DOI: 10.1016/bs.pmbts.2015.01.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Review of the Diagnosis, Management and Treatment of Fecal Incontinence. Female Pelvic Med Reconstr Surg 2015; 21:8-17. [DOI: 10.1097/spv.0000000000000102] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Fujita W, Gomes I, Dove LS, Prohaska D, McIntyre G, Devi LA. Molecular characterization of eluxadoline as a potential ligand targeting mu-delta opioid receptor heteromers. Biochem Pharmacol 2014; 92:448-56. [PMID: 25261794 PMCID: PMC4769596 DOI: 10.1016/j.bcp.2014.09.015] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Revised: 09/16/2014] [Accepted: 09/17/2014] [Indexed: 12/21/2022]
Abstract
Eluxadoline, an orally active mixed μ opioid receptor (μOR) agonist δ opioid receptor (δOR) antagonist developed for the treatment of diarrhea-predominant irritable bowel syndrome, normalizes gastrointestinal (GI) transit and defecation under conditions of novel environment stress or post-inflammatory altered GI function. Furthermore, compared to loperamide, which is used to treat non-specific diarrhea, the effects of eluxadoline on GI transit occur over a wider dosage range. However, the mechanisms of action of eluxadoline are unclear. In this study, we compared the ability of eluxadoline and loperamide to activate G-protein- and β-arrestin-mediated signaling at μOR homomers or μOR-δOR heteromers in heterologous cells. We also examined the ability of both compounds to reduce castor oil induced diarrhea in wild type (WT) and mice lacking δOR. We find that eluxadoline is more potent than loperamide in eliciting G-protein activity and β-arrestin recruitment in μOR expressing cells. However, in cells expressing μOR-δOR heteromers, the potency of eluxadoline is higher, but its maximal effect is lower than that of loperamide. Moreover, in these cells the signaling mediated by eluxadoline but not loperamide is reduced by μOR-δOR heteromer-selective antibodies. We find that in castor oil-induced diarrhea eluxadoline is more efficacious compared to loperamide in WT mice, and δOR appears to play a role in this process. Taken together these results indicate that eluxadoline behaves as a potent μOR agonist in the absence of δOR, while in the presence of δOR eluxadoline's effects are mediated through the μOR-δOR heteromer.
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MESH Headings
- Animals
- Arrestins/metabolism
- Castor Oil/adverse effects
- Diarrhea/chemically induced
- Diarrhea/drug therapy
- Humans
- Imidazoles/pharmacology
- Ligands
- Loperamide/pharmacology
- Male
- Mice, Inbred C57BL
- Mice, Mutant Strains
- Phenylalanine/analogs & derivatives
- Phenylalanine/pharmacology
- Protein Multimerization
- Receptors, Opioid, delta/antagonists & inhibitors
- Receptors, Opioid, delta/genetics
- Receptors, Opioid, delta/metabolism
- Receptors, Opioid, mu/agonists
- Receptors, Opioid, mu/metabolism
- Signal Transduction/drug effects
- beta-Arrestins
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Affiliation(s)
- Wakako Fujita
- Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ivone Gomes
- Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Leonard S Dove
- Furiex Pharmaceuticals, Inc., 3900 Paramount Parkway, Suite 150, Morrisville, NC 27560, USA
| | - David Prohaska
- Furiex Pharmaceuticals, Inc., 3900 Paramount Parkway, Suite 150, Morrisville, NC 27560, USA
| | - Gail McIntyre
- Furiex Pharmaceuticals, Inc., 3900 Paramount Parkway, Suite 150, Morrisville, NC 27560, USA
| | - Lakshmi A Devi
- Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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Barboza JL, Talley NJ, Moshiree B. Current and emerging pharmacotherapeutic options for irritable bowel syndrome. Drugs 2014; 74:1849-1870. [PMID: 25260888 DOI: 10.1007/s40265-014-0292-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Treatment of irritable bowel syndrome (IBS) is challenging for both primary care physicians and gastroenterologists because of the heterogeneity of the patient population and the multifactorial pathophysiologies responsible for the symptoms in IBS. This review focuses on the current and emerging pharmacological treatments for IBS. Many of the current medications used to treat this disorder have distinct properties such as efficacy for different symptoms, safety profiles, contraindications, costs, dosing regimens, treatment duration and long-term data. All of these factors, in addition to patient preference and cognitive, food and environmental triggers, must be considered prior to any medication selection. This review will focus on randomized controlled trials with a general uniformity in study design, a rigorous patient selection and appropriate treatment durations. We will also discuss other exciting emerging treatments for IBS such as the µ-opioid receptor (agonists and antagonists), selective κ-opioid receptor agonists, anti-inflammatory drugs, serotonergic agents, bile acid modulators and intestinal bile acid transporters, which may prove promising in treating our patients.
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Affiliation(s)
- Jose L Barboza
- University of South Florida College of Pharmacy, 12901 Bruce B. Downs Blvd. MDC30, Tampa, FL, 33612, USA.
| | - Nicholas J Talley
- University of Newcastle, Callaghan, NSW, 2308, Australia
- Mayo Clinic, Jacksonville, FL, USA
| | - Baharak Moshiree
- Division of Gastroenterology, University of Miami Miller School of Medicine, 1120 NW 14th Street, Miami, FL, 33136, USA
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Lazaraki G, Chatzimavroudis G, Katsinelos P. Recent advances in pharmacological treatment of irritable bowel syndrome. World J Gastroenterol 2014; 20:8867-8885. [PMID: 25083060 PMCID: PMC4112893 DOI: 10.3748/wjg.v20.i27.8867] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Revised: 03/13/2014] [Accepted: 06/23/2014] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a highly prevalent functional disorder that reduces patients’ quality of life. It is a chronic disorder characterized by abdominal pain or discomfort associated with disordered defecation in the absence of identifiable structural or biochemical abnormalities. IBS imposes a significant economic burden to the healthcare system. Alteration in neurohumoral mechanisms and psychological factors, bacterial overgrowth, genetic factors, gut motility, visceral hypersensitivity, and immune system factors are currently believed to influence the pathogenesis of IBS. It is possible that there is an interaction of one or more of these etiologic factors leading to heterogeneous symptoms of IBS. IBS treatment is predicated upon the patient’s most bothersome symptoms. Despite the wide range of medications and the high prevalence of the disease, to date no completely effective remedy is available. This article reviews the literature from January 2008 to July 2013 on the subject of IBS peripherally acting pharmacological treatment. Drugs are categorized according to their administration for IBS-C, IBS-D or abdominal pain predominant IBS.
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