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Xiao Y, Meng X, Luo Q, Hou X, Jin J, Zhong X, Gong W, Li X, Chen M. Real-world safety of linaclotide in Chinese patients with irritable bowel syndrome with constipation: a multicenter, single-arm, prospective observational study. Therap Adv Gastroenterol 2025; 18:17562848251314819. [PMID: 39917729 PMCID: PMC11800259 DOI: 10.1177/17562848251314819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 01/06/2025] [Indexed: 02/09/2025] Open
Abstract
Background Linaclotide, a guanylate cyclase-C agonist, is indicated for irritable bowel syndrome with constipation (IBS-C). However, real-world data on the safety and patient-reported outcomes (PROs) of linaclotide are scarce in Chinese patients with IBS-C. Objectives To assess the real-world safety and PROs of linaclotide in the Chinese IBS-C population. Design Multicenter, prospective observational study. Methods Adults with IBS-C who had taken or planned to take at least one dose of linaclotide 290 μg were enrolled and followed up for 3 months. Face-to-face visits were conducted at baseline (V1), Week 4 ± 7 days (V2), and Week 12 ± 7 days (V3). Primary endpoints included the incidences of adverse events (AEs), AEs by severity, adverse drug reactions (ADRs), serious AEs (SAEs), and AEs leading to treatment interruption, discontinuation, and death. Secondary endpoints included mean treatment satisfaction at V2 and V3, and mean overall Irritable Bowel Syndrome-Quality of Life (IBS-QoL) at V2. Results Out of 3000 enrolled patients, 2963 took at least one dose of linaclotide and were analyzed. Overall, 712 patients (24.0%) reported 1095 AEs, which were mostly mild (89.9%). Diarrhea, reported in 297 out of the 2963 patients analyzed (10.0%), was the most common AE. No severe diarrhea was reported. Totally, 319 patients (10.8%) reported ADRs. Forty-six patients (1.6%) reported 50 SAEs and two cases were considered related to linaclotide treatment. Fifty-one (1.7%) and 70 patients (2.4%) interrupted and discontinued treatment due to AEs, respectively. One patient died of hepatic cancer, which was considered unrelated to linaclotide treatment. During the follow-up, the mean (±SD) treatment satisfaction increased numerically and continuously (V1, 2.8 ± 1.3 (n = 1721); V2, 3.5 ± 1.1 (n = 1705); V3, 3.9 ± 1.0 (n = 833)). The mean (±SD) overall IBS-QoL increased numerically from 73.2 ± 16.6 (n = 1924) at V1 to 80.2 ± 15.5 (n = 1738) at V2. Conclusion In the Chinese real-world setting, linaclotide was safe and well tolerated in patients with IBS-C. Numerically, there are trends toward improvement in PROs with linaclotide treatment.
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Affiliation(s)
- Yinglian Xiao
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xianmei Meng
- Department of Gastroenterology, The Second Affiliated Hospital of Baotou Medical College, Baotou, China
| | - Qingfeng Luo
- Department of Gastroenterology, Beijing Hospital, Beijing, China
| | - Xiaohua Hou
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jie Jin
- Department of Gastroenterology, Wenzhou Central Hospital, Wenzhou, China
| | - Xianfei Zhong
- Department of Gastroenterology, The People’s Hospital of Leshan, Leshan, China
| | - Wei Gong
- Department of Gastroenterology, Shenzhen Hospital of Southern Medical University, Shenzhen, China
| | - Xiuling Li
- Department of Gastroenterology, Henan Provincial People’s Hospital, Zhengzhou, China
| | - Minhu Chen
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, No. 58 Zhongshan 2nd Road, Yuexiu District, Guangzhou, China
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Decraecker L, De Looze D, Hirsch DP, De Schepper H, Arts J, Caenepeel P, Bredenoord AJ, Kolkman J, Bellens K, Van Beek K, Pia F, Peetermans W, Vanuytsel T, Denadai-Souza A, Belmans A, Boeckxstaens G. Treatment of non-constipated irritable bowel syndrome with the histamine 1 receptor antagonist ebastine: a randomised, double-blind, placebo-controlled trial. Gut 2024; 73:459-469. [PMID: 38191268 DOI: 10.1136/gutjnl-2023-331634] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 12/19/2023] [Indexed: 01/10/2024]
Abstract
OBJECTIVE We evaluated the histamine 1 receptor antagonist ebastine as a potential treatment for patients with non-constipated irritable bowel syndrome (IBS) in a randomised, placebo-controlled phase 2 study. METHODS Non-constipated patients with IBS fulfilling the Rome III criteria were randomly assigned to 20 mg ebastine or placebo for 12 weeks. Subjects scored global relief of symptoms (GRS) and abdominal pain intensity (API). A subject was considered a weekly responder for GRS if total or obvious relief was reported and a responder for API if the weekly average pain score was reduced by at least 30% vs baseline. The primary endpoints were the proportion of subjects who were weekly responders for at least 6 out of the 12 treatment weeks for both GRS and API ('GRS+API', composite endpoint) and for GRS and API separately. RESULTS 202 participants (32±11 years, 68% female) were randomly allocated to receive ebastine (n=101) or placebo (n=101). Treatment with ebastine resulted in significantly more responders (12%, 12/92) for GRS+API compared with placebo (4%, 4/87, p=0.047) while the proportion of responders for GRS and API separately was higher for ebastine compared with placebo, although not statistically significant (placebo vs ebastine, GRS: 7% (6/87) vs 15% (14/91), p=0.072; API: 25% (20/85) vs 37% (34/92), p=0.081). CONCLUSIONS Our study shows that ebastine is superior to placebo and should be further evaluated as novel treatment for patients with non-constipated IBS. TRIAL REGISTRATION NUMBER The study protocol was approved by the local ethics committee of each study site (EudraCT number: 2013-001199-39; ClinicalTrials.gov identifier: NCT01908465).
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Affiliation(s)
- Lisse Decraecker
- Department of Chronic Diseases, Metabolism, and Ageing, KU Leuven, Leuven, Belgium
| | - Danny De Looze
- Department of Gastroenterology and Hepatology, UZ Gent, Gent, Belgium
| | - David P Hirsch
- Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands
| | - Heiko De Schepper
- Department of Translational Research in Immunology and Inflammation, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
- Department of Gastroenterology and Hepatology, University Hospital Antwerp, Edegem, Belgium
| | - Joris Arts
- Department of Gastroenterology, AZ Sint-Lucas Brugge, Brugge, Belgium
- Department of Gastroenterology and Hepatology, KU Leuven University Hospitals Leuven Gasthuisberg Campus, Leuven, Belgium
| | - Philip Caenepeel
- Department of Gastroenterology and Hepatology, KU Leuven University Hospitals Leuven Gasthuisberg Campus, Leuven, Belgium
- Department of Gastroenterology, Ziekenhuis Oost-Limburg - Campus Sint Jan, Genk, Belgium
| | - Albert J Bredenoord
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Jeroen Kolkman
- Department of Gastroenterology, Medisch Spectrum Twente, Enschede, The Netherlands
| | - Koen Bellens
- Department of Chronic Diseases, Metabolism, and Ageing, KU Leuven, Leuven, Belgium
- Department of Gastroenterology and Hepatology, KU Leuven University Hospitals Leuven Gasthuisberg Campus, Leuven, Belgium
| | - Kim Van Beek
- Clinical Trial Center, KU Leuven University Hospitals Leuven Gasthuisberg Campus, Leuven, Belgium
| | - Fedrica Pia
- Department of Chronic Diseases, Metabolism, and Ageing, KU Leuven, Leuven, Belgium
| | - Willy Peetermans
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Department of Internal Medicine, KU Leuven University Hospitals Leuven Gasthuisberg Campus, Leuven, Belgium
| | - Tim Vanuytsel
- Department of Chronic Diseases, Metabolism, and Ageing, KU Leuven, Leuven, Belgium
- Department of Gastroenterology and Hepatology, KU Leuven University Hospitals Leuven Gasthuisberg Campus, Leuven, Belgium
| | | | - Ann Belmans
- Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium
| | - Guy Boeckxstaens
- Department of Chronic Diseases, Metabolism, and Ageing, KU Leuven, Leuven, Belgium
- Department of Gastroenterology and Hepatology, KU Leuven University Hospitals Leuven Gasthuisberg Campus, Leuven, Belgium
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Pohl D, Vavricka S, Fox M, Madisch A, Studerus D, Wiesel P, Heinrich H, Linas I, Schoepfer A, Schwizer A, Wildi S. [Frequent Gastro-Intestinal Disorders: Management of Functional Dyspepsia and Irritable Bowel Syndrome in Clinical Practice]. PRAXIS 2023; 112:304-316. [PMID: 37042398 DOI: 10.1024/1661-8157/a003988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/19/2023]
Abstract
Frequent Gastro-Intestinal Disorders: Management of Functional Dyspepsia and Irritable Bowel Syndrome in Clinical Practice Abstract: Functional dyspepsia (FD) and irritable bowel syndrome (IBS), two common gastrointestinal entities with overlapping symptoms, should be diagnosed according to Rome IV criteria. This includes one or more of the following symptoms: in FD, postprandial fullness, early satiation, epigastric pain or burning; in IBS, recurrent abdominal pain associated with defecation, change in frequency of stool or form of stool. To exclude structural diseases, attention should be paid to alarm symptoms. As far as treatment is concerned, a stepwise scheme proves to be effective for both diseases. Step 1: doctor-patient discussion with explanation of diagnosis and prognosis as well as clarification of therapy goals; lifestyle adaptations; use of phytotherapeutics; step 2: symptom-oriented medication: for FD, PPIs or prokinetics; for IBS, antispasmodics, secretagogues, laxatives, bile acid sequestrants, antidiarrheals, antibiotics, probiotics; step 3: visceral analgesics (antidepressants).
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Affiliation(s)
- Daniel Pohl
- Klinik für Gastroenterologie und Hepatologie, Universitätsspital Zürich, Schweiz
| | | | - Mark Fox
- Zentrum für Integrative Gastroenterologie, Klinik Arlesheim, Schweiz
| | | | | | - Paul Wiesel
- Gastro-entérologie, Centre Médical d'Epalinges, Epalinges, Schweiz
| | | | - Ioannis Linas
- Gastroenterologische Gruppenpraxis, Hirslanden Campus Bern, Schweiz
| | - Alain Schoepfer
- Service de gastro-entérologie et hépatologie, Centre hospitalier universitaire vaudois CHUV, Lausanne, Schweiz
| | - Alexandra Schwizer
- Klinik für Gastroenterologie und Hepatologie, Kantonsspital St. Gallen, St. Gallen, Schweiz
| | - Stephan Wildi
- Klinik für Gastroenterologie und Hepatologie, Kantonsspital St. Gallen, St. Gallen, Schweiz
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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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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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Serra J. Management of bloating. Neurogastroenterol Motil 2022; 34:e14333. [PMID: 35143108 DOI: 10.1111/nmo.14333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 01/24/2022] [Accepted: 01/24/2022] [Indexed: 02/08/2023]
Abstract
Abdominal bloating is a subjective sensation of trapped abdominal gas, producing abdominal pressure, fullness sensation, and, in some patients, associated objective abdominal distension. In this month's edition of the journal, a new validated questionnaire to assess the prevalence and impact of gas-related symptoms is presented by Duracinsky et al., showing that gas-related abdominal symptoms are prevalent in patients with irritable bowel syndrome and have a measurable impact on patients daily life. A parallel study by Gardiner et al. assessing the severity of bloating in functional gastrointestinal disorders shows that severe bloating is associated with the severity of abdominal pain, constipation, and somatization, advancing our understanding of the clinical characteristics and relevance of gas-related symptoms in the broad spectrum of functional gastrointestinal disorders. Management of bloating includes non-pharmacological and pharmacological strategies. Dietary interventions to reduce intestinal fermentation and ingestion of food supplements like prebiotics or probiotics can reduce bloating by reducing gas production. The main targets of pharmacological treatments are to improve transit and evacuation with prokinetics, to improve intestinal gas tolerance with antispasmodics and/or neuromodulators, and to modify intestinal microbiota with antibiotics. Secretagogues act by increasing intestinal secretion and decreasing visceral sensitivity and have been reported to be an effective treatment alternative for patients with bloating associated with constipation. Biofeedback therapy addressed to correct abdomino-phrenic dysynergia may be useful for patients with objective abdominal distension, and patients with bloating associated with outlet obstructed defecation may benefit from anorectal biofeedback.
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Affiliation(s)
- Jordi Serra
- Digestive System Research Unit, University Hospital Vall d'Hebrón, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
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Peng LH, Fang JY, Dai N, Shen XZ, Yang YL, Sun J, Yang YS. Efficacy and safety of linaclotide in patients with irritable bowel syndrome with constipation: Chinese sub-cohort analysis of a phase III, randomized, double-blind, placebo-controlled trial. J Dig Dis 2022; 23:99-110. [PMID: 35019221 PMCID: PMC9314117 DOI: 10.1111/1751-2980.13081] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 01/10/2022] [Accepted: 01/10/2022] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To conduct a sub-cohort analysis to evaluate the efficacy and safety of linaclotide in Chinese patients with constipation-predominant irritable bowel syndrome (IBS-C) using data from a completed trial (NCT01880424). METHODS In this phase III, double-blind, placebo-controlled trial, IBS-C patients were randomized to receive linaclotide (290 μg/d) or placebo for 12 weeks. Efficacy was assessed with two co-primary responder end-points (12-wk abdominal pain/discomfort: ≥30% reduction in either score with neither deteriorating from baseline for ≥6 wks; 12-wk IBS degree of relief: score ≤2 for ≥ 6 wks), seven secondary endpoints and several additional end-points. RESULTS In total, 659 Chinese IBS-C patients received linaclotide (n = 327) or placebo (n = 332). The 12-week abdominal pain/discomfort end-point was met in 62.1% and 53.3% of the linaclotide-treated and placebo-treated patients, respectively (odds ratio [OR] 1.43, 95% confidence interval [CI] 1.05-1.96, P = 0.023); the 12-week IBS degree of relief end-point was achieved in 32.7% and 16.9% of the patients treated with linaclotide and placebo, respectively (OR 2.40, 95% CI 1.66-3.47, P < 0.001). The linaclotide-treated patients had a shorter time to the first spontaneous bowel movement than the placebo-treated patients (23.6 h vs 43.7 h, P < 0.001). Linaclotide produced significantly greater improvement than placebo in all secondary end-points from the first 2 weeks (all P < 0.001). Diarrhea was reported in 8.3% of linaclotide-treated patients and 1.2% of placebo-treated patients. CONCLUSION Linaclotide (290 μg/d) was efficacious and well-tolerated in Chinese IBS-C patients with a rapid onset of effect.
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Affiliation(s)
- Li Hua Peng
- Department of Gastroenterology and Hepatology, The First Medical CenterChinese PLA General HospitalBeijingChina
| | - Jing Yuan Fang
- State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and HepatologyShanghai Cancer Institute, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityShanghaiChina
| | - Ning Dai
- Department of Gastroenterology, Sir Run Run Shaw HospitalZhejiang University School of MedicineHangzhouZhejiang ProvinceChina
| | - Xi Zhong Shen
- Department of GastroenterologyZhongshan Hospital, Fudan UniversityShanghaiChina
| | - You Lin Yang
- Department of GastroenterologyThe First Affiliated Hospital of Harbin Medical UniversityHarbinHeilongjiang ProvinceChina
| | - Jing Sun
- Department of GastroenterologyRuijin Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
| | - Yun Sheng Yang
- Department of Gastroenterology and Hepatology, The First Medical CenterChinese PLA General HospitalBeijingChina
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Meling S, Bertoli D, Sangnes DA, Brock C, Drewes A, Ejskjaer N, Dimcevski G, Søfteland E. Diabetic Gastroenteropathy: Soothe the Symptoms or Unravel a Cure? Curr Diabetes Rev 2022; 18:e220321192412. [PMID: 34225633 DOI: 10.2174/1573399817666210322154618] [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: 11/16/2020] [Revised: 01/19/2021] [Accepted: 02/13/2021] [Indexed: 11/22/2022]
Abstract
Autonomic neuropathy in patients with diabetes mellitus, and especially complications related to gastrointestinal neuropathy, are often overlooked in the clinic. Diabetic gastroenteropathy affects every segment of the gastrointestinal tract and generates symptoms that may include nausea, early satiety, vomiting, abdominal pain, constipation, and diarrhea. Severe cases can be complicated by weight loss, dehydration, and electrolyte disturbances. The pathophysiology is complex, the diagnostics and treatment options are multidisciplinary, and there is generally a lack of evidence for the treatment options. The aims for this review are first to summarize the pathophysiology and describe possible and expected symptoms and complications.Further, we will try to supply the clinician with a straightforward tool for diagnostics, and then, we shall summarize established treatment options, including diet recommendations, pharmacological and non-pharmacological options. Finally, we will explore the multiple possibilities of novel treatment, looking at medications related to the pathophysiology of neuropathy, other manifestations of autonomic neuropathies, and symptomatic treatment for other gastrointestinal disorders, also including new knowledge of endosurgical and neuromodulatory treatment. The overall goal is to increase awareness and knowledge on this frequent diabetic complication and to provide better tools for diagnosis and treatment. Ultimately, we hope to encourage further research in this field, as there are clear shortcomings in terms of biomarkers, pathophysiology, as well as treatment possibilities. In conclusion, diagnosis and management of diabetic gastroenteropathy are challenging and often require multidisciplinary teams and multimodal therapies. Treatment options are sparse, but new pharmacological, endoscopic, and neuromodulatory techniques have shown promising results in initial studies.
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Affiliation(s)
- Sondre Meling
- Department of Medicine, Stavanger University Hospital, Stavanger, Norway
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Davide Bertoli
- Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Dag A Sangnes
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Department of Medicine, Haukeland University Hospital, Bergen, Norway
| | - Christina Brock
- Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
- Steno Diabetes Center North Jutland, Aalborg, Denmark
| | - Asbjørn Drewes
- Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
- Steno Diabetes Center North Jutland, Aalborg, Denmark
| | - Niels Ejskjaer
- Steno Diabetes Center North Jutland, Aalborg, Denmark
- Department of Clinical Medicine and Endocrinology, Aalborg University Hospital, Aalborg, Denmark
| | - Georg Dimcevski
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Eirik Søfteland
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Department of Medicine, Haukeland University Hospital, Bergen, Norway
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9
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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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Liu JJ, Brenner DM. Review article: current and future treatment approaches for IBS with constipation. Aliment Pharmacol Ther 2021; 54 Suppl 1:S53-S62. [PMID: 34927760 DOI: 10.1111/apt.16607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 08/17/2021] [Accepted: 09/03/2021] [Indexed: 12/09/2022]
Abstract
BACKGROUND Multiple efficacious therapies are currently available for treating irritable bowel syndrome with constipation (IBS-C). IBS-C specific survey tools that assess symptom relief, treatment satisfaction, and quality of life are important for gauging real-world effectiveness. AIMS/METHODS This article reviews clinical trial efficacy data as well as survey data on adequate relief and quality of life from pivotal trials for lubiprostone, linaclotide, plecanatide, tenapanor, and tegaserod. A brief discussion of agents in development with novel mechanisms of action is also provided. RESULTS/CONCLUSIONS Quality of life and symptom metrics should be standardized and continue to be represented in future IBS-C trials. The choice of agent should be tailored to probability of improving symptoms, safety, tolerability, and cost.
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Affiliation(s)
- Joy J Liu
- Division of Gastroenterology, Feinberg School of Medicine at Northwestern University, Chicago, Illinois, USA
| | - Darren M Brenner
- Division of Gastroenterology, Feinberg School of Medicine at Northwestern University, Chicago, Illinois, USA
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11
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Yang J, Lei Y. Comparison of the Efficacy and Safety of Different Doses of Linaclotide for Patients with Chronic Constipation: A Meta-Analysis and Bayesian Analysis. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2021; 2021:9923879. [PMID: 34691232 PMCID: PMC8531776 DOI: 10.1155/2021/9923879] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 09/04/2021] [Accepted: 09/17/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND It is ambiguous whether a higher dose of linaclotide provides higher efficacy for chronic constipation (CC) patients. The meta-analysis aimed to assess the efficacy and safety of linaclotide doses ranging from 62.5 μg to 600 μg for CC patients. METHODS A comprehensive search was conducted, and STATA16 software was used for data analysis. RESULTS Seven studies with 4,107 patients were eligible. A significantly enhanced number of completely spontaneous bowel movement (CSBM) responders were found in the extremely low-dose group (OR: 2.94; 95% CI: 1.98-4.34; p < 0.001), the low-dose group (OR: 3.24; 95% CI: 2.44-4.31; p < 0.001), the medium-dose group (OR: 3.08; 95% CI: 1.46-6.50; p=0.003), and high-dose group (OR: 4.79; 95% CI: 3.04-7.54; p < 0.001). Bayesian analysis showed the high-dose group obtained the maximum CSBM responder rate (OR: 4.94; 95% credible interval (CrI): 3.22-7.79; probability rank = 0.87) indirectly compared with extremely low-dose, low-dose, and medium-dose groups. However, no significant difference presented in the CSBM responder rate by pairwise comparisons of the different dose groups. Additionally, no more any adverse events occurred in the higher linaclotide dose group (RR: 0.91; 95% CrI: 0.60-1.38) indirectly compared with other dose groups. CONCLUSIONS High dose of linaclotide could be more effective and safer for CC patients, which need more trials to confirm in the future.
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Affiliation(s)
- Jiao Yang
- Department of Gastroenterology, WenChang Road 8, Liuzhou People's Hospital, Liuzhou 545000, Guangxi, China
| | - YanChang Lei
- Department of Gastroenterology, WenChang Road 8, Liuzhou People's Hospital, Liuzhou 545000, Guangxi, China
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12
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Biopsychosocial Model and Perceived Constipation Severity According to the Constipation Phenotype. Dig Dis Sci 2021; 66:3588-3596. [PMID: 33073331 DOI: 10.1007/s10620-020-06654-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 10/03/2020] [Indexed: 12/09/2022]
Abstract
PURPOSE Constipation is a frequent complaint of patients with functional bowel disorders. The present study aimed to evaluate the relationship between the perceived constipation severity with demographics, clinical, physiological, and psychological parameters in constipated patients. PATIENTS AND METHODS Four hundred seven constipated patients were included and had clinical, physiological, and psychological evaluation. The self-reported severity of constipation was analyzed using stepwise linear regression in the total population and within each clinical group. RESULTS The patients were mainly of female gender (81%) and were 47.4 ± 16.5 years old. They complained of IBS (65%), and 62% had defecation disorders. The depression scale was abnormal in 200 patients (49%). The relationships of the constipation severity varied according to the Rome IV phenotype. In all phenotypes, it was positively associated with bloating severity, and negatively with Bristol stool form. In IBS patients, perceived constipation severity was also associated with abdominal pain severity. CONCLUSION Our data support the hypothesis that perceived constipation severity is associated with clinical and physiological factors but not demographics and psychological factors. Besides, the relationships of perceived constipation severity with these factors vary according to clinical phenotypes.
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13
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Sharma A, Rao SSC, Kearns K, Orleck KD, Waldman SA. Review article: diagnosis, management and patient perspectives of the spectrum of constipation disorders. Aliment Pharmacol Ther 2021; 53:1250-1267. [PMID: 33909919 PMCID: PMC8252518 DOI: 10.1111/apt.16369] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 12/24/2020] [Accepted: 03/31/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Chronic constipation is a common, heterogeneous disorder with multiple symptoms and pathophysiological mechanisms. Patients are often referred to a gastroenterology provider after laxatives fail. However, there is limited knowledge of the spectrum and management of constipation disorders. AIM To discuss the latest understanding of the spectrum of constipation disorders, tools for identifying a pathophysiologic-based diagnosis in the specialist setting, treatment options and the patient's perspective of constipation. METHODS Literature searches were conducted using PubMed for constipation diagnostic criteria, diagnostic tools and approved treatments. The authors provided insight from their own practices. RESULTS Clinical assessment, stool diaries and Rome IV diagnostic criteria can facilitate diagnosis, evaluate severity and distinguish between IBS with constipation, chronic idiopathic constipation and dyssynergic defecation. Novel smartphone applications can help track constipation symptoms. Rectal examinations, anorectal manometry and balloon expulsion, assessments of neuromuscular function with colonic transit time and colonic manometry can provide mechanistic understanding of underlying pathophysiology. Treatments include lifestyle and diet changes, biofeedback therapy and pharmacological agents. Several classes of laxatives, as well as prokinetic and prosecretory agents, are available; here we describe their mechanisms of action, efficacy and side effects. CONCLUSIONS Constipation includes multiple overlapping subtypes identifiable using detailed history, current diagnostic tools and smartphone applications. Recognition of individual subtype(s) could pave the way for optimal, evidence-based treatments by a gastroenterology provider.
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Affiliation(s)
- Amol Sharma
- Division of Gastroenterology/HepatologyMedical College of GeorgiaAugusta UniversityAugustaGAUSA
| | - Satish S. C. Rao
- Division of Gastroenterology/HepatologyMedical College of GeorgiaAugusta UniversityAugustaGAUSA
| | | | | | - Scott A. Waldman
- Department of Pharmacology and Experimental TherapeuticsThomas Jefferson UniversityPhiladelphiaPAUSA
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14
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Abstract
PURPOSE OF REVIEW Chronic constipation is a common problem that substantially impacts the quality of life of patients and families, healthcare professionals, and resources. The purpose of this review is to discuss the medications that are available for management of chronic constipation, including medications that have been approved by the FDA for adults, other been studied in pediatrics now, and might become available within the upcoming years. RECENT FINDINGS Recent developments in the evaluation of childhood constipation are providing a better understanding into defecation disorders in children and not only new therapies are becoming available, including medications, but also other therapies, such as biofeedback for treatment of functional defecation disorders, electrical stimulation, and surgeries. The aim of this article is to provide an update on the medications that are available for management of chronic constipation, especially with the development and study of newer medications, such as Linaclotide and Lubiprostone with promising results in both adult and pediatric patients. SUMMARY This review will help us identify and have a better understanding regarding what medications are available for use and the indications, so that we can better manage patients with chronic constipation. VIDEO ABSTRACT.
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15
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Wong MYW, Hebbard G, Gibson PR, Burgell RE. Chronic constipation and abdominal pain: Independent or closely interrelated symptoms? J Gastroenterol Hepatol 2020; 35:1294-1301. [PMID: 31900961 DOI: 10.1111/jgh.14970] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 12/20/2019] [Accepted: 01/02/2020] [Indexed: 02/06/2023]
Abstract
Constipation is both a symptom and a disorder, seen in both functional constipation and irritable bowel syndrome with constipation predominance (IBS-C). Despite the Rome IV criteria distinguishing between these conditions, they share many therapeutic approaches. This review aims to explore the relationship between constipation and abdominal pain and assess the evidence surrounding whether laxation improves abdominal pain and whether such a response to laxation differs between IBS-C and functional constipation. In patients with functional constipation, increasing frequency of bowel motions by laxatives regardless of mechanism of action is associated with reductions in the severity of abdominal pain, supporting the role of constipation as a contributor to abdominal discomfort. In patients with IBS-C, evidence from systematic reviews indicates that abdominal pain is driven by factors additional to constipation alone and that visceral analgesic modulation is also needed to optimize pain. Changing definitions of IBS-C and heterogeneity in clinical trial design including endpoints have raised uncertainty about the comparative ability of older laxatives without known neuromodulatory effects to improve chronic abdominal pain compared with new secretagogues and prokinetics for the management of IBS-C. While it is known that abdominal pain is associated with constipation and laxation contributes to relief of that pain, it remains unproven whether proposed visceral analgesic properties of new laxatives provide greater pain relief than laxation alone. However, it is likely that the response to laxation in IBS-C is only part of the puzzle.
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Affiliation(s)
- May Y W Wong
- Department of Gastroenterology, Alfred Health and Monash University, Melbourne, Victoria, Australia.,Department of Gastroenterology, The Royal Melbourne Hospital and Melbourne University, Melbourne, Victoria, Australia
| | - Geoffrey Hebbard
- Department of Gastroenterology, The Royal Melbourne Hospital and Melbourne University, Melbourne, Victoria, Australia
| | - Peter R Gibson
- Department of Gastroenterology, Alfred Health and Monash University, Melbourne, Victoria, Australia
| | - Rebecca E Burgell
- Department of Gastroenterology, Alfred Health and Monash University, Melbourne, Victoria, Australia
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16
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Schmulson MJ, Chiu-Ugalde J, Sáez-Ríos A, López-Colombo A, Mateos-Pérez GJ, Remes-Troche JM, Sobrino-Cossio S, Soto-Pérez JC, Tamayo de la Cuesta JL, Teramoto-Matsubara OT, López-Alvarenga JC. Efficacy of the Combination of Pinaverium Bromide 100 mg Plus Simethicone 300 mg in Abdominal Pain and Bloating in Irritable Bowel Syndrome: A Randomized, Placebo-controlled Trial. J Clin Gastroenterol 2020; 54:e30-e39. [PMID: 31385885 PMCID: PMC7069394 DOI: 10.1097/mcg.0000000000001242] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Accepted: 06/06/2019] [Indexed: 12/12/2022]
Abstract
GOALS We aimed to evaluate the efficacy and safety of PB+S (pinaverium bromide 100 mg plus simethicone 300 mg) in patients with irritable bowel syndrome (IBS). BACKGROUND IBS is a multifactorial disorder; thus, combination therapy with different mechanisms of action is expected to be useful. PB+S has shown effectiveness in an open-label clinical study in IBS. However, there are no placebo-controlled trials. MATERIALS AND METHODS IBS-Rome III patients with abdominal pain/discomfort for at least 2 days within the week prior to baseline assessment were included in this 12-week, randomized, double-blind, placebo-controlled study of PB+S versus placebo, bid. The primary endpoint was overall symptom improvement, evaluated weekly by the patient (Likert Scale). Secondary endpoints included the weekly improvement in the severity of abdominal pain and bloating assessed both by patients (10-cm Visual Analogue Scale) and investigators (Likert Scale); frequency of Bristol Scale stool types (consistency) evaluated by patients and the IBS Quality of Life scores. RESULTS A total of 285 patients (female: 83%; 36.5±8.9 y old) received at least 1 dose of PB+S (n=140) or placebo (n=145). No difference was observed in overall symptom improvement between the groups (P=0.13). However, PB+S was superior in abdominal pain (effect size: 31%, P=0.038) and bloating (33%, P=0.019). Patients with IBS-C and IBS-M showed the best improvement in the frequency of stool types with PB+S. No differences were observed in IBS Quality of Life scores and adverse events. CONCLUSIONS PB+S was superior to placebo in improving abdominal pain and bloating in patients with active IBS. The effect on the frequency of stool consistency was particularly significant in IBS-C and IBS-M.
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Affiliation(s)
- Max J. Schmulson
- Laboratory of Liver, Pancreas and Motility (HIPAM)-Unit of Research in Experimental Medicine, Faculty of Medicine, National Autonomous University of Mexico (UNAM). General Hospital of Mexico “Dr. Eduardo Liceada”
- Gastroenterology and Endoscopy in MGP, ABC Medical Center
- Lomas Altas SC Clinic, Mexico City
| | | | - Adolfo Sáez-Ríos
- Central Military Hospital
- Faculty of Medicine, and Mano Amiga Foundation-Anahuac University, Mexico City
- Medical Department Takeda Ecuador and Peru
| | - Aurelio López-Colombo
- Department of Health Education and Research, Specialty Hospital-Manuel Avila Camacho National Medical Center, National Institute of Social Security (IMSS), Puebla
| | | | - José María Remes-Troche
- Laboratory of Digestive Physiology and Gastrointestinal Motility, Institute of Medical-Biologic Research, University of Veracruz, Veracruz, Ver.-México
| | - Sergio Sobrino-Cossio
- Pedregal Angeles Hospital
- Service of Gastroenterology and Digestive Endoscopy, High Specialty South Central Hospital of Petroleos Mexicanos (PEMEX), Mexico City
| | - Julio C. Soto-Pérez
- Digestive Physiology Clinic, Metropolitan Angeles Hospital
- Center for Research and Education in Health Sciences, Autonomous University of Sinaloa, Civil Hospital of Culiacan
| | - José L. Tamayo de la Cuesta
- Center for Research and Education in Health Sciences, Autonomous University of Sinaloa, Civil Hospital of Culiacan
| | | | - Juan C. López-Alvarenga
- Department of Human Genetics, School of Medicine, University of Texas Rio Grande Valley, TX
- Research Division Mexican-American University of the North (UMAN), Reynosa, Tamaulipas, Mexico
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17
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Lembo AJ, Covington PS, Dove LS, Andrae DA. Effects of treatment with eluxadoline on abdominal pain in patients with IBS-D: Additional post hoc analyses of Phase 3 trials. Neurogastroenterol Motil 2020; 32:e13774. [PMID: 31984655 PMCID: PMC7154635 DOI: 10.1111/nmo.13774] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Revised: 11/02/2019] [Accepted: 11/19/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND Recurring abdominal pain is a characteristic and often unpredictable and debilitating symptom of irritable bowel syndrome with diarrhea (IBS-D). Measuring the effects of IBS-D treatments on abdominal pain remains a significant challenge in clinical trials. Here, we aimed to examine the effect of eluxadoline through various post hoc analyses. METHODS Data from two eluxadoline Phase 3 trials were pooled over 26 weeks, comparing eluxadoline 100 mg twice daily to placebo. Worst abdominal pain (WAP) was measured daily on a 0-10 scale. WAP responder criteria were prospectively defined as a ≥30% improvement in daily WAP score on ≥50% of days. Pairwise, two-sided Cochran-Mantel-Haenszel tests assessed treatment effects. Cumulative distribution functions were used to plot WAP response rates using variations on the response criteria. KEY RESULTS Of 1615 patients with IBS-D (66% female, mean age 46 years), 806 received eluxadoline and 809 received placebo; 48.3% and 44.0% were WAP responders (≥30% improvement), respectively (P value not significant). When the response threshold was increased to 50% daily WAP improvement from baseline, a significantly greater percentage of eluxadoline-treated patients versus placebo-treated patients were WAP responders (38.7% vs 32.5%, respectively; P = .009). At Week 26, average WAP changes from baseline were -3.4 and -3.0 points, respectively (P = .002). CONCLUSIONS AND INFERENCES Despite small effect sizes, eluxadoline demonstrated consistent and sustained improvement in WAP compared to placebo across a range of prospective and post hoc analyses. Assessing WAP response across a range of measures is important for fully understanding a treatment's efficacy.
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Affiliation(s)
| | - Paul S. Covington
- Former employee of Furiex Pharmaceuticals, Inc.an affiliate of Allergan plcMadisonNJUSA
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18
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Aziz I, Whitehead WE, Palsson OS, Törnblom H, Simrén M. An approach to the diagnosis and management of Rome IV functional disorders of chronic constipation. Expert Rev Gastroenterol Hepatol 2020; 14:39-46. [PMID: 31893959 DOI: 10.1080/17474124.2020.1708718] [Citation(s) in RCA: 173] [Impact Index Per Article: 34.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Introduction: Chronic constipation is highly prevalent, affecting between 10% and 15% of the population. The Rome IV criteria categorizes disorders of chronic constipation into four subtypes: (a) functional constipation, (b) irritable bowel syndrome with constipation, (c) opioid-induced constipation, and (d) functional defecation disorders, including inadequate defecatory propulsion and dyssynergic defecation. The initial management approach for these disorders is similar, focusing on diet, lifestyle and the use of standard over-the-counter laxatives. If unsuccessful, further therapy is tailored according to subtype.Areas covered: This review covers the definition, epidemiology, diagnostic criteria, investigations and management of the Rome IV disorders of chronic constipation.Expert opinion: By adopting a logical step-wise approach toward the diagnosis of chronic constipation and its individual subtypes, clinicians have the opportunity to tailor therapy accordingly and improve symptoms, quality of life, and patient satisfaction.
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Affiliation(s)
- Imran Aziz
- Academic Department of Gastroenterology, Sheffield Teaching Hospitals, Sheffield, UK.,Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK
| | - William E Whitehead
- Center for Functional Gastrointestinal and Motility Disorders, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Olafur S Palsson
- Center for Functional Gastrointestinal and Motility Disorders, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Hans Törnblom
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Magnus Simrén
- Center for Functional Gastrointestinal and Motility Disorders, University of North Carolina, Chapel Hill, North Carolina, USA.,Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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19
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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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20
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Meldgaard T, Keller J, Olesen AE, Olesen SS, Krogh K, Borre M, Farmer A, Brock B, Brock C, Drewes AM. Pathophysiology and management of diabetic gastroenteropathy. Therap Adv Gastroenterol 2019; 12:1756284819852047. [PMID: 31244895 PMCID: PMC6580709 DOI: 10.1177/1756284819852047] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Accepted: 04/26/2019] [Indexed: 02/04/2023] Open
Abstract
Polyneuropathy is a common complication to diabetes. Neuropathies within the enteric nervous system are associated with gastroenteropathy and marked symptoms that severely reduce quality of life. Symptoms are pleomorphic but include nausea, vomiting, dysphagia, dyspepsia, pain, bloating, diarrhoea, constipation and faecal incontinence. The aims of this review are fourfold. First, to provide a summary of the pathophysiology underlying diabetic gastroenteropathy. Secondly to give an overview of the diagnostic methods. Thirdly, to provide clinicians with a focussed overview of current and future methods for pharmacological and nonpharmacological treatment modalities. Pharmacological management is categorised according to symptoms arising from the upper or lower gut as well as sensory dysfunctions. Dietary management is central to improvement of symptoms and is discussed in detail, and neuromodulatory treatment modalities and other emerging management strategies for diabetic gastroenteropathy are discussed. Finally, we propose a diagnostic/investigation algorithm that can be used to support multidisciplinary management.
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Affiliation(s)
| | - Jutta Keller
- Israelitic Hospital in Hamburg, Academic
Hospital University of Hamburg, Germany
| | - Anne Estrup Olesen
- Mech-Sense, Department of Gastroenterology and
Hepatology and Department of Clinical Medicine, Aalborg University Hospital,
Denmark,Department of Clinical Medicine, Aalborg
University, Denmark
| | - Søren Schou Olesen
- Mech-Sense, Department of Gastroenterology and
Hepatology and Department of Clinical Medicine, Aalborg University Hospital,
Denmark,Department of Clinical Medicine, Aalborg
University, Denmark
| | - Klaus Krogh
- Department of Hepatology and Gastroenterology,
Aarhus University Hospital, Denmark
| | - Mette Borre
- Department of Hepatology and Gastroenterology,
Aarhus University Hospital, Denmark
| | - Adam Farmer
- Department of Gastroenterology, University
Hospitals of North Midlands, Stoke on Trent, Staffordshire, UK,Centre for Digestive Diseases, Blizard
Institute of Cell and Molecular Science, Wingate Institute of
Neurogastroenterology, Barts and the London School of Medicine and
Dentistry, Queen Mary University of London, UK
| | - Birgitte Brock
- Department of Clinical Research, Steno Diabetes
Center Copenhagen (SDCC), Denmark
| | - Christina Brock
- Mech-Sense, Department of Gastroenterology and
Hepatology and Department of Clinical Medicine, Aalborg University Hospital,
Denmark,Department of Clinical Medicine, Aalborg
University, Denmark
| | - Asbjørn Mohr Drewes
- Mech-Sense, Department of Gastroenterology and
Hepatology and Department of Clinical Medicine, Aalborg University Hospital,
Denmark,Department of Clinical Medicine, Aalborg
University, Denmark
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21
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Mari A, Abu Backer F, Mahamid M, Amara H, Carter D, Boltin D, Dickman R. Bloating and Abdominal Distension: Clinical Approach and Management. Adv Ther 2019; 36:1075-1084. [PMID: 30879252 PMCID: PMC6824367 DOI: 10.1007/s12325-019-00924-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Indexed: 12/16/2022]
Abstract
Functional abdominal bloating and distension (FABD) are common gastrointestinal complaints, encountered on a daily basis by gastroenterologists and healthcare providers. Functional abdominal bloating is a subjective sensation that is commonly associated with an objective abdominal distension. FABD may be diagnosed as a single entity (the sole or cardinal complaint) or may overlap with other functional gastrointestinal disorders such as functional constipation, irritable bowel syndrome, and functional dyspepsia. The pathophysiology of FABD is not completely understood. Proposed underlying mechanisms include visceral hypersensitivity, behavioral induced abnormal abdominal wall-phrenic reflexes, the effect of poorly absorbed fermentable carbohydrates, and microbiome alterations. Management includes behavioral therapy, dietary interventions, microbiome modulation, and medical therapy. This review presents the current knowledge on the pathophysiology, evaluation, and management of FABD.
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Affiliation(s)
- Amir Mari
- Gastroenterology Institute, Hillel Yaffe Medical Center, Hadera, Israel
- Gastroenterology Institute, Nazareth EMMS Hospital, Nazareth, Israel
- Faculty of Medicine in the Galilee, Bar-Ilan University, Ramat Gan, Israel
| | - Fadi Abu Backer
- Gastroenterology Institute, Hillel Yaffe Medical Center, Hadera, Israel
| | - Mahmud Mahamid
- Gastroenterology Institute, Nazareth EMMS Hospital, Nazareth, Israel
- Faculty of Medicine in the Galilee, Bar-Ilan University, Ramat Gan, Israel
| | - Hana Amara
- Gastroenterology Institute, Nazareth EMMS Hospital, Nazareth, Israel
| | - Dan Carter
- Department of Gastroenterology, Chaim Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Doron Boltin
- Division of Gastroenterology, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ram Dickman
- Division of Gastroenterology, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel.
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
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22
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Kilgallon E, Vasant DH, Green D, Shields PL, Hamdy S, Lal S, Paine P. Chronic continuous abdominal pain: evaluation of diagnostic features, iatrogenesis and drug treatments in a cohort of 103 patients. Aliment Pharmacol Ther 2019; 49:1282-1292. [PMID: 30950110 DOI: 10.1111/apt.15241] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 11/23/2018] [Accepted: 03/11/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Chronic continuous abdominal pain (CCAP) is characteristic of centrally mediated gastrointestinal pain disorders. It consumes significant healthcare resources yet is poorly understood, with minimal cohort-specific data in the literature. AIMS To examine in a large cohort of CCAP patients, (a) diagnostic features, (b) iatrogenic impact of opioids and surgery, (c) drug treatment effects and tolerance. METHODS Consecutive tertiary CCAP referrals to a neurogastroenterology clinic (2009-2016) were reviewed for Rome IV and neuropathic pain criteria. Medical, surgical and drug histories, interventions and outcomes were correlated with clinical diagnosis and associated opioid use. RESULTS Of 103 CCAP patients (mean age 40 ± 14, 85% female), 50% had physiological exacerbations precluding full Rome IV Centrally Mediated Abdominal Pain Syndrome criteria. However, there were no significant differences between patients who satisfied Rome IV criteria and those who did not. Overall, 81% had allodynia (a nonpainful stimulus evoking pain sensation). Opioid use was associated with allodynia (P = 0.003). Prior surgery was associated with further operations post CCAP onset (P < 0.001). Although 68% had undergone surgical interventions, surgery did not resolve pain in any patient and worsened pain in 35%. Whilst duloxetine was the most effective neuromodulator (P = 0.003), combination therapy was superior to monotherapy (P = 0.007). CONCLUSIONS This is currently the largest cohort CCAP dataset that supports eliciting neuropathic features, including allodynia, for a positive clinical diagnosis, to guide treatment. Physiological exacerbation of CCAP may represent visceral allodynia, and need not preclude central origin. Use of centrally acting neuromodulators, and avoidance of detrimental opioids and surgical interventions appear to predict favourable outcomes.
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Affiliation(s)
| | - Dipesh H Vasant
- Division of Diabetes, Endocrinology and Gastroenterology, University of Manchester, Manchester, UK.,Manchester University Foundation Trust, Wythenshawe Hospital, Manchester, UK
| | - Darren Green
- Division of Cardiovascular Sciences, University of Manchester, Manchester, UK
| | | | - Shaheen Hamdy
- Gastroenterology, Salford Royal NHS Foundation Trust, Salford, UK.,Division of Diabetes, Endocrinology and Gastroenterology, University of Manchester, Manchester, UK
| | - Simon Lal
- Gastroenterology, Salford Royal NHS Foundation Trust, Salford, UK.,Division of Diabetes, Endocrinology and Gastroenterology, University of Manchester, Manchester, UK
| | - Peter Paine
- Gastroenterology, Salford Royal NHS Foundation Trust, Salford, UK.,Division of Diabetes, Endocrinology and Gastroenterology, University of Manchester, Manchester, UK
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23
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Mascarenhas-Saraiva MJ, Mascarenhas-Saraiva M. Effectiveness and tolerability of linaclotide in the treatment of IBS-C in a "real-life" setting: Results from a Portuguese single-center study. Neurogastroenterol Motil 2019; 31:e13508. [PMID: 30569519 DOI: 10.1111/nmo.13508] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 10/08/2018] [Accepted: 10/16/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND Although linaclotide has been approved to treat moderate to severe IBS-C, no data are available on its effectiveness and tolerability in patients in a real-life setting. METHODS A prospective single-center study of the effectiveness and tolerability of linaclotide was carried out on patients (n = 40) with moderate to severe IBS-C, all fulfilling the Rome IV criteria. Clinical information was recorded using a dietary questionnaire at baseline, and 3 and 6 months after initiating treatment. The end-points to measure effectiveness included abdominal pain and bloating (11-NRS), the number of bowel movements and patient satisfaction. Tolerability was assessed through the frequency of adverse events. KEY RESULTS In terms of efficacy, an improvement in abdominal pain and in the intensity of bloating was evident in the cohort after 6 months of linaclotide therapy. The proportion of patients with moderate or severe symptoms of bloating fell from 93.3% to 33.3% and those with pain from 93.4% to 20%. Weekly bowel movements also improved and accordingly, 97% of the patients were moderately or very satisfied with the treatment. At the end of the study, diarrhea was the most frequent adverse event (10%), although it was considered mild in 66.7% of these subjects and moderate in 33.3%. A lack of efficacy (n = 3) and excessive diarrhea (n = 7) were motives for discontinuing the treatment. CONCLUSIONS AND INFERENCES Linaclotide proved to be a safe and effective drug to reduce the main symptoms of IBS-C in everyday clinical practice, with an improvement comparable to that seen in clinical trials.
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24
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Fukudo S, Miwa H, Nakajima A, Haruma K, Kosako M, Nakagawa A, Akiho H, Yamaguchi Y, Johnston JM, Currie M, Kinoshita Y. A randomized controlled and long-term linaclotide study of irritable bowel syndrome with constipation patients in Japan. Neurogastroenterol Motil 2018; 30:e13444. [PMID: 30136447 DOI: 10.1111/nmo.13444] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 07/16/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND Clinical testing was required to verify the effect of linaclotide 0.5 mg/d in patients with irritable bowel syndrome with constipation (IBS-C) in Japan. METHODS This was a randomized, double-blind, placebo-controlled (Part 1) and long-term, open-label extension (Part 2) study of linaclotide at 60 hospitals and clinics in Japan. Patients with IBS-C diagnosed using Rome III criteria (n = 500) were randomly assigned to linaclotide 0.5 mg (n = 249) or placebo (n = 251) for a 12-week treatment period followed by open-label treatment with linaclotide (n = 324) for an additional 40 weeks. The primary endpoints were the responder rate of global improvement of IBS symptoms and complete spontaneous bowel movement (CSBM) during 12 weeks. The secondary endpoints included responder rates of SBM and abdominal pain/discomfort relief. KEY RESULTS Part 1: The responder rates for global improvement and for CSBM frequency were significantly higher for linaclotide compared to placebo (P < 0.001). Secondary endpoints including responder rates for SBM and abdominal pain/discomfort relief in the linaclotide group were also significantly greater than those in the placebo group. Part 2: Patients switched from placebo to linaclotide showed similar responder rates for global improvement and CSBM frequency to those in patients who continued to receive linaclotide, supporting sustained efficacy. Diarrhea was seen in 14.5% of patients; all cases were mild or moderate. CONCLUSIONS AND INFERENCES This study suggests that a linaclotide dose of 0.5 mg is effective and safe for IBS-C patients in Japan.
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Affiliation(s)
- Shin Fukudo
- Department of Behavioral Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hiroto Miwa
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University, Yokohama, Japan
| | - Ken Haruma
- General Internal Medicine 2, General Medical Center, Kawasaki Medical School, Kurashiki, Japan
| | - Masanori Kosako
- Japan-Asia Clinical Development 2, Development, Astellas Pharma Inc., Tokyo, Japan
| | - Ayako Nakagawa
- Japan-Asia Clinical Development 2, Development, Astellas Pharma Inc., Tokyo, Japan
| | - Hiraku Akiho
- Japan-Asia Clinical Development 2, Development, Astellas Pharma Inc., Tokyo, Japan
| | - Yusuke Yamaguchi
- Japan-Asia Data Science, Development, Astellas Pharma Inc., Tokyo, Japan
| | | | - Mark Currie
- Ironwood Pharmaceuticals Inc., Cambridge, Massachusetts
| | - Yoshikazu Kinoshita
- Department of Gastroenterology, Faculty of Medicine, Shimane University, Izumo, Japan
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25
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McHugh DR, Cotton CU, Moss FJ, Vitko M, Valerio DM, Kelley TJ, Hao S, Jafri A, Drumm ML, Boron WF, Stern RC, McBennett K, Hodges CA. Linaclotide improves gastrointestinal transit in cystic fibrosis mice by inhibiting sodium/hydrogen exchanger 3. Am J Physiol Gastrointest Liver Physiol 2018; 315:G868-G878. [PMID: 30118317 PMCID: PMC9925117 DOI: 10.1152/ajpgi.00261.2017] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Gastrointestinal dysfunction in cystic fibrosis (CF) is a prominent source of pain among patients with CF. Linaclotide, a guanylate cyclase C (GCC) receptor agonist, is a US Food and Drug Administration-approved drug prescribed for chronic constipation but has not been widely used in CF, as the cystic fibrosis transmembrane conductance regulator (CFTR) is the main mechanism of action. However, anecdotal clinical evidence suggests that linaclotide may be effective for treating some gastrointestinal symptoms in CF. The goal of this study was to determine the effectiveness and mechanism of linaclotide in treating CF gastrointestinal disorders using CF mouse models. Intestinal transit, chloride secretion, and intestinal lumen fluidity were assessed in wild-type and CF mouse models in response to linaclotide. CFTR and sodium/hydrogen exchanger 3 (NHE3) response to linaclotide was also evaluated. Linaclotide treatment improved intestinal transit in mice carrying either F508del or null Cftr mutations but did not induce detectable Cl- secretion. Linaclotide increased fluid retention and fluidity of CF intestinal contents, suggesting inhibition of fluid absorption. Targeted inhibition of sodium absorption by the NHE3 inhibitor tenapanor produced improvements in gastrointestinal transit similar to those produced by linaclotide treatment, suggesting that inhibition of fluid absorption by linaclotide contributes to improved gastrointestinal transit in CF. Our results demonstrate that linaclotide improves gastrointestinal transit in CF mouse models by increasing luminal fluidity through inhibiting NHE3-mediated sodium absorption. Further studies are necessary to assess whether linaclotide could improve CF intestinal pathologies in patients. GCC signaling and NHE3 inhibition may be therapeutic targets for CF intestinal manifestations. NEW & NOTEWORTHY Linaclotide's primary mechanism of action in alleviating chronic constipation is through cystic fibrosis transmembrane conductance regulator (CFTR), negating its use in patients with cystic fibrosis (CF). For the first time, our findings suggest that in the absence of CFTR, linaclotide can improve fluidity of the intestinal lumen through the inhibition of sodium/hydrogen exchanger 3. These findings suggest that linaclotide could improve CF intestinal pathologies in patients.
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Affiliation(s)
- Daniel R. McHugh
- 1Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Calvin U. Cotton
- 2Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio,3Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Fraser J. Moss
- 2Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Megan Vitko
- 1Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Dana M. Valerio
- 3Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Thomas J. Kelley
- 3Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio,4Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Shuyu Hao
- 1Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Anjum Jafri
- 3Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Mitchell L. Drumm
- 1Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio,3Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Walter F. Boron
- 2Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio,5Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio,6Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Robert C. Stern
- 3Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio,7Rainbow Babies and Children’s Hospital, Cleveland, Ohio
| | - Kimberly McBennett
- 3Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio,7Rainbow Babies and Children’s Hospital, Cleveland, Ohio
| | - Craig A. Hodges
- 1Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio,3Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio
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26
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Yiannakou Y, Agrawal A, Allen PB, Arebi N, Brown SR, Eugenicos MP, Farmer AD, McLain-Smith S, McLaughlin J, Sanders DS, Lawrance D, Emmanuel A. UK clinical experience up to 52 weeks with linaclotide for irritable bowel syndrome with constipation. Therap Adv Gastroenterol 2018; 11:1756284818798791. [PMID: 30302125 PMCID: PMC6170957 DOI: 10.1177/1756284818798791] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 07/25/2018] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Linaclotide, a guanylate cyclase C agonist, has been shown in clinical trials to improve symptoms of irritable bowel syndrome with constipation (IBS-C). Here we report data from a real-world study of linaclotide in the UK. METHODS This 1-year, multicentre, prospective, observational study in the UK enrolled patients aged 18 years and over initiating linaclotide for IBS-C. The primary assessment was change from baseline in IBS Symptom Severity Scale (IBS-SSS) score at 12 weeks, assessed in patients with paired baseline and 12-week data. Change from baseline in IBS-SSS score at 52 weeks was a secondary assessment. Adverse events were recorded. RESULTS In total, 202 patients were enrolled: 185 (91.6%) were female, median age was 44.9 years (range 18.1-77.2) and 84 (41.6%) reported baseline laxative use. Mean (standard deviation) baseline IBS-SSS score was 339 (92), with most patients (n = 129; 66.8%) classified as having severe disease (score ⩾300). In patients with paired data, there was a significant mean (95% confidence interval) decrease in IBS-SSS score from baseline to 12 weeks [-77.0 (-96.3, -57.7); p < 0.001; n = 124] and baseline to 52 weeks [-70.7 (-95.0, -46.5); p < 0.001; n = 76]. Overall, 174 adverse events were reported in 77 (38.1%) patients, most commonly diarrhoea (n = 54; 26.7%), abdominal pain (n = 21; 10.4%) and abdominal distension (n = 13; 6.4%). CONCLUSION Linaclotide significantly improved IBS-SSS score at 12 and 52 weeks. These results provide insights into outcomes with linaclotide treatment over 1 year in patients with IBS-C in real-world clinical practice.
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Affiliation(s)
- Yan Yiannakou
- University Hospital of North Durham, County Durham and Darlington NHS Foundation Trust, North Road, Durham DH1 5TW, UK
| | - Anu Agrawal
- Doncaster Royal Infirmary, Doncaster and Bassetlaw Hospitals NHS Foundation Trust, Doncaster, UK
| | - Patrick B. Allen
- The Ulster Hospital, South Eastern Health and Social Care Trust, Belfast, UK
| | - Naila Arebi
- St Mark’s Hospital, London North West University Healthcare NHS Trust and Imperial College, London, UK
| | - Steven R. Brown
- Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | | | - Adam D. Farmer
- University Hospitals of North Midlands NHS Trust, Stoke-on-Trent, UK and Institute of Applied Clinical Sciences, University of Keele, Keele, UK
| | | | - John McLaughlin
- The University of Manchester, Manchester, UK, Salford Royal NHS Foundation Trust, Salford, UK and Manchester Academic Health Sciences Centre, Manchester, UK
| | - David S. Sanders
- Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | | | - Anton Emmanuel
- University College Hospital, University College London Hospitals NHS Foundation Trust, London, UK
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27
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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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Mearin F, Rey E, Santander C. Irritable bowel syndrome: How to improve decision making in clinical practice. Med Clin (Barc) 2018; 151:489-497. [PMID: 30243429 DOI: 10.1016/j.medcli.2018.06.020] [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: 04/17/2018] [Revised: 06/05/2018] [Accepted: 06/07/2018] [Indexed: 11/26/2022]
Abstract
Irritable bowel syndrome (IBS) is a highly prevalent functional disorder, characterised by the presence of recurrent abdominal pain associated with changes in bowel habits. Its physiopathology is complex, its clinical manifestations are diverse, and the therapeutic possibilities are multiple and not well known. In clinical practice, the diagnosis of IBS represents an important challenge; this means that in many cases the patients do not receive the proper diagnosis, which implies an absence of a targeted treatment, and therefore bad symptomatic control. In this article, the fundamental questions posed by the doctor when dealing with a patient with symptoms compatible with IBS are presented chronologically. The main objective is to provide clinical and eminently practical information that facilitates the management of patients with IBS, from both diagnostic and therapeutic points of view.
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Affiliation(s)
- Fermín Mearin
- Servicio de Aparato Digestivo, Centro Médico Teknon, Barcelona, España.
| | - Enrique Rey
- Servicio de Aparato Digestivo, Hospital Clínico San Carlos, Universidad Complutense, Madrid, España
| | - Cecilio Santander
- Servicio de Aparato Digestivo, Hospital Universitario de La Princesa, Madrid, España
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29
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Mestre TA, Shamy M, Benedetti F, Lang AE. Harnessing the power of placebos in movement disorders: Insights from Parkinson's disease in clinical research and practice. Mov Disord 2018; 33:1195-1203. [PMID: 30145820 DOI: 10.1002/mds.27409] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2018] [Revised: 03/13/2018] [Accepted: 03/20/2018] [Indexed: 12/17/2022] Open
Abstract
The placebo effect alongside the detrimental nocebo and lessebo effects associated with the use of placebos are well-recognized phenomena. Research conducted in the last two decades has demonstrated that the placebo effect is a measurable health benefit with well-known neurobiological correlates. In this review, we describe the current knowledge about how to best make use of the placebo effect to improve clinical research and optimize clinical care. We will cover four key topics: (1) setting the stage: historical perspectives on the use of placebos; (2) optimizing the use of placebos in clinical trials; (3) use of placebos in clinical practice; and (4) how can we minimize the ethical risks of using placebos? The adoption of the placebo-controlled trial as a standard in the therapeutic development reduced the placebo effect to background noise in a therapeutic signal. Strategies to minimize the placebo effect in clinical trials have been used to obtain positive efficacy results. In more recent years, new study paradigms encouraged a change in the views on placebos and the placebo effect. Alternative study designs and the development of biomarkers for a placebo response permit a better understanding of the contribution of the placebo effect to the results of interventional studies, without minimizing it. In clinical practice, optimizing the placebo effect (and reducing nocebo effects) has the potential to improve care for our patients, but raises ethical challenges. An enhanced patient-physician relationship would be central to any evidence-based intervention used in clinical care to heighten the placebo effect. © 2018 International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Tiago A Mestre
- Parkinson's Disease and Movement Disorders Center, Division of Neurology, Department of Medicine, The Ottawa Hospital Research Institute, University of Ottawa Brain and Mind Institute, Ottawa, Ontario, Canada
| | - Michel Shamy
- Division of Neurology, Department of Medicine, The Ottawa Hospital Research Institute, University of Ottawa Brain and Mind Institute, Ottawa, Ontario, Canada
| | - Fabrizio Benedetti
- Department of Neuroscience, University of Turin Medical School, Turin, Italy
| | - Anthony E Lang
- Edmond J Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, Ontario, Canada
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30
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Spiller R. Inhibiting glucose absorption to treat constipation. Lancet Gastroenterol Hepatol 2018; 3:588-589. [PMID: 30056027 DOI: 10.1016/s2468-1253(18)30214-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 06/22/2018] [Indexed: 12/13/2022]
Affiliation(s)
- Robin Spiller
- Nottingham Digestive Diseases Biomedical Research Unit, Nottingham Digestive Diseases Centre, Nottingham University Hospital, Nottingham NG2 7UH, UK.
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31
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Geijo Martínez F, Sánchez Garrido A, Marcos Prieto H, Piñeiro Pérez C, Prieto Bermejo AB, Álvarez Delgado A, Velasco Guardado A, Rodríguez Pérez A. Long-term results of linaclotide in the treatment of constipation-type irritable bowel syndrome. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2018; 110:451-457. [PMID: 29685047 DOI: 10.17235/reed.2018.5268/2017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
BACKGROUND constipation-predominant irritable bowel syndrome (C-IBS) is a prevalent, complex and multifactorial disorder that represents a challenge in terms of diagnosis and therapeutic management. OBJECTIVE to evaluate the effectiveness, safety and treatment satisfaction of linaclotide in C-IBS patients. METHODS prospective, single-center and observational study conducted in patients diagnosed with C-IBS. The patients were treated with linaclotide (Constella®, Allergan Inc., Irvine, CA), once-daily via an oral capsule of 290-μg, 30 minutes before breakfast. The primary effectiveness endpoint was the number of bowel movements per week. The secondary endpoints included treatment satisfaction and changes from baseline in frequency and severity of symptoms (abdominal pain and bloating). This was assessed via an 11-point visual analog scale (VAS) reported by the patients in a daily register. RESULTS thirty female patients were consecutively included. The median follow-up time was 18 months. The mean (standard deviation [SD]) number of weekly bowel movements significantly increased from 0.9 (0.6) at baseline to 4.7 (3.9) at the end of follow-up, p < 0.0001. Abdominal pain significantly decreased from 5.7 (2.3) at baseline to 3.1 (2.8) at the end of the follow-up period, p < 0.0001. Similarly, bloating significantly decreased from 6.8 (1.6) to 2.9 (2.5) at the beginning and end of the treatment period, respectively, p < 0.0001. The mean (SD) degree of satisfaction at the end of the study was 6.7 (3.0). CONCLUSIONS long-term linaclotide treatment in patients with C-IBS is effective and safe in the clinical setting.
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Affiliation(s)
| | - Ana Sánchez Garrido
- Servicio de Aparato Digestivo, Hospital Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL)
| | - Héctor Marcos Prieto
- Servicio de Aparato Digestivo, Hospital Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL)
| | - Concepción Piñeiro Pérez
- Servicio de Aparato Digestivo, Hospital Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL)
| | | | - Alberto Álvarez Delgado
- Aparato Digestivo, Hospital Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL)
| | - Antonio Velasco Guardado
- Aparato Digestivo, Hospital Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL)
| | - Antonio Rodríguez Pérez
- Servicio de Aparato Digestivo, Hospital Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL)
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Fukudo S, Nakajima A, Fujiyama Y, Kosako M, Nakagawa A, Akiho H, Nakashima Y, Johnston JM, Miwa H. Determining an optimal dose of linaclotide for use in Japanese patients with irritable bowel syndrome with constipation: A phase II randomized, double-blind, placebo-controlled study. Neurogastroenterol Motil 2018; 30:e13275. [PMID: 29278278 DOI: 10.1111/nmo.13275] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2017] [Accepted: 12/04/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND Clinical testing to determine a suitable dose of linaclotide for Japanese patients with irritable bowel syndrome with constipation (IBS-C) was needed. METHODS This was a randomized, double-blind, placebo-controlled, dose-finding trial. Japanese patients with IBS-C diagnosed using Rome III criteria (n = 559, men/women: 49/510) were randomly assigned to 1 of 4 linaclotide doses (0.0625, 0.125, 0.25, or 0.5 mg) or placebo for the 12-week treatment period. The primary endpoint was responder rate of global assessment of relief of IBS symptoms during 12 weeks. The secondary endpoints included responder rates of complete spontaneous bowel movement (CSBM), SBM and abdominal pain/discomfort relief and others. KEY RESULTS The primary endpoint was 23.2%, 36.2%, 38.7%, 34.8%, and 38.3% in placebo (n = 112), 0.0625 (n = 116), 0.125 (n = 111), 0.25 (n = 112), and 0.5 (n = 107) mg of linaclotide groups with the difference from the placebo group in each linaclotide group (13.0%, 15.5%, 11.6%, 15.1%, P > .05). Monthly responder rate of global assessment of relief of IBS symptoms at month 3 (48.6%), responder rate of CSBM during 12 weeks (45.8%), and responder rate of abdominal pain/discomfort relief during 12 weeks (32.7%) in the 0.5 mg were significantly higher than those in placebo group (29.5%, P < .01; 25.9%, P < .01; and 18.8%, P < .05 respectively). The most frequent adverse event in the linaclotide groups was diarrhea. CONCLUSIONS & INFERENCES This study suggests that a linaclotide dose of 0.5 mg may be appropriate in Japanese patients with IBS-C.
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Affiliation(s)
- S Fukudo
- Department of Behavioral Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - A Nakajima
- Department of Gastroenterology, Yokohama City University, Yokohama, Japan
| | - Y Fujiyama
- Shiga University of Medical Science, Ohtsu, Japan
| | - M Kosako
- Japan-Asia Clinical Development 2, Development, Astellas Pharma Inc., Tokyo, Japan
| | - A Nakagawa
- Japan-Asia Clinical Development 2, Development, Astellas Pharma Inc., Tokyo, Japan
| | - H Akiho
- Japan-Asia Clinical Development 2, Development, Astellas Pharma Inc., Tokyo, Japan
| | - Y Nakashima
- Japan-Asia Data Science, Development, Astellas Pharma Inc., Tokyo, Japan
| | - J M Johnston
- Ironwood Pharmaceuticals Inc., Cambridge, MA, USA
| | - H Miwa
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
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33
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Shearer J, Paine P, Agrawal A, Ford AC. Efficacy of linaclotide in irritable bowel syndrome with constipation: Real-world data. Neurogastroenterol Motil 2018; 30:e13328. [PMID: 29700960 DOI: 10.1111/nmo.13328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- J Shearer
- Leeds Gastroenterology Institute, St. James's University Hospital, Leeds, UK
| | - P Paine
- Department of Gastroenterology, Salford Royal Hospital NHS Trust, Salford, UK
| | - A Agrawal
- Doncaster Royal Infirmary, Doncaster, UK
| | - A C Ford
- Leeds Gastroenterology Institute, St. James's University Hospital, Leeds, UK.,Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds, UK
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34
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Yang Y, Fang J, Guo X, Dai N, Shen X, Yang Y, Sun J, Bhandari BR, Reasner DS, Cronin JA, Currie MG, Johnston JM, Zeng P, Montreewasuwat N, Chen GZ, Lim S. Linaclotide in irritable bowel syndrome with constipation: A Phase 3 randomized trial in China and other regions. J Gastroenterol Hepatol 2018; 33:980-989. [PMID: 29319191 DOI: 10.1111/jgh.14086] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 12/22/2017] [Accepted: 01/01/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIM Linaclotide is a guanylate cyclase-C agonist approved in multiple countries to treat irritable bowel syndrome with constipation (IBS-C). China has unmet need for well-tolerated therapy that is effective in treating both bowel and abdominal symptoms of IBS-C. This trial evaluated linaclotide's efficacy and safety in IBS-C patients in China and other regions. METHODS This Phase 3, double-blind trial randomized IBS-C patients to once-daily oral 290-μg linaclotide or placebo at centers in China, North America, and Oceania. Patients reported bowel and abdominal symptoms daily; adverse events were monitored. Co-primary and secondary endpoints were tested using a predefined three-step serial gatekeeping multiple comparisons procedure. RESULTS The intent-to-treat population included 839 patients (mean age = 41 years; 82% female; 81% Asian). The trial met all co-primary and secondary endpoints. Co-primary responder criteria were met by 60.0% of linaclotide patients versus 48.8% of placebo patients for abdominal pain/discomfort (≥ 30% decrease for ≥ 6/12 weeks; P < 0.05), and 31.7% of linaclotide versus 15.4% of placebo patients for IBS degree of relief (score ≤ 2 for ≥ 6/12 weeks; P < 0.0001). Secondary 12-week change-from-baseline endpoints (spontaneous bowel movement/complete spontaneous bowel movement frequency, stool consistency, straining, abdominal pain, abdominal discomfort, and abdominal bloating) were significantly improved with linaclotide versus placebo (all P < 0.0001). Diarrhea was the most common adverse event (9.4% linaclotide, 1.2% placebo). Discontinuation rates due to diarrhea were low (0.7% linaclotide, 0.2% placebo). CONCLUSIONS Once-daily 290-μg linaclotide improved bowel habits, abdominal symptoms, and global measures in a predominantly Chinese IBS-C population.
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Affiliation(s)
| | | | - Xiaozhong Guo
- General Hospital of Shenyang Military Region of Chinese PLA, Shenyang, China
| | - Ning Dai
- Sir Run Shaw Hospital, Hangzhou, China
| | | | - Youlin Yang
- First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jing Sun
- Ruijin Hospital, Shanghai, China
| | | | - David S Reasner
- Ironwood Pharmaceuticals, Inc., Cambridge, Massachusetts, USA
| | | | - Mark G Currie
- Ironwood Pharmaceuticals, Inc., Cambridge, Massachusetts, USA
| | | | | | | | | | - Sam Lim
- AstraZeneca AB, Shanghai, China.,Duke-NUS Medical School Office of Clinical Sciences, Singapore
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Abstract
Chronic constipation is a very common medical problem with relevant impact on the patients' quality of life. Modern definitions recognize constipation as a polysymptomatic disorder, including various aspects of disturbed defecation. Current guidelines recommend a stepwise approach in the management of chronic constipation. Isolated or concomitant evacuation disorders should be identified and may need differential/additional treatment. Baseline measures include lifestyle components and bulking agents. The next step recommends treatment with conventional laxatives. In refractory patients, modern medical therapies, such as the prokinetic prucalopride or the secretagogues linalotide or lubiprostone, may be used effectively. For patients with opioid-induced constipation, the modern concept of peripherally acting µ-opioid antagonists has shown to successfully improve this increasing medical problem and even to potentially increase survival time in terminally ill patients on opioid therapy. Prolonged-released oral naloxone (in fixed combination with oxycodone), oral naloxegol or naldemedine, and subcutaneous methylnaltrexone have all demonstrated good efficacy and tolerability in the treatment of opioid-induced constipation. To adequately apply stepwise treatment algorithms, a simple tool to identify treatment failure may improve patient care.
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Affiliation(s)
- Viola Andresen
- Israelitic Hospital, University of Hamburg, Hamburg, Germany
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36
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Linaclotide in constipation-predominant irritable bowel syndrome and chronic idiopathic constipation: a profile of its use in the USA. DRUGS & THERAPY PERSPECTIVES 2017. [DOI: 10.1007/s40267-017-0448-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Moayyedi P, Mearin F, Azpiroz F, Andresen V, Barbara G, Corsetti M, Emmanuel A, Hungin APS, Layer P, Stanghellini V, Whorwell P, Zerbib F, Tack J. Irritable bowel syndrome diagnosis and management: A simplified algorithm for clinical practice. United European Gastroenterol J 2017; 5:773-788. [PMID: 29026591 PMCID: PMC5625880 DOI: 10.1177/2050640617731968] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Accepted: 08/16/2017] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Effective management of irritable bowel syndrome (IBS), a common functional gastrointestinal disorder, can be challenging for physicians because of the lack of simple diagnostic tests and the wide variety of treatment approaches available. OBJECTIVE The objective of this article is to outline a simple algorithm for day-to-day clinical practice to help physicians navigate key stages to reaching a positive IBS diagnosis and guidance on how to prioritise the use of specific management strategies. METHODS This algorithm was based on the opinion of an expert panel evaluating current evidence. RESULTS The key principles forming the foundation of this evidence-supported algorithm are: confidently naming and explaining an IBS diagnosis for the patient, followed by assessment of key patient characteristics likely to influence the choice of therapy, such as predominant symptoms, and exploring the patient agenda and preferences. Consultation should always include education and reassurance with an explanatory model of IBS tailored to the patient. Individualised lifestyle changes, dietary modifications, pharmacological therapies, psychological strategies or a combination of interventions may be used to optimise treatment for each patient. CONCLUSION The simple visual tools developed here navigate the key stages to reaching a positive diagnosis of IBS, and provide a stepwise approach to patient-centred management targeted towards the most bothersome symptoms. Establishing a strong patient-physician relationship is central to all stages of the patient journey from diagnosis to effective management.
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Affiliation(s)
- Paul Moayyedi
- Department of Medicine, Division of Gastroenterology, McMaster University, Hamilton, ON, Canada
| | - Fermín Mearin
- Institute of Functional and Motor Digestive Disorders, Centro Médico Teknon, Barcelona, Spain
| | - Fernando Azpiroz
- Digestive System Research Unit, University Hospital Vall d’Hebron, CIBERehd, Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Viola Andresen
- Israelitic Hospital, University of Hamburg, Hamburg, Germany
| | - Giovanni Barbara
- Department of Medical and Surgical Sciences, Centre for Applied Biomedical Research, University of Bologna, Bologna, Italy
| | - Maura Corsetti
- Nottingham Digestive Diseases Biomedical Research Centre, National Institute for Health Research, Nottingham University Hospitals NHS Trust, University of Nottingham, Nottingham, UK
| | - Anton Emmanuel
- National Hospital for Neurology and Neurosurgery, University College London, London, UK
| | - A Pali S Hungin
- School of Medicine and Health, Durham University, Centre for Integrated Health Research, Wolfson Research Institute, Stockton on Tees, UK
| | - Peter Layer
- Israelitic Hospital, University of Hamburg, Hamburg, Germany
| | - Vincenzo Stanghellini
- Department of Medical and Surgical Sciences, Centre for Applied Biomedical Research, University of Bologna, Bologna, Italy
| | - Peter Whorwell
- Centre for Gastrointestinal Sciences, University of Manchester, Manchester, UK
| | - Frank Zerbib
- Department of Gastroenterology, Bordeaux University Hospital and Université de Bordeaux, Bordeaux, France
| | - Jan Tack
- Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
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Sinagra E, Morreale GC, Mohammadian G, Fusco G, Guarnotta V, Tomasello G, Cappello F, Rossi F, Amvrosiadis G, Raimondo D. New therapeutic perspectives in irritable bowel syndrome: Targeting low-grade inflammation, immuno-neuroendocrine axis, motility, secretion and beyond. World J Gastroenterol 2017; 23:6593-6627. [PMID: 29085207 PMCID: PMC5643283 DOI: 10.3748/wjg.v23.i36.6593] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Revised: 04/15/2017] [Accepted: 07/04/2017] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a chronic, recurring, and remitting functional disorder of the gastrointestinal tract characterized by abdominal pain, distention, and changes in bowel habits. Although there are several drugs for IBS, effective and approved treatments for one or more of the symptoms for various IBS subtypes are needed. Improved understanding of pathophysiological mechanisms such as the role of impaired bile acid metabolism, neurohormonal regulation, immune dysfunction, the epithelial barrier and the secretory properties of the gut has led to advancements in the treatment of IBS. With regards to therapies for restoring intestinal permeability, multiple studies with prebiotics and probiotics are ongoing, even if to date their efficacy has been limited. In parallel, much progress has been made in targeting low-grade inflammation, especially through the introduction of drugs such as mesalazine and rifaximin, even if a better knowledge of the mechanisms underlying the low-grade inflammation in IBS may allow the design of clinical trials that test the efficacy and safety of such drugs. This literature review aims to summarize the findings related to new and investigational therapeutic agents for IBS, most recently developed in preclinical as well as Phase 1 and Phase 2 clinical studies.
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Affiliation(s)
- Emanuele Sinagra
- Gastroenterology and Endoscopy Unit, Fondazione Istituto Giuseppe Giglio, Contrada Pietra Pollastra Pisciotto, 90015 Cefalù, Italy
- Euro-Mediterranean Institute of Science and Technology, 90100 Palermo, Italy
- Department of Experimental Biomedicine and Clinical Neuroscience, Section of Human Anatomy, University of Palermo, 90100 Palermo, Italy
| | | | - Ghazaleh Mohammadian
- Department of Medicine, Division of Gastroenterology and Hepatology, Karolinska Institutet, Karolinska University Hospital, Huddinge, 17176 Stockholm, Sweden
| | - Giorgio Fusco
- Unit of Internal Medicine, Ospedali Riuniti Villa Sofia-Vincenzo Cervello, 90100 Palermo, Italy
| | - Valentina Guarnotta
- Section of Cardio-Respiratory and Endocrine-Metabolic Diseases, Biomedical Department of Internal and Specialist Medicine, University of Palermo, Palermo 90127, Italy
| | - Giovanni Tomasello
- Euro-Mediterranean Institute of Science and Technology, 90100 Palermo, Italy
- Department of Experimental Biomedicine and Clinical Neuroscience, Section of Human Anatomy, University of Palermo, 90100 Palermo, Italy
| | - Francesco Cappello
- Euro-Mediterranean Institute of Science and Technology, 90100 Palermo, Italy
- Department of Experimental Biomedicine and Clinical Neuroscience, Section of Human Anatomy, University of Palermo, 90100 Palermo, Italy
| | - Francesca Rossi
- Gastroenterology and Endoscopy Unit, Fondazione Istituto Giuseppe Giglio, Contrada Pietra Pollastra Pisciotto, 90015 Cefalù, Italy
| | - Georgios Amvrosiadis
- Unit of Gastroenterology, Ospedali Riuniti Villa Sofia-Vincenzo Cervello, 90100 Palermo, Italy
| | - Dario Raimondo
- Gastroenterology and Endoscopy Unit, Fondazione Istituto Giuseppe Giglio, Contrada Pietra Pollastra Pisciotto, 90015 Cefalù, Italy
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Kim SJ, Park KS. [Pharmacotherapy in Patients with Chronic Constipation]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2017; 70:64-71. [PMID: 28830131 DOI: 10.4166/kjg.2017.70.2.64] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Chronic constipation is one of the most common digestive diseases frequently observed in a clinical setting. It has been known to cause considerable damage to the quality of life of patients. Despite recent developments, there are considerable limitations in the use of constipation-modulating agents in Korea. Chloride channel inhibitors, such as lubiprostone and linaclotide, have not been introduced in Korea yet, and prucalopride and several kinds of polyethylene glycol are not covered under medical insurance. This article assesses medicines that are clinically available for the management of constipation in Korea, with a brief review of agents that have recently developed around the world.
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Affiliation(s)
- Sang Jin Kim
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Kyung Sik Park
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
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40
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Yang H, Ma T. Luminally Acting Agents for Constipation Treatment: A Review Based on Literatures and Patents. Front Pharmacol 2017; 8:418. [PMID: 28713271 PMCID: PMC5491688 DOI: 10.3389/fphar.2017.00418] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 06/13/2017] [Indexed: 12/11/2022] Open
Abstract
Constipation is one of the most frequently reported gastrointestinal (GI) disorders that negatively impacts quality of life and is associated with a significant economic burden to the patients and society. Traditional treatments including lifestyle modification and laxatives are often ineffective in the more severe forms of constipation and over the long term. New medications targeting at intestinal chloride channels and colonic serotonin receptors have been demonstrated effective in recent years. Emerging agents focusing on improving intestinal secretion and/or colonic motility have been shown effective in animal models and even in clinical trials. Recognization of the role of cystic fibrosis transmembrane regulator (CFTR) and calcium-activated chloride channels (CaCCs) in intestine fluid secretion and motility modulation makes CFTR and CaCCs promising molecule targets for anti-constipation therapy. Although there are multiple choices for constipation treatment, there is still a recognized need for new medications in anti-constipation therapy. The present review covers the discovery of luminally acting agents for constipation treatment described in both patents (2011–present) and scientific literatures.
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Affiliation(s)
- Hong Yang
- Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, School of Life Sciences, Liaoning Normal UniversityDalian, China
| | - Tonghui Ma
- Institute of Traditional Chinese Medicine, Nanjing University of Chinese MedicineNanjing, China
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41
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Chey WD, Lembo AJ, Rosenbaum DP. Tenapanor Treatment of Patients With Constipation-Predominant Irritable Bowel Syndrome: A Phase 2, Randomized, Placebo-Controlled Efficacy and Safety Trial. Am J Gastroenterol 2017; 112:763-774. [PMID: 28244495 PMCID: PMC5418559 DOI: 10.1038/ajg.2017.41] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2016] [Accepted: 01/03/2017] [Indexed: 02/08/2023]
Abstract
OBJECTIVES Tenapanor is a first-in-class, small-molecule inhibitor of the gastrointestinal sodium/hydrogen exchanger NHE3. This study assessed the efficacy and safety of tenapanor in patients with constipation-predominant irritable bowel syndrome (IBS-C). METHODS In this phase 2, double-blind study, patients with IBS-C (Rome III criteria) were randomized (1:1:1:1) to receive tenapanor 5 mg, 20 mg, or 50 mg b.i.d., or placebo b.i.d. for 12 weeks. The primary end point was the complete spontaneous bowel movement (CSBM) responder rate, defined as the proportion of patients reporting an increase from baseline of ≥1 CSBM/week for ≥6/12 treatment weeks. Secondary end points included abdominal symptom responder rates (≥30% score improvement from baseline for ≥6/12 weeks) and a composite responder rate (CSBM and abdominal pain response in the same week for ≥6/12 weeks). RESULTS Overall, 356 patients were randomized (mean age: 45.7 years; 86.8% women) and 304 completed the study. The CSBM responder rate was significantly higher in the tenapanor 50 mg b.i.d. group than in the placebo group (60.7 vs. 33.7%; P<0.001), as was the composite responder rate (50.0 vs. 23.6%; P<0.001). Responder rates for abdominal symptoms (pain, discomfort, bloating, cramping, and fullness) were significantly higher in the tenapanor 50 mg b.i.d. group than in the placebo group (all P<0.05). Diarrhea was the most frequent adverse event (tenapanor b.i.d.: 20 mg, 12.4%; 50 mg, 11.2%). CONCLUSIONS Tenapanor 50 mg b.i.d. significantly increased stool frequency and reduced abdominal symptoms in patients with IBS-C. Further research into tenapanor as a potential treatment for these patients is justified.
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Affiliation(s)
- William D Chey
- Division of Gastroenterology, Department of Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA,Division of Gastroenterology, Department of Medicine, University of Michigan Health System, 1500 East Medical Center Drive, 3912 Taubman Center, SPC 5362, Ann Arbor, Michigan 48109-5362, USA. E-mail:
| | - Anthony J Lembo
- Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
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Rey E, Mearin F, Alcedo J, Ciriza C, Delgado-Aros S, Freitas T, Mascarenhas M, Mínguez M, Santos J, Serra J. Optimizing the Use of Linaclotide in Patients with Constipation-Predominant Irritable Bowel Syndrome: An Expert Consensus Report. Adv Ther 2017; 34:587-598. [PMID: 28083815 PMCID: PMC5350198 DOI: 10.1007/s12325-016-0473-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by chronic or recurrent abdominal pain in association with defecation or a change in bowel habits. A predominant disorder of bowel habits, IBS is classified into three main subtypes: constipation-predominant IBS (IBS-C), diarrhea-predominant IBS (IBS-D) and IBS alternating between constipation and diarrhea (IBS-M). Linaclotide is a first-in-class, oral, once-daily guanylate cyclase-C receptor agonist (GC-CA) that is licensed for the symptomatic treatment of moderate-to-severe IBS-C in adults. This review aims to facilitate and optimize clinical practices, establishing common guidelines to monitor patients with IBS-C that are treated with linaclotide. METHODS A group of experts in functional digestive disorders was convened to review the efficacy and safety of linaclotide and to develop an updated consensus report for the treatment of patients with IBS-C. A search was performed for English, French and Spanish language articles in PubMed. On the basis of the articles identified, an initial document was drafted addressing different issues frequently raised by general practitioners and GI specialists that are related to the prescription, efficacy and safety of linaclotide. This document was then reviewed and modified by the expert panel until a final text was agreed upon and validated. RESULTS Based on the evidence, the panel addressed the following recommendations: (1) Linaclotide is indicated for the treatment of moderate to severe IBS-C in adults; (2) it is recommended that patients take linaclotide continuously and not sporadically; (3) patients should be warned about the risk of diarrhea and given choices concerning how to deal with this possible side effect; (4) the absence of tachyphylaxis or potential risks implies that linaclotide treatment can be maintained for long periods of time. CONCLUSIONS This document seeks to lay down a set of recommendations and to identify key issues that may be useful for the clinical management of IBS-C patients treated with linaclotide.
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Affiliation(s)
- Enrique Rey
- Division of Digestive Diseases, Hospital Universitario Clínico de San Carlos, Madrid, Spain.
- Department of Medicine, Instituto de Investigacion San Carlos (IdISSC), School of Medicine, Complutense University, Madrid, Spain.
| | - Fermín Mearin
- Institute of Functional and Motor Digestive Disorders, Centro Médico Teknon, Barcelona, Spain
| | - Javier Alcedo
- Division of Digestive Diseases, Hospital Universitario Miguel Servet, Zaragoza, Spain
| | - Constanza Ciriza
- Division of Digestive Diseases, Hospital Universitario Doce de Octubre, Madrid, Spain
| | | | - Teresa Freitas
- Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Centro Hospitalar Vila Nova de Gaia, Porto, Portugal
| | | | - Miguel Mínguez
- Division of Digestive Diseases, Hospital Clínic, Universitat of Valencia, Valencia, Spain
| | - Javier Santos
- Digestive System Research Unit, Laboratory of Neuro-Immuno-Gastroenterology, Valld'Hebron Institut de Recerca VHIR, Barcelona, Spain
- Department of Gastroenterology, Hospital Universitari Vall d'Hebron, Barcelona, Spain
- Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Jordi Serra
- Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
- Motility and Functional Gut Disorders Unit, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), University Hospital Germans Trias i Pujol, Barcelona, Spain
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Chavarria V, Vian J, Pereira C, Data-Franco J, Fernandes BS, Berk M, Dodd S. The Placebo and Nocebo Phenomena: Their Clinical Management and Impact on Treatment Outcomes. Clin Ther 2017; 39:477-486. [PMID: 28237673 DOI: 10.1016/j.clinthera.2017.01.031] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Revised: 01/25/2017] [Accepted: 01/30/2017] [Indexed: 12/18/2022]
Abstract
PURPOSE This overview focuses on placebo and nocebo effects in clinical trials and routine care. Our goal was to propose strategies to improve outcomes in clinical practice, maximizing placebo effects and reducing nocebo effects, as well as managing these phenomena in clinical trials. METHODS A narrative literature search of PubMed was conducted (January 1980-September 2016). Systematic reviews, randomized controlled trials, observational studies, and case series that had an emphasis on placebo or nocebo effects in clinical practice were included in the qualitative synthesis. Search terms included: placebo, nocebo, clinical, clinical trial, clinical setting, placebo effect, nocebo effect, adverse effects, and treatment outcomes. This search was augmented by a manual search of the references of the key articles and the related literature. FINDINGS Placebo and nocebo effects are psychobiological events imputable to the therapeutic context. Placebo is defined as an inert substance that provokes perceived benefits, whereas the term nocebo is used when an inert substance causes perceived harm. Their major mechanisms are expectancy and classical conditioning. Placebo is used in several fields of medicine, as a diagnostic tool or to reduce drug dosage. Placebo/nocebo effects are difficult to disentangle from the natural course of illness or the actual effects of a new drug in a clinical trial. There are known strategies to enhance clinical results by manipulating expectations and conditioning. IMPLICATIONS Placebo and nocebo effects occur frequently and are clinically significant but are underrecognized in clinical practice. Physicians should be able to recognize these phenomena and master tactics on how to manage these effects to enhance the quality of clinical practice.
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Affiliation(s)
- Victor Chavarria
- Institut de Neuropsiquiatria i Adiccions (INAD), Parc de salut Mar (PSM), Barcelona, Spain
| | - João Vian
- Psychiatry and Mental Health Department, Centro Hospitalar Lisboa Norte, Lisbon, Portugal; Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
| | - Círia Pereira
- Psychiatry and Mental Health Department, Centro Hospitalar Lisboa Norte, Lisbon, Portugal; Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
| | - João Data-Franco
- Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal; Departamento de Psiquiatria e Saúde Mental, Hospital Beatriz Ângelo, Lisboa, Portugal
| | - Brisa S Fernandes
- IMPACT Strategic Research Centre, School of Medicine, Deakin University, Geelong, VIC, Australia; Laboratory of Calcium Binding Proteins in the Central Nervous System, Department of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Michael Berk
- IMPACT Strategic Research Centre, School of Medicine, Deakin University, Geelong, VIC, Australia; University Hospital Geelong, Barwon Health, Geelong, VIC Australia; Department of Psychiatry, The University of Melbourne, Parkville, VIC, Australia; Centre for Youth Mental Health, Parkville, VIC, Australia; Florey Institute, University of Melbourne, Parkville, VIC, Australia
| | - Seetal Dodd
- IMPACT Strategic Research Centre, School of Medicine, Deakin University, Geelong, VIC, Australia; University Hospital Geelong, Barwon Health, Geelong, VIC Australia; Department of Psychiatry, The University of Melbourne, Parkville, VIC, Australia; Centre for Youth Mental Health, Parkville, VIC, Australia.
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Mosaffa-Jahromi M, Lankarani KB, Pasalar M, Afsharypuor S, Tamaddon AM. Efficacy and safety of enteric coated capsules of anise oil to treat irritable bowel syndrome. JOURNAL OF ETHNOPHARMACOLOGY 2016; 194:937-946. [PMID: 27815079 DOI: 10.1016/j.jep.2016.10.083] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2016] [Revised: 10/07/2016] [Accepted: 10/29/2016] [Indexed: 02/08/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Anise is a well-recognized plant in Traditional Persian Medicine (TPM) sources. Anise oil has been suggested for the treatment of bowel disorders in Persian medical textbooks. Based on TPM scholars, this ingredient has a favorable effect on gastrointestinal diseases. We did this trial to determine the efficacy and safety of enteric coated capsules of anise oil for clinical symptoms of irritable bowel syndrome (IBS). METHODS AND MATERIALS This three-armed double-blind clinical trial was carried out from August 2014 to February 2015. 120 patients were divided into three groups by block randomization: AnisEncap, placebo and Colpermin®. Patients in each group received 3 similar capsules per day for 4 weeks. The primary outcome was measured as a visual analogue scale (VAS) score, and the secondary outcome was assessed with an IBS-quality of life questionnaire. Chi-squared tests were used for categorical variables and t-tests to compare continuous variables. RESULTS There were no significant differences in demographic characteristics among the three groups. According to intention-to-treat sample analysis, 75% of patients in the treatment group, 35% in the placebo group and 52.5% in active control group were free from IBS symptoms (P<0.001). The effectiveness of AnisEncap in improving IBS symptoms (abdominal discomfort or pain, bloating, diarrhea, constipation severity, difficulty in defecation, gastroesophageal reflux, headache, tiredness, overall satisfaction and quality of life) was significantly greater than placebo or Colpermin® after the 4-week treatment period and the 2-week follow-up period (P<0.0001). The number needed to treat for enteric coated capsules of anise oil was 4, which indicated significantly superior efficacy compared to the other two groups (P<0.001). CONCLUSION The effectiveness of AnisEncap was superior to that of placebo or Colpermin® in patients with IBS. Further studies are suggested to find the main mechanism of action of anise oil in this regard.
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Affiliation(s)
- Maryam Mosaffa-Jahromi
- Research Center for Traditional Medicine and History of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Mehdi Pasalar
- Research Center for Traditional Medicine and History of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Suleiman Afsharypuor
- Department of Pharmacognosy, School of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ali-Mohammad Tamaddon
- Center for Nanotechnology in Drug Delivery, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
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Kane JS, Ford AC. Rifaximin for the treatment of diarrhea-predominant irritable bowel syndrome. Expert Rev Gastroenterol Hepatol 2016; 10:431-42. [PMID: 26753693 DOI: 10.1586/17474124.2016.1140571] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Irritable bowel syndrome (IBS) is a chronic, functional bowel disorder characterized by abdominal pain or discomfort and altered bowel habit. The pathophysiology is unclear, but may include altered gut motility, visceral hypersensitivity, abnormal central pain processing, chronic low-grade intestinal inflammation, or disturbances in the gut microbiome. These etiological mechanisms, alongside environmental factors such as stress and anxiety, vary between individuals and represent potential targets for treatment. Rifaximin is a poorly absorbed oral antibiotic proposed to act on the gut microenvironment, used in the treatment of travelers' diarrhea and hepatic encephalopathy. Clinical trials suggest the drug can reduce global IBS symptoms and improve bloating, abdominal pain, and stool consistency in some patients with non-constipated IBS, leading to Food and Drug Administration approval in the United States. This article considers the pharmacology of rifaximin, the evidence for its use in IBS, and the safety and tolerability of the drug.
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Affiliation(s)
- John S Kane
- a Leeds Gastroenterology Institute , St James's University Hospital , Leeds , UK
| | - Alexander C Ford
- a Leeds Gastroenterology Institute , St James's University Hospital , Leeds , UK
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Koppen IJN, Di Lorenzo C, Saps M, Dinning PG, Yacob D, Levitt MA, Benninga MA. Childhood constipation: finally something is moving! Expert Rev Gastroenterol Hepatol 2016; 10:141-55. [PMID: 26466201 DOI: 10.1586/17474124.2016.1098533] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Recent developments in the evaluation and treatment of childhood constipation are likely to influence the way we deal with pediatric defecation disorders in the near future. Innovations in both colonic and anorectal manometry are leading to novel insights into functional defecation disorders in children. Promising results have been achieved with innovative therapies such as electrical stimulation and new drugs with targets that differ from conventional pharmacological treatments. Also, new surgical approaches, guided by manometric findings, have led to improvement in patient outcome. Finally, utilization of non-pharmacological interventions such as fiber and probiotics has been a field of particular interest in recent years. The aim of this article is to provide an update on these and other novel diagnostic and therapeutic tools related to childhood constipation.
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Affiliation(s)
- Ilan J N Koppen
- a Department of Pediatric Gastroenterology and Nutrition , Emma Children's Hospital/Academic Medical Center , Amsterdam , The Netherlands.,b Division of Pediatric Gastroenterology, Hepatology, and Nutrition , Nationwide Children's Hospital , Columbus , OH , USA
| | - Carlo Di Lorenzo
- b Division of Pediatric Gastroenterology, Hepatology, and Nutrition , Nationwide Children's Hospital , Columbus , OH , USA
| | - Miguel Saps
- b Division of Pediatric Gastroenterology, Hepatology, and Nutrition , Nationwide Children's Hospital , Columbus , OH , USA
| | - Phil G Dinning
- c Departments of Gastroenterology & Surgery , Flinders Medical Centre, Flinders University , South Australia , Australia
| | - Desale Yacob
- b Division of Pediatric Gastroenterology, Hepatology, and Nutrition , Nationwide Children's Hospital , Columbus , OH , USA
| | - Marc A Levitt
- d Center for Colorectal and Pelvic Reconstruction, Nationwide Children's Hospital, Department of Surgery , The Ohio State University , Columbus , OH , USA
| | - Marc A Benninga
- a Department of Pediatric Gastroenterology and Nutrition , Emma Children's Hospital/Academic Medical Center , Amsterdam , The Netherlands
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Serra J, Caballero N. Dexloxiglumide for the treatment of constipation predominant irritable bowel syndrome. Expert Opin Pharmacother 2016; 17:1969-74. [DOI: 10.1080/14656566.2016.1229306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Consenso mexicano sobre el síndrome de intestino irritable. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2016; 81:149-67. [DOI: 10.1016/j.rgmx.2016.01.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Revised: 01/11/2016] [Accepted: 01/22/2016] [Indexed: 12/19/2022]
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Carmona-Sánchez R, Icaza-Chávez M, Bielsa-Fernández M, Gómez-Escudero O, Bosques-Padilla F, Coss-Adame E, Esquivel-Ayanegui F, Flores-Rendón Á, González-Martínez M, Huerta-Iga F, López-Colombo A, Méndez-Gutiérrez T, Noble-Lugo A, Nogueira-de Rojas J, Raña-Garibay R, Remes-Troche J, Roesch-Dietlen F, Schmulson M, Soto-Pérez J, Tamayo J, Uscanga L, Valdovinos M, Valerio-Ureña J, Zavala-Solares M. The Mexican consensus on irritable bowel syndrome. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2016. [DOI: 10.1016/j.rgmxen.2016.01.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Abstract
Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disorder, which represents a major cost to healthcare services. Current pharmacological treatment includes fibre supplements, antispasmodics, laxatives, loperamide and antidepressants. This article reviews the novel pharmacological treatments already or recently approved for patients with IBS-C (lubiprostone, linaclotide) and IBS-D (alosetron, ramosetron, rifaximin, eluxadoline). Furthermore, results for drugs in development (plecanatide, ibudutant and ebastine) or used in chronic constipation or for other indications, with potential application in IBS (prucalopride, elobixibat, mesalazine, ondansetron and colesevelam) are also reviewed.
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Affiliation(s)
- Maura Corsetti
- a Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven , Leuven , Belgium
| | - Peter Whorwell
- b Centre for Gastrointestinal Sciences , University Manchester , Manchester , UK
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