|
1
|
An J, Wu K, Wu T, Xu P, Yang C, Fan Y, Li Q, Dong X. Assessing the association between drug use and ischaemic colitis: a retrospective pharmacovigilance study using FDA Adverse Event data. BMJ Open 2025; 15:e088512. [PMID: 40398943 PMCID: PMC12097096 DOI: 10.1136/bmjopen-2024-088512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 04/30/2025] [Indexed: 05/23/2025] Open
Abstract
OBJECTIVE Drug-induced ischaemic colitis is a significant adverse event (AE) in clinical practice. This study aimed to recognise the top drugs associated with the risk of ischaemic colitis based on the FDA Adverse Event Reporting System (FAERS) database. DESIGN A cross-sectional design. SETTING All data retrieved from the FAERS database from the first quarter of 2004 to the fourth quarter of 2023. PARTICIPANTS A total of 5664 drug-induced ischaemic colitis AEs eligible for screening. PRIMARY AND SECONDARY OUTCOME MEASURES The Medical Dictionary for Regulatory Activities was used to identify ischaemic colitis (code: 10009895) cases. Disproportionality analysis for drug-associated ischaemic colitis signals. RESULTS Drug-induced ischaemic colitis AEs were more prevalent in females (60.12%) and individuals aged ≥65 years (34.25%). The common outcomes were hospitalisation (46.85%) and death (9.73%). Disproportionality analysis identified 91 ischaemic colitis signals and the top 30 drugs mainly involved in the gastrointestinal and nervous systems. The top five drugs with the highest reported OR, proportional reporting ratio, information component and the empirical Bayesian geometric mean, were alosetron, tegaserod, osmoprep, naratriptan and kayexalate. Additionally, 20 of the top 30 drugs did not have ischaemic colitis risk indicated in the package insert. CONCLUSIONS This study identified key drugs associated with ischaemic colitis, particularly alosetron, tegaserod, osmoprep, naratriptan and kayexalate. Notably, two-thirds of these drugs lacked ischaemic colitis warnings in their package inserts. These findings underscore the need for greater clinical vigilance, improved regulatory oversight and further research to clarify underlying mechanisms and support safer medication use.
Collapse
Affiliation(s)
- Jie An
- Department of General Surgery, Shanxi Bethune Hospital, Taiyuan, Shanxi, China
| | - Kaiqi Wu
- Third Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Teng Wu
- Department of General Surgery, Third Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Pengyang Xu
- Department of General Surgery, Third Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Chuanli Yang
- Department of General Surgery, Shanxi Bethune Hospital, Taiyuan, Shanxi, China
- Southeast University, Nanjing, Jiangsu, China
| | - Yunhe Fan
- Department of General Surgery, Shanxi Bethune Hospital, Taiyuan, Shanxi, China
| | - Qing Li
- Department of Pharmacy, Third Hospital of Shanxi Medical University, Taiyuan, China
| | - Xiushan Dong
- Department of General Surgery, Shanxi Bethune Hospital, Taiyuan, Shanxi, China
| |
Collapse
|
|
2
|
Lacy BE, Gagnon-Sanschagrin P, Heimanson Z, Bungay R, Bellefleur R, Guérin A, Bumpass B, Borroto D, Joseph G, Dashputre AA. Treatment-Free Interval: A Novel Approach to Assessing Real-World Treatment Effectiveness and Economic Impact Among Patients with Irritable Bowel Syndrome with Diarrhea. Adv Ther 2024; 41:2253-2266. [PMID: 38619720 PMCID: PMC11133130 DOI: 10.1007/s12325-024-02832-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 02/26/2024] [Indexed: 04/16/2024]
Abstract
INTRODUCTION Objective assessment of treatment effectiveness using real-world claims data is challenging. This study assessed treatment-free intervals (TFI) as a proxy for treatment effectiveness, and all-cause healthcare costs among adult patients with irritable bowel syndrome with diarrhea (IBS-D) treated with rifaximin or eluxadoline in the USA. METHODS Adult patients (18-64 years) with IBS-D and ≥ 1 rifaximin or eluxadoline prescription were identified in the IQVIA PharMetrics® Plus database (10/01/2015-12/31/2021) and classified into two mutually exclusive cohorts (i.e., rifaximin and eluxadoline). Index date was the date of rifaximin or eluxadoline initiation. Entropy-balanced baseline characteristics, TFI (periods of ≥ 30 consecutive days without IBS-D treatment), and healthcare costs were reported. Healthcare costs were compared between cohorts using mean cost differences. RESULTS There were 7094 and 2161 patients in the rifaximin and eluxadoline cohorts, respectively. After balancing, baseline characteristics (mean age 44.1 years; female 72.4%) were similar between cohorts. A higher proportion of patients treated with rifaximin achieved a TFI of ≥ 30 days (76.2% vs. 66.7%), ≥ 60 days (67.0% vs. 47.0%), ≥ 90 days (61.0% vs. 38.7%), ≥ 180 days (51.7% vs. 31.0%), and ≥ 240 days (47.7% vs. 27.9%) compared to eluxadoline. Among patients with a TFI ≥ 30 days, mean TFI durations were 8.3 and 6.0 months for the rifaximin and eluxadoline cohorts. Mean all-cause healthcare costs were lower for rifaximin vs. eluxadoline ($18,316 vs. $23,437; p = 0.008), primarily driven by pharmacy costs ($7348 vs. $10,250; p < 0.001). In a simulated health plan of one million commercially insured lives, initiating 50% of patients on rifaximin instead of eluxadoline resulted in total cost savings of $2.1 million per year or $0.18 per-member-per-month. CONCLUSIONS This real-world study suggests that TFI is a meaningful surrogate measure of treatment effectiveness in IBS-D. Patients treated with rifaximin had longer treatment-free periods and lower healthcare costs than patients treated with eluxadoline.
Collapse
Affiliation(s)
- Brian E Lacy
- Division of Gastroenterology, Mayo Clinic, Jacksonville, FL, USA
| | | | | | - Rebecca Bungay
- Analysis Group, Inc., 1190 Avenue Des Canadiens-de-Montréal, Suite 1500, Montréal, QC, H3B 0G7, Canada.
| | - Remi Bellefleur
- Analysis Group, Inc., 1190 Avenue Des Canadiens-de-Montréal, Suite 1500, Montréal, QC, H3B 0G7, Canada
| | - Annie Guérin
- Analysis Group, Inc., 1190 Avenue Des Canadiens-de-Montréal, Suite 1500, Montréal, QC, H3B 0G7, Canada
| | | | | | - George Joseph
- Bausch Health, Bridgewater Township, NJ, USA
- BioNTech US Inc., 40 Erie St, Cambridge, MA, 02139, USA
| | | |
Collapse
|
|
3
|
Mozaffari S, Nikfar S, Abdollahi M. Pharmacokinetic considerations for drugs that treat diarrhea-predominant irritable bowel syndrome: what's new? Expert Opin Drug Metab Toxicol 2024; 20:307-317. [PMID: 38668452 DOI: 10.1080/17425255.2024.2348488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 04/24/2024] [Indexed: 05/03/2024]
Abstract
INTRODUCTION Irritable bowel syndrome (IBS), which presents a significant healthcare and socioeconomic burden, is one of the main issues in the field of therapy. Hence, it is imperative to tackle this matter by evaluating the safety and efficacy of the available treatments and determining the ideal approach for each patient. AREAS COVERED We reviewed the pharmacokinetics and safety of pharmacologic interventions administered in diarrhea-predominant IBS (IBS-D) patients. PubMed, Google Scholar and the USFDA databases were searched up to November 2023 to include all updated information on eluxadoline, alosetron, and rifaximin. EXPERT OPINION The most effective way to treat IBS-D is to focus on managing the most common symptoms. However, healthcare providers face a challenge when it comes to identifying the right treatment for each patient, and the root cause of this is the diversity of IBS-D population. Studies have shown that there are differences in how men and women metabolize drugs, which may lead to gender-specific adverse reactions. Women tend to have higher drug concentrations in their bloodstream and take longer to eliminate them. Therefore, healthcare providers may need to reduce the dosage for female patients. Integrating IBS care into sustainable development efforts can indirectly contribute to achieving SDGs and promote health and well-being for all.
Collapse
Affiliation(s)
- Shilan Mozaffari
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center (PSRC), Tehran University of Medical Sciences, Tehran, Iran
| | - Shekoufeh Nikfar
- Department of Pharmacoeconomics and Pharmaceutical Administration, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Personalized Medicine Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Abdollahi
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, and Pharmaceutical Sciences Research Center (PSRC), Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
4
|
Marasco G, Cremon C, Barbaro MR, Stanghellini V, Barbara G. Journal of Clinical Gastroenterology Lectureship Dubai 2022 : Management of Irritable Bowel Syndrome With Diarrhea. J Clin Gastroenterol 2024; 58:221-231. [PMID: 38227850 DOI: 10.1097/mcg.0000000000001964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 12/13/2023] [Indexed: 01/18/2024]
Abstract
Irritable bowel syndrome (IBS) with diarrhea (IBS-D) affects ~1% of the general population and is characterized by abdominal pain associated with diarrhea. IBS-D symptoms significantly impact the quality of life of patients. Major uncertainties remain regarding the optimal management of these patients. Several therapies have been investigated over the years for the treatment of IBS-D. In the initial management, commonly prescribed approaches with an effect on global IBS symptoms include a low Fermentable Oligo-, Di-, Mono-Saccharides and Polyols diet and probiotics, while antispasmodics are used for targeting abdominal pain and loperamide for diarrhea only. Additional therapeutic options for the relief of global IBS symptoms include rifaximin, 5-HT 3 antagonists, gut-directed psychological therapies, and eluxadoline, while tricyclic antidepressants can target abdominal pain and bile acid sequestrants diarrhea. Promising evidence exists for the use of mesalazine and fecal microbiota transplantation in IBS-D, although further evidence is needed for definitive conclusions regarding their efficacy.
Collapse
Affiliation(s)
- Giovanni Marasco
- IRCCS Azienda Ospedaliero Universitaria di Bologna
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Cesare Cremon
- IRCCS Azienda Ospedaliero Universitaria di Bologna
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | | | - Vincenzo Stanghellini
- IRCCS Azienda Ospedaliero Universitaria di Bologna
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Giovanni Barbara
- IRCCS Azienda Ospedaliero Universitaria di Bologna
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| |
Collapse
|
|
5
|
Travers P, Lacy BE, Cangemi DJ. Irritable bowel syndrome - less irritable, or better treatments? Curr Opin Gastroenterol 2024; 40:27-33. [PMID: 38078610 DOI: 10.1097/mog.0000000000000987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2023]
Abstract
PURPOSE OF REVIEW Irritable bowel syndrome (IBS) is a chronic, often bothersome disorder of gut-brain interaction (DGBI) characterized by abdominal pain associated with a change in stool frequency and/or caliber. Recent advancements have improved our understanding of the underlying pathophysiology, thus opening new avenues for therapeutic intervention. The purpose of this review is to summarize the current literature regarding treatment modalities for IBS. RECENT FINDINGS Altering the gut microbiome via probiotic and antibiotic administration, avoiding dietary triggers, and modulating the gut-brain axis have all proven efficacious for the management of IBS symptoms. Several gut-specific pharmacotherapies are approved for the treatment of IBS, many of which primarily address either diarrhea or constipation, although many patients remain symptomatic despite appropriate use. Brain-gut behavioral therapies (BGBTs) are increasingly used to treat symptoms of IBS, particularly in those who do not respond to traditional therapies. Virtual reality represents an exciting new approach to treating DGBIs, like IBS, though data are limited. SUMMARY As our understanding of IBS continues to evolve, so should our therapeutic approach. Individualizing the therapeutic approach is of utmost importance.
Collapse
Affiliation(s)
| | - Brian E Lacy
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA
| | - David J Cangemi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA
| |
Collapse
|
|
6
|
Hung TH, Wang CY, Lee HF. Update in diagnosis and management of irritable bowel syndrome. Tzu Chi Med J 2023; 35:306-311. [PMID: 38035060 PMCID: PMC10683518 DOI: 10.4103/tcmj.tcmj_104_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 06/13/2023] [Accepted: 08/09/2023] [Indexed: 12/02/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by a lack of structural or biochemical abnormalities. The current diagnosis of IBS is based on the Rome IV criteria, and it is recommended to approach IBS patients using a multidimensional clinical profile (MDCP). The pathophysiology of IBS is multifactorial and involves motility disorders, genetic factors, immune responses, visceral hypersensitivity, brain-gut dysregulation, and altered intestinal microbiota. The management of IBS includes both nonpharmacologic and pharmacologic therapies. Nonpharmacologic therapy options include physical activity, low fermentable oligosaccharides, disaccharides, monosaccharides, and polyol diet, as well as cognitive behavioral therapy. Pharmacologic therapy options include probiotics, antidepressants, antispasmodics, and new agents. In clinical practice, a multidisciplinary strategy, including nonpharmacologic or/and pharmacologic treatment for IBS, is emphasized. Therefore, clinicians should carefully consider the underlying pathophysiology before selecting an appropriate therapeutic option for the treatment of IBS. In other words, individualized treatment plans are necessary for managing IBS.
Collapse
Affiliation(s)
- Tsung-Hsing Hung
- Division of Gastroenterology, Department of Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
- School of Medicine, Tzu Chi University, Hualien, Taiwan
| | - Chih-Ying Wang
- Department of Medical Research, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
| | - Hsing-Feng Lee
- Division of Gastroenterology, Department of Medicine, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
- School of Medicine, Tzu Chi University, Hualien, Taiwan
| |
Collapse
|
|
7
|
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.
Collapse
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
| |
Collapse
|
|
8
|
Boinpally R, Weissman D. Single-dose Pharmacokinetics of Eluxadoline in Healthy Participants With Normal Renal Function and Participants With Renal Impairment. Clin Pharmacol Drug Dev 2023; 12:132-140. [PMID: 36504331 PMCID: PMC10108264 DOI: 10.1002/cpdd.1204] [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: 06/06/2022] [Accepted: 10/31/2022] [Indexed: 12/14/2022]
Abstract
Eluxadoline is approved for the treatment of diarrhea-predominant irritable bowel syndrome in the United States. The impact of renal impairment on the pharmacokinetic (PK) parameters of eluxadoline is currently unknown. This phase 1, open-label, parallel-group study evaluated the PK and safety profile of eluxadoline in 8 participants with renal impairment and 8 matched healthy controls. Of the participants with renal impairment, 2 had severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2 ) and 6 had end-stage renal disease while not yet on dialysis (eGFR <15 mL/min/1.73 m2 ). The primary objective was to assess plasma and urine PKs, and plasma protein binding of eluxadoline. In participants with renal impairment, mean plasma concentrations of eluxadoline were consistently higher compared with matched healthy controls: 1.4-fold higher for mean maximum plasma concentration (Cmax ) and 2.2-fold higher for mean area under the plasma concentration-time curve from time 0 to time t. The median time to Cmax was 2.5 hours in both groups. Although eluxadoline is a locally acting drug with low oral bioavailability, because of the increased systemic exposure in participants with renal impairment as a cautionary measure the lower approved dose of 75 mg twice daily is recommended for individuals with severe renal impairment and end-stage renal disease while not yet on dialysis. Eluxadoline 100 mg single dose was well tolerated in participants with renal impairment and matched healthy controls.
Collapse
|
|
9
|
Current and Future Therapeutic Options for Irritable Bowel Syndrome with Diarrhea and Functional Diarrhea. Dig Dis Sci 2022; 68:1677-1690. [PMID: 36376576 DOI: 10.1007/s10620-022-07700-8] [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: 06/16/2022] [Accepted: 09/12/2022] [Indexed: 11/15/2022]
Abstract
Irritable bowel syndrome with diarrhea and functional diarrhea are disorders of gut-brain interaction presenting with chronic diarrhea; they have significant impact on quality of life. The two conditions may exist as a continuum and their treatment may overlap. Response to first-line therapy with antispasmodics and anti-diarrheal agents is variable, leaving several patients with suboptimal symptom control and need for alternative therapeutic options. Our aim was to discuss current pharmacologic options and explore alternative therapeutic approaches and future perspectives for symptom management in irritable bowel syndrome with diarrhea and functional diarrhea. We conducted a search of PubMed, Cochrane, clinicaltrial.gov, major meeting abstracts for publications on current, alternative, and emerging drugs for irritable bowel syndrome with diarrhea and functional diarrhea. Currently approved therapeutic options for patients with first-line refractory irritable bowel syndrome with diarrhea and functional diarrhea include serotonin-3 receptor antagonists, eluxadoline and rifaximin. Despite their proven efficacy, cost and availability worldwide impact their utilization. One-third of patients with disorders of gut-brain interaction with diarrhea have bile acid diarrhea and may benefit from drugs targeting bile acid synthesis and excretion. Further understanding of underlying pathophysiology of irritable bowel syndrome with diarrhea and functional diarrhea related to bile acid metabolism, gastrointestinal transit, and microbiome has led to evaluation of novel therapeutic approaches, including fecal microbiota transplantation and enterobacterial "crapsules". These opportunities to treat disorders of gut-brain interaction with diarrhea should be followed with formal studies utilizing large samples of well-characterized patients at baseline and validated response outcomes as endpoints for regulatory approval.
Collapse
|
|
10
|
Wang Y, Chen N, Niu F, Li Y, Guo K, Shang X, E F, Yang C, Yang K, Li X. Probiotics therapy for adults with diarrhea-predominant irritable bowel syndrome: a systematic review and meta-analysis of 10 RCTs. Int J Colorectal Dis 2022; 37:2263-2276. [PMID: 36251040 DOI: 10.1007/s00384-022-04261-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/27/2022] [Indexed: 02/04/2023]
Abstract
PURPOSE Accumulating evidence showed that probiotics therapy might be effective in treating diarrhea-predominant irritable bowel syndrome (IBS-D). This study aimed to evaluate the effectiveness and safety of probiotics therapy for the treatment of IBS-D. METHODS We performed a comprehensive literature search in eight electronic databases, and gray literature from inception to August 4, 2021. Randomized controlled trials (RCTs) of probiotics therapy for the treatment of IBS-D were included and the quality was assessed using the risk of bias tool recommended by the Cochrane Handbook version 5.1.0. RevMan 5.4 software was used to perform the meta-analysis on the outcomes of IBS-D symptoms, abdominal pain, quality of life, and abdominal distension. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of evidence. RESULTS Ten RCTs evaluating 943 patients were identified. Only one study had unclear risk of bias, while nine studies had a high risk of bias. The meta-analysis results showed that, compared to the placebo, probiotics therapy significantly decreased the score of IBS-D symptoms (SMD = - 0.55, 95% CI: [- 0.83, - 0.27], P < 0.05), abdominal pain (SMD = - 0.43, 95% CI: [- 0.57, - 0.29], P < 0.05), and abdominal distension (SMD = - 0.45, 95%CI: [- 0.81, - 0.09], P < 0.05). There was no statistical difference in the quality of life. However, all the certainty of evidence was very low. CONCLUSION Very low certainty evidence showed that probiotics might be an effective treatment for improving the IBS-D symptoms, abdominal pain, and abdominal distension, in adult IBS-D patients. However, these conclusions should be supported by high-quality evidence.
Collapse
Affiliation(s)
- Yan Wang
- Evidence-Based Social Science Research Center & Health Technology Assessment Center, School of Public Health, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, China.,Evidence Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, China.,Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China
| | - Nan Chen
- Research and Education Department, Shaanxi Provincial Rehabilitation Hospital, Xi'an, China
| | - Fangfen Niu
- First Hospital of Lanzhou University, Lanzhou, China
| | - Yanfei Li
- Evidence-Based Social Science Research Center & Health Technology Assessment Center, School of Public Health, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, China.,Evidence Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, China.,Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China
| | - Kangle Guo
- Gansu Provincial Hospital, Lanzhou, China
| | - Xue Shang
- Evidence-Based Social Science Research Center & Health Technology Assessment Center, School of Public Health, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, China.,Evidence Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, China.,Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China
| | - Fenfen E
- Evidence-Based Social Science Research Center & Health Technology Assessment Center, School of Public Health, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, China.,Evidence Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, China.,Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China
| | - Chaoqun Yang
- Evidence-Based Social Science Research Center & Health Technology Assessment Center, School of Public Health, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, China.,Evidence Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, China.,Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China
| | - Kehu Yang
- Evidence-Based Social Science Research Center & Health Technology Assessment Center, School of Public Health, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, China. .,Evidence Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, China. .,Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China.
| | - Xiuxia Li
- Evidence-Based Social Science Research Center & Health Technology Assessment Center, School of Public Health, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, China. .,Evidence Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, China. .,Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, China.
| |
Collapse
|
|
11
|
Boinpally R, McGeeney D, Kaczynski E, Weissman D. An Open-Label Study to Evaluate the Effect of Eluxadoline on the Single-Dose Pharmacokinetics of Midazolam in Healthy Participants. Clin Pharmacol Drug Dev 2022; 11:1341-1348. [PMID: 35938453 PMCID: PMC9805131 DOI: 10.1002/cpdd.1150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 07/05/2022] [Indexed: 01/27/2023]
Abstract
Eluxadoline is a mixed μ-opioid, κ-opioid receptor agonist, and δ-opioid receptor antagonist, approved in the United States for adults with diarrhea-predominant irritable bowel syndrome. This phase 1, single-center, open-label, single-sequence study was conducted on 30 healthy participants to establish whether steady-state eluxadoline increases systemic exposure of the cytochrome P450 (CYP) 3A4 substrate midazolam. Participants received oral midazolam 4 mg on day 1 with a 7-day washout period. On days 8-16, oral eluxadoline 100 mg was administered twice daily. On day 15, midazolam 4 mg was coadministered with the eluxadoline 100-mg morning dose. Primary outcome measures were pharmacokinetic parameters of midazolam and 1-hydroxy-midazolam. The midazolam and 1-hydroxy-midazolam geometric mean ratios and 90%CIs for maximum plasma drug concentration were 99.0% (91.6-107.0) and 113.8% (104.9-123.5), respectively, and area under the plasma concentration-time curves were 90.5% (83.9-97.6) and 105.1% (99.8-110.7), respectively, demonstrating the 2 treatments were bioequivalent, and there was no clinically significant drug interaction. All treatment-emergent adverse events were treatment related, mild in intensity, with no serious adverse events. These results suggest that eluxadoline has no clinically significant effect on CYP3A4 activity and is, therefore, unlikely to affect the pharmacokinetics of other CYP3A4 substrates.
Collapse
|
|
12
|
Ciriza de Los Ríos C, Aparicio Cabezudo M, Zatarain Vallés A, Rey E. Practical approach to irritable bowel syndrome-diarrhea beyond low-FODMAP diet. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2022; 114:481-488. [PMID: 35694883 DOI: 10.17235/reed.2022.8749/2022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by abdominal pain and altered defecation, usually accompanied by abdominal bloating or distension. The integrated model of bidirectional interaction between the central, autonomic, enteric nervous system, the microbiome, and the gut barrier allows a better understanding of the pathophysiology of IBS, as well as consideration of potential therapeutic strategies. IBS with predominant diarrhea (IBS-D) represents a therapeutic challenge. Dietary changes or restrictions are most commonly used by patients in an attempt at symptom control. Therefore, a number of diets, especially low-FODMAP diet, have increasingly gained interest as a therapy for IBS-D or mixed IBS. However, this kind of diet, while effective, is not exempt of problems. It is therefore necessary that other therapeutic options be considered while bearing pathophysiological mechanisms and general symptom management in mind.
Collapse
Affiliation(s)
| | | | | | - Enrique Rey
- Aparato Digestivo, Hospital Clínico San Carlos, España
| |
Collapse
|
|
13
|
Qin D, Tao QF, Huang SL, Chen M, Zheng H. Eluxadoline Versus Antispasmodics in the Treatment of Irritable Bowel Syndrome: An Adjusted Indirect Treatment Comparison Meta-analysis. Front Pharmacol 2022; 13:757969. [PMID: 35281934 PMCID: PMC8906885 DOI: 10.3389/fphar.2022.757969] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 02/08/2022] [Indexed: 12/12/2022] Open
Abstract
Objective: Eluxadoline is a newly approved drug for irritable bowel syndrome (IBS), but it has rarely been compared with positive controls. We aimed to compare eluxadoline with antispasmodics in the treatment of IBS. Methods: We searched the OVID Medline, Embase, and the Cochrane Central Register of Controlled Trials databases for randomized controlled trials (RCTs) comparing eluxadoline or antispasmodics with placebo. The search was conducted from 1 January 1980, to 1 September 2020, without any language restrictions. The primary efficacy outcome was the relief of abdominal pain, defined by a reduction of pain scores of at least 30% from baseline. The secondary efficacy outcome was the relief of global IBS symptoms, defined by a composite response of a decrease in abdominal pain and improvement in stool consistency on the same day for at least 50% of the days assessed. The data were pooled using a random-effects model. Outcome estimates were pooled by using Risk Ratios (RRs) and P-scores. Results: Forty-two trials with 8,457 participants were included from 45 articles. Compared with placebo, each of drotaverine, pinaverium, alverine combined with simethicone (ACS) and eluxadoline 100 mg was highly effective in the relief of abdominal pain, with drotaverine [RR, 2.71 (95% CI, 1.70 to 4.32), P-score = 0.95] ranking first. Drotaverine, otilonium, cimetropium, pinaverium, and eluxadoline 100 mg had significantly high the relief of global IBS symptomss, for which drotaverine [RR, 2.45 (95% CI, 1.42 to 4.22), P-score = 0.95] was ranked first. No significant difference was found between these interventions. Pinaverium had a significantly higher the relief of global IBS symptoms than eluxadoline [RR, 1.72 (95% CI, 1.33 to 2.21)] on sensitivity analysis. However, no significant difference was found in the number of adverse events between each intervention and the placebo. Conclusion: Our network meta-analysis showed that eluxadoline 100 mg was at least as effective as antispasmodics in relieving abdominal pain in IBS. But eluxadoline had more reported adverse events. Antispasmodics are still the first choice for the treatment of IBS.
Collapse
Affiliation(s)
- Di Qin
- Third Hospital/Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qing-Feng Tao
- Third Hospital/Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Shi-Le Huang
- Acupuncture department, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Min Chen
- Department of Colorectal Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Hui Zheng
- Third Hospital/Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| |
Collapse
|
|
14
|
Shah ED, Salwen-Deremer JK, Gibson PR, Muir JG, Eswaran S, Chey WD. Comparing Costs and Outcomes of Treatments for Irritable Bowel Syndrome With Diarrhea: Cost-Benefit Analysis. Clin Gastroenterol Hepatol 2022; 20:136-144.e31. [PMID: 33010413 DOI: 10.1016/j.cgh.2020.09.043] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 08/28/2020] [Accepted: 09/21/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is one of the most expensive gastroenterological conditions and is an ideal target for developing a value-based care model. We assessed the comparative cost-benefit of treatments for IBS with diarrhea (IBS-D), the most common IBS subtype from insurer and patient perspectives. METHODS We constructed a decision analytic model assessing trade-offs among guideline-recommended and recently FDA-approved drugs, supplements, low FODMAP diet, cognitive behavioral therapy (CBT). Outcomes and costs were derived from systematic reviews of clinical trials and national databases. Health-gains were represented using quality-adjusted life years (QALY). RESULTS From an insurer perspective, on-label prescription drugs (rifaximin, eluxadoline, alosetron) were significantly more expensive than off-label treatments, low FODMAP, or CBT. Insurer treatment preferences were driven by average wholesale prescription drug prices and were not affected by health gains in sensitivity analysis within standard willingness-to-pay ranges up to $150,000/QALY-gained. From a patient perspective, prescription drug therapies and neuromodulators appeared preferable due to a reduction in lost wages due to IBS with effective therapy, and also considering out-of-pocket costs of low FODMAP food and out-of-pocket costs to attend CBT appointments. Comparative health outcomes exerted influence on treatment preferences from a patient perspective in cost-benefit analysis depending on a patients' willingness-to-pay threshold for additional health-gains, but health outcomes were less important than out-of-pocket costs at lower willingness-to-pay thresholds. CONCLUSIONS Costs are critical determinants of IBS treatment value to patients and insurers, but different costs drive patient and insurer treatment preferences. Divergent cost drivers appear to explain misalignment between patient and insurer IBS treatment preferences in practice.
Collapse
Affiliation(s)
- Eric D Shah
- Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
| | - Jessica K Salwen-Deremer
- Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire; Department of Psychiatry, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
| | - Peter R Gibson
- Department of Gastroenterology, Central Clinical School, Monash University, Melbourne, Australia
| | - Jane G Muir
- Department of Gastroenterology, Central Clinical School, Monash University, Melbourne, Australia
| | - Shanti Eswaran
- Division of Gastroenterology, Michigan Medicine, Ann Arbor, Michigan
| | - William D Chey
- Division of Gastroenterology, Michigan Medicine, Ann Arbor, Michigan
| |
Collapse
|
|
15
|
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
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
16
|
Shah ED, Chang L, Lembo A, Staller K, Curley MA, Chey WD. Price Is Right: Exploring Prescription Drug Coverage Barriers for Irritable Bowel Syndrome Using Threshold Pricing Analysis. Dig Dis Sci 2021; 66:4140-4148. [PMID: 33433804 DOI: 10.1007/s10620-020-06806-1] [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: 09/12/2020] [Accepted: 12/22/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Prescription drug costs exert profound effects on commercial insurance coverage and access to effective therapy. AIMS We aimed to assess threshold pricing to achieve budget neutrality of FDA-approved drugs treating irritable bowel syndrome from an insurance perspective, based on cost-savings resulting in decreased healthcare utilization through effective disease management. METHODS We constructed a decision-analytic model from an insurance perspective to assess the budget impact of IBS prescription drugs under usual insurance coverage levels in practice: (1) unrestricted drug access or (2) step therapy in a primary care population of middle-age, care-seeking IBS patients. Budget-neutral drug prices were then calculated which resulted in $0 budget impact to insurers with a short-term, one-year time horizon. RESULTS If used according to FDA labeling, IBS-D drugs cost between $4778 and $16,844 per year and IBS-C drugs cost between $4319 and $4955 per year. These drug costs often exceed insurance expenditures of $6999 for IBS-D and $3929 for IBS-C if left untreated. Therefore, for drugs to have $0 budget impact to insurers, their prices would need to be discounted 36.7-74.2% for IBS-D drugs and 59.3-82.5% for IBS-C. IBS drugs are already priced to support step therapy "failing one of several common, inexpensive IBS treatments with a responder rate > 30-40%," reflecting the subpopulation with more severe disease and greater healthcare costs. CONCLUSIONS Broader prescription drug coverage for patients failing common, inexpensive IBS treatments to which at least 30-40% of patients would typically respond appears warranted to enable gastroenterologists to offer personalized approaches targeting specific mechanisms of this heterogeneous disease.
Collapse
Affiliation(s)
- Eric D Shah
- Center for Gastrointestinal Motility, Esophageal, and Swallowing Disorders, Section of Gastroenterology and Hepatology, Geisel School of Medicine at Dartmouth College, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH, 03766, USA.
| | - Lin Chang
- Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Anthony Lembo
- Digestive Disease Center, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Kyle Staller
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA
| | - Michael A Curley
- Center for Gastrointestinal Motility, Esophageal, and Swallowing Disorders, Section of Gastroenterology and Hepatology, Geisel School of Medicine at Dartmouth College, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH, 03766, USA
| | - William D Chey
- Division of Gastroenterology, Michigan Medicine, Ann Arbor, MI, USA
| |
Collapse
|
|
17
|
Paine P. Review article: current and future treatment approaches for pain in IBS. Aliment Pharmacol Ther 2021; 54 Suppl 1:S75-S88. [PMID: 34927753 DOI: 10.1111/apt.16550] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 07/15/2021] [Accepted: 07/15/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Abdominal pain is a core symptom of IBS and a primary driver of care seeking. Visceral hypersensitivity is a key pathophysiological mechanism and therapeutic target for pain in IBS, with components of peripheral and central sensitisation and psychological factors. AIM To review current and future treatment approaches specifically for the pain component of IBS. METHODS Pubmed search terms included combinations of irritable bowel, pain, visceral hypersensitivity, novel, new, emerging, future and advances. RESULTS Established non-pharmacological treatments for IBS pain include the low FODMAP diet, probiotics and psychological interventions, especially hypnotherapy. Tricyclics remain the best evidenced pharmacological approach with GCC agonists, tenapanor, lubiprostone, eluxadoline and 5HT3 antagonists second line according to patient characteristics and availability. Less well-evidenced current options include anti-spasmodics, peppermint oil, SSRIs, SNRIs, alpha 2 delta ligands, melatonin and histamine antagonists. Patients are vulnerable to iatrogenesis and harmful approaches to be avoided include opioids and unwarranted surgical interventions. For severe pain, the concept of augmentation with combined gut-brain neuromodulators and psychotherapy in a multi-disciplinary setting is considered. A plethora of molecular targets and ligands are emerging from pre-clinical studies, together with early clinical evidence for a range of pharmacological, dietary, neurostimulation and novel psychological treatment delivery methods which are reviewed. The history of such emerging approaches, however, merits both caution and optimism in equal measure. CONCLUSIONS Despite good in-roads and emerging options, the management of abdominal pain remains one of the biggest challenges and research priorities for patients with IBS.
Collapse
Affiliation(s)
- Peter Paine
- Department of Gastroenterology, University of Manchester, Salford Royal Foundation Trust, Salford, UK
| |
Collapse
|
|
18
|
Medical Therapies for Diarrhea-Predominant Irritable Bowel Syndrome. Gastroenterol Clin North Am 2021; 50:611-637. [PMID: 34304791 DOI: 10.1016/j.gtc.2021.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2023]
Abstract
Diarrhea-predominant irritable bowel syndrome is a common functional gastrointestinal disorder that manifests with abdominal pain and diarrheal bowel patterns, without structural explanation. Diarrhea-predominant irritable bowel syndrome is a heterogeneous condition resulting from diverse pathophysiologic processes. Treatment strategies with varied mechanisms of action are beneficial in its management. The clinician must become familiar with a multi-dimensional approach to irritable bowel syndrome. The 3 approved medications are central to disease management. Effective treatment uses off-label medications and emerging therapies and a growing number of over-the-counter and supplemental agents to optimize symptom improvement for the patient with diarrhea-predominant irritable bowel syndrome.
Collapse
|
|
19
|
Vasant DH, Paine PA, Black CJ, Houghton LA, Everitt HA, Corsetti M, Agrawal A, Aziz I, Farmer AD, Eugenicos MP, Moss-Morris R, Yiannakou Y, Ford AC. British Society of Gastroenterology guidelines on the management of irritable bowel syndrome. Gut 2021; 70:1214-1240. [PMID: 33903147 DOI: 10.1136/gutjnl-2021-324598] [Citation(s) in RCA: 269] [Impact Index Per Article: 67.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 03/30/2021] [Accepted: 04/06/2021] [Indexed: 12/11/2022]
Abstract
Irritable bowel syndrome (IBS) remains one of the most common gastrointestinal disorders seen by clinicians in both primary and secondary care. Since publication of the last British Society of Gastroenterology (BSG) guideline in 2007, substantial advances have been made in understanding its complex pathophysiology, resulting in its re-classification as a disorder of gut-brain interaction, rather than a functional gastrointestinal disorder. Moreover, there has been a considerable amount of new evidence published concerning the diagnosis, investigation and management of IBS. The primary aim of this guideline, commissioned by the BSG, is to review and summarise the current evidence to inform and guide clinical practice, by providing a practical framework for evidence-based management of patients. One of the strengths of this guideline is that the recommendations for treatment are based on evidence derived from a comprehensive search of the medical literature, which was used to inform an update of a series of trial-based and network meta-analyses assessing the efficacy of dietary, pharmacological and psychological therapies in treating IBS. Specific recommendations have been made according to the Grading of Recommendations Assessment, Development and Evaluation system, summarising both the strength of the recommendations and the overall quality of evidence. Finally, this guideline identifies novel treatments that are in development, as well as highlighting areas of unmet need for future research.
Collapse
Affiliation(s)
- Dipesh H Vasant
- Neurogastroenterology Unit, Gastroenterology, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK.,Division of Diabetes, Endocrinology and Gastroenterology, University of Manchester, Manchester, UK
| | - Peter A Paine
- Division of Diabetes, Endocrinology and Gastroenterology, University of Manchester, Manchester, UK.,Gastroenterology, Salford Royal Foundation Trust, Salford, UK
| | - Christopher J Black
- Leeds Gastroenterology Institute, Leeds Teaching Hospitals NHS Trust, Leeds, UK.,Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
| | - Lesley A Houghton
- Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.,Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA
| | - Hazel A Everitt
- Primary Care and Population Sciences, University of Southampton, Southampton, UK
| | - Maura Corsetti
- Nottingham Digestive Diseases Biomedical Research Unit, University of Nottingham, Nottingham, UK
| | - Anurag Agrawal
- Gastroenterology, Doncaster and Bassetlaw Hospitals NHS Trust, Armthorpe Road, Doncaster, UK
| | - Imran Aziz
- Academic Unit of Gastroenterology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.,Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK
| | - Adam D Farmer
- Department of Gastroenterology, University Hospitals of North Midlands NHS Trust, Stoke-on-Trent, UK.,School of Medicine, Keele University, Keele, UK
| | - Maria P Eugenicos
- Department of Gastroenterology, University of Edinburgh, Western General Hospital, Edinburgh, UK
| | - Rona Moss-Morris
- Department of Psychology, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Yan Yiannakou
- Department of Gastroenterology, County Durham and Darlington NHS Foundation Trust, Durham, UK
| | - Alexander C Ford
- Leeds Gastroenterology Institute, Leeds Teaching Hospitals NHS Trust, Leeds, UK .,Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
| |
Collapse
|
|
20
|
Cash BD, Lacy BE, Watton C, Schoenfeld PS, Weissman D. Post-marketing reports of pancreatitis in eluxadoline-treated patients pre and post US label change. Therap Adv Gastroenterol 2021; 14:17562848211001725. [PMID: 33953798 PMCID: PMC8042552 DOI: 10.1177/17562848211001725] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 02/22/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Eluxadoline, a United States Food and Drug Administration (FDA)-approved treatment for irritable bowel syndrome with diarrhea (IBS-D), underwent a change to its US prescribing information on 21 April 2017, contraindicating it in patients without a gallbladder due to increased risk of pancreatitis. This study aimed to elucidate the potential role of eluxadoline's label change on the number of reported spontaneous adverse events (AEs) of pancreatitis. METHODS A pharmacovigilance database (Oracle Argus) was searched for eluxadoline use and spontaneously reported pancreatitis cases from 1 January 2016 to 30 June 2018. Pancreatitis cases were reported as a proportion of the total number of reported AE cases in the safety database. The FDA's adverse event reporting system (AERS) was also interrogated for cases of pancreatitis concomitantly reported with eluxadoline use. RESULTS In patients who received eluxadoline, 273 reported cases of pancreatitis were recorded (total AEs n = 2191; 12.5%). When known, 28.2% of patients reporting pancreatitis had intact gallbladders (49/174). Eluxadoline was withdrawn in 97.5% of cases, with 87.1% of patients improving or recovered at time of reporting. Importantly, the reporting proportion of pancreatitis cases decreased from 14.4% to 8.9% post label change. Findings were supported by the AERS results, which demonstrated a decrease in reporting proportion from 21.2% to 12.8%. CONCLUSIONS While cautious interpretation is warranted, post-marketing data indicate that the contraindication of eluxadoline in patients without a gallbladder led to reduced reported cases of pancreatitis, with no additional reports of moderately severe or severe cases. Eluxadoline is a safe and well-tolerated treatment option for IBS-D when used according to the label.
Collapse
Affiliation(s)
- Brooks D Cash
- Department of Gastroenterology, Hepatology and Nutrition, University of Texas Health Science Center at Houston, 6431 Fannin Street, MSB 4.234, Houston, TX 77030, USA
| | - Brian E Lacy
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA
| | | | - Philip S Schoenfeld
- Division of Gastroenterology, John D. Dingell Veterans Affairs Medical Center, Detroit, MI, USA
| | - Darren Weissman
- Global Patient Safety and Epidemiology, AbbVie Inc., Madison, NJ, USA
| |
Collapse
|
|
21
|
Contrasting Clinician and Insurer Perspectives to Managing Irritable Bowel Syndrome: Multilevel Modeling Analysis. Am J Gastroenterol 2021; 116:748-757. [PMID: 33982945 DOI: 10.14309/ajg.0000000000000989] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Insurance coverage is an important determinant of treatment choice in irritable bowel syndrome (IBS), often taking precedence over desired mechanisms of action or patient goals/values. We aimed to determine whether routine and algorithmic coverage restrictions are cost-effective from a commercial insurer perspective. METHODS A multilevel microsimulation tracking costs and outcomes among 10 million hypothetical moderate-to-severe patients with IBS was developed to model all possible algorithms including common global IBS treatments (neuromodulators; low fermentable oligo-, di-, and mono-saccharides, and polyols; and cognitive behavioral therapy) and prescription drugs treating diarrhea-predominant IBS (IBS-D) or constipation-predominant IBS (IBS-C) over 1 year. RESULTS Routinely using global IBS treatments (central neuromodulator; low fermentable oligo-, di-, and mono-saccharides, and polyols; and cognitive behavioral therapy) before US Food and Drug Administration-approved drug therapies resulted in per-patient cost savings of $9,034.59 for IBS-D and $2,972.83 for IBS-C over 1 year to insurers, compared with patients starting with on-label drug therapy. Health outcomes were similar, regardless of treatment sequence. Costs varied less than $200 per year, regardless of the global IBS treatment order. The most cost-saving and cost-effective IBS-D algorithm was rifaximin, then eluxadoline, followed by alosetron. The most cost-saving and cost-effective IBS-C algorithm was linaclotide, followed by either plecanatide or lubiprostone. In no scenario were prescription drugs routinely more cost-effective than global IBS treatments, despite a stronger level of evidence with prescription drugs. These findings were driven by higher prescription drug prices as compared to lower costs with global IBS treatments. DISCUSSION From an insurer perspective, routine and algorithmic prescription drug coverage restrictions requiring failure of low-cost behavioral, dietary, and off-label treatments appear cost-effective. Efforts to address insurance coverage and drug pricing are needed so that healthcare providers can optimally care for patients with this common, heterogenous disorder.
Collapse
|
|
22
|
Brenner DM, Sayuk GS, Abel JL, Burslem K. Improved work productivity and health-related quality of life in patients with irritable bowel syndrome with diarrhea receiving eluxadoline following inadequate response to loperamide. J Manag Care Spec Pharm 2021. [DOI: 10.18553/jmcp.2021.27.4.469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Affiliation(s)
- Darren M Brenner
- Feinberg School of Medicine, Northwestern University, Chicago, IL
| | | | | | | |
Collapse
|
|
23
|
Arokiadoss A, Weber HC. Targeted pharmacotherapy of irritable bowel syndrome. Curr Opin Endocrinol Diabetes Obes 2021; 28:214-221. [PMID: 33481423 DOI: 10.1097/med.0000000000000618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW Irritable bowel syndrome (IBS) is a highly prevalent functional gastrointestinal (GI) disorder with negative impact on quality of life and it represents a substantial economic burden on healthcare cost. The medical management of IBS is symptom directed. This review provides an update related to clinical trial data for novel treatment modalities in IBS targeting the gut epithelium secretagogue receptors and channels. RECENT FINDINGS The new Rome IV criteria define functional gastrointestinal disorders (FGID) as disorders of the gut-brain interaction. Pharmacological treatment modalities for IBS target gastrointestinal receptors and ion channels, peripheral opioid receptor, gut serotonin receptors, and the gut microbiome. New targeted pharmacotherapies have shown efficacy and safety in the treatment of patients with IBS. SUMMARY Diagnostic criteria for FGID, including IBS, have been revised in Rome IV and are defined as gut-brain disorders. Newly approved pharmacotherapy options with proven efficacy and acceptable side-effect profiles are available for the symptom-based management of IBS.
Collapse
Affiliation(s)
| | - H Christian Weber
- Boston University School of Medicine, Section of Gastroenterology
- VA Boston Healthcare System, Section of Gastroenterology and Hepatology, Boston, Massachusetts, USA
| |
Collapse
|
|
24
|
Jones J, Lembo A, Heidelbaugh J, Kuritzky L, Lacy B. Management of irritable bowel syndrome with diarrhea: focus on eluxadoline. Curr Med Res Opin 2021; 37:567-578. [PMID: 33566707 DOI: 10.1080/03007995.2021.1888705] [Citation(s) in RCA: 2] [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] [Indexed: 12/16/2022]
Abstract
OBJECTIVE We sought to summarize current recommendations for the diagnosis of diarrhea-predominant irritable bowel syndrome (IBS-D) and describe available management options, highlighting a newer US Food and Drug Administration (FDA)-approved agent, eluxadoline. METHODS Literature on IBS-D was assessed up to January 2020 using PubMed, with key search terms including "IBS-D diagnosis", "IBS-D management", and "eluxadoline". RESULTS IBS is a common gastrointestinal disorder affecting up to 14% of US adults and is particularly prevalent in women and those aged under 50. Symptoms include abdominal pain associated with altered bowel habits (i.e. diarrhea and/or constipation subtyped based on the predominant stool pattern). As IBS-D is challenging to manage with varying symptom severity, effective treatment requires a personalized management approach. Evidence-based therapeutic options endorsed by the American Gastroenterological Association and the American College of Gastroenterology can be used to effectively guide treatment. Dietary and lifestyle modifications, including adequate hydration, reducing caffeine and alcohol intake, and increasing soluble fiber intake may lead to symptom improvement. Over-the-counter medications such as loperamide are frequently recommended and may improve stool frequency and rectal urgency; however, for the outcome of abdominal pain, mixed results have been observed. Several off-label prescription medications are useful in IBS-D management, including tricyclic antidepressants, bile acid sequestrants, and antispasmodics. Three prescription medications have been approved by the FDA for IBS-D: alosetron, eluxadoline, and rifaximin. CONCLUSIONS IBS-D can be effectively managed in the primary care setting in the absence of alarm features. Benefits and risks of pharmacologic interventions should be weighed during treatment selection.
Collapse
Affiliation(s)
- Jennifer Jones
- UCF College of Medicine, HCA Consortium Family Medicine Residency, Gainesville, FL, USA
| | - Anthony Lembo
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Joel Heidelbaugh
- Departments of Family Medicine and Urology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Louis Kuritzky
- Department of Community Health and Family Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Brian Lacy
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA
| |
Collapse
|
|
25
|
Fukudo S, Okumura T, Inamori M, Okuyama Y, Kanazawa M, Kamiya T, Sato K, Shiotani A, Naito Y, Fujikawa Y, Hokari R, Masaoka T, Fujimoto K, Kaneko H, Torii A, Matsueda K, Miwa H, Enomoto N, Shimosegawa T, Koike K. Evidence-based clinical practice guidelines for irritable bowel syndrome 2020. J Gastroenterol 2021; 56:193-217. [PMID: 33538894 PMCID: PMC7932982 DOI: 10.1007/s00535-020-01746-z] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Accepted: 10/27/2020] [Indexed: 02/06/2023]
Abstract
Managing irritable bowel syndrome (IBS) has attracted international attention because single-agent therapy rarely relieves bothersome symptoms for all patients. The Japanese Society of Gastroenterology (JSGE) published the first edition of evidence-based clinical practice guidelines for IBS in 2015. Much more evidence has accumulated since then, and new pharmacological agents and non-pharmacological methods have been developed. Here, we report the second edition of the JSGE-IBS guidelines comprising 41 questions including 12 background questions on epidemiology, pathophysiology, and diagnostic criteria, 26 clinical questions on diagnosis and treatment, and 3 questions on future research. For each question, statements with or without recommendations and/or evidence level are given and updated diagnostic and therapeutic algorithms are provided based on new evidence. Algorithms for diagnosis are requisite for patients with chronic abdominal pain or associated symptoms and/or abnormal bowel movement. Colonoscopy is indicated for patients with one or more alarm symptoms/signs, risk factors, and/or abnormal routine examination results. The diagnosis is based on the Rome IV criteria. Step 1 therapy consists of diet therapy, behavioral modification, and gut-targeted pharmacotherapy for 4 weeks. For non-responders, management proceeds to step 2 therapy, which includes a combination of different mechanistic gut-targeted agents and/or psychopharmacological agents and basic psychotherapy for 4 weeks. Step 3 therapy is for non-responders to step 2 and comprises a combination of gut-targeted pharmacotherapy, psychopharmacological treatments, and/or specific psychotherapy. These updated JSGE-IBS guidelines present best practice strategies for IBS patients in Japan and we believe these core strategies can be useful for IBS diagnosis and treatment globally.
Collapse
Affiliation(s)
- Shin Fukudo
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan.
- Department of Behavioral Medicine Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.
| | - Toshikatsu Okumura
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Masahiko Inamori
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Yusuke Okuyama
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Motoyori Kanazawa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Takeshi Kamiya
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Ken Sato
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Akiko Shiotani
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Yuji Naito
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Yoshiko Fujikawa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Ryota Hokari
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Tastuhiro Masaoka
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Kazuma Fujimoto
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Hiroshi Kaneko
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Akira Torii
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Kei Matsueda
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Hiroto Miwa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Nobuyuki Enomoto
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Tooru Shimosegawa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Kazuhiko Koike
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| |
Collapse
|
|
26
|
ACG Clinical Guideline: Management of Irritable Bowel Syndrome. Am J Gastroenterol 2021; 116:17-44. [PMID: 33315591 DOI: 10.14309/ajg.0000000000001036] [Citation(s) in RCA: 440] [Impact Index Per Article: 110.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 10/08/2020] [Indexed: 02/07/2023]
Abstract
Irritable bowel syndrome (IBS) is a highly prevalent, chronic disorder that significantly reduces patients' quality of life. Advances in diagnostic testing and in therapeutic options for patients with IBS led to the development of this first-ever American College of Gastroenterology clinical guideline for the management of IBS using Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Twenty-five clinically important questions were assessed after a comprehensive literature search; 9 questions focused on diagnostic testing; 16 questions focused on therapeutic options. Consensus was obtained using a modified Delphi approach, and based on GRADE methodology, we endorse the following: We suggest that a positive diagnostic strategy as compared to a diagnostic strategy of exclusion be used to improve time to initiating appropriate therapy. We suggest that serologic testing be performed to rule out celiac disease in patients with IBS and diarrhea symptoms. We suggest that fecal calprotectin be checked in patients with suspected IBS and diarrhea symptoms to rule out inflammatory bowel disease. We recommend a limited trial of a low fermentable oligosaccharides, disacchardies, monosaccharides, polyols (FODMAP) diet in patients with IBS to improve global symptoms. We recommend the use of chloride channel activators and guanylate cyclase activators to treat global IBS with constipation symptoms. We recommend the use of rifaximin to treat global IBS with diarrhea symptoms. We suggest that gut-directed psychotherapy be used to treat global IBS symptoms. Additional statements and information regarding diagnostic strategies, specific drugs, doses, and duration of therapy can be found in the guideline.
Collapse
|
|
27
|
Andrews CN, Bradette M. Diarrhea-Predominant Irritable Bowel Syndrome: Medical Management Update. J Can Assoc Gastroenterol 2020; 3:e37-e48. [PMID: 33241185 PMCID: PMC7678738 DOI: 10.1093/jcag/gwz034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 10/29/2019] [Indexed: 11/24/2022] Open
Abstract
Irritable bowel syndrome (IBS) is a prevalent gastrointestinal disorder, which impacts the quality of life, work productivity and social activities of patients. Diarrhea-predominant IBS (IBS-D) is one of several subtypes, and accounts for approximately one third of all cases. Currently available treatments are typically unable to alleviate the cardinal symptoms of IBS-D, including abdominal pain and diarrhea, and a clinical unmet need remains for an effective treatment which simultaneously relieves multiple symptoms. Patients may benefit from a multipronged, individualized approach, including dietary modifications, and psychological and pharmacological therapies. The aim of this review is to provide an update on the available and upcoming treatment options for IBS-D in Canada, with reference to the recently updated Canadian IBS consensus guidelines. Initial treatment approaches include lifestyle modifications, dietary modifications, and non-prescription therapies such as peppermint oil. While some medications such as tricyclic antidepressants are also used to treat IBS-D symptoms, eluxadoline and rifaximin are the only two pharmacological therapies approved for the treatment of IBS-D in Canada. Key clinical trial data for the currently available pharmacological options are presented to provide an overview of the efficacy and safety of these agents.
Collapse
Affiliation(s)
| | - Marc Bradette
- Division of Gastroenterology, Centre Hospitalier Universitaire de Québec (CHU), Laval University, Québec, Québec, Canada
| |
Collapse
|
|
28
|
Mousavi T, Nikfar S, Abdollahi M. An update on efficacy and safety considerations for the latest drugs used to treat irritable bowel syndrome. Expert Opin Drug Metab Toxicol 2020; 16:583-604. [PMID: 32380874 DOI: 10.1080/17425255.2020.1767067] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Irritable bowel syndrome (IBS), globally affecting 11.2% of the population and imposing a direct annual cost of $1.7bn-$10bn in the US, is one of the today's major therapeutic challenges. Therefore, there is urgent need to address this issue through reviewing the tolerability and efficacy of available medications. AREAS COVERED Over the past decade, related experiments were cited through Clinicaltrials.gov, PubMed, WHO ICTRP, and Cochrane library. Pharmacological parameters of approved medications available in the USFDA, EMA, TGA and PMDA were also stated. EXPERT OPINION Anti-spasmodics are used as the first-line treatment in pain-predominant IBS and IBS-D, among which calcium channel blockers and neurokinin-type 2 receptor antagonists seem to replace anti-cholinergic drugs. As second-line treatments, rifaximin is considered to be the best for IBS-D though it has lower efficacy than alosetron and eluxadoline. For IBS-C, linaclotide is the most effective and the safest second-line therapy, following laxatives/fibers, which may be replaced by tenapanor, in the future. When moderate to severe IBS is associated with severe pain or comorbid psychological disorders, gut-brain neuromodulators could also be prescribed. Regarding all this, there is still a paramount need to conduct careful clinical studies on efficacy, safety and cost-effectiveness of current approved and non-approved treatments.
Collapse
Affiliation(s)
- Taraneh Mousavi
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences , Tehran, Iran.,Department of Toxicology and Pharmacology, School of Pharmacy, Tehran University of Medical Sciences , Tehran, Iran
| | - Shekoufeh Nikfar
- Personalized Medicine Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences , Tehran, Iran.,Evidence-Based Evaluation of Cost-Effectiveness and Clinical Outcomes Group, Pharmaceutical Sciences Research Center (PSRC), and The Pharmaceutical Management and Economics Research Center (PMERC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences , Tehran, Iran.,Department of Pharmacoeconomics and Pharmaceutical Administration, School of Pharmacy, Tehran University of Medical Sciences , Tehran, Iran
| | - Mohammad Abdollahi
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences , Tehran, Iran.,Department of Toxicology and Pharmacology, School of Pharmacy, Tehran University of Medical Sciences , Tehran, Iran.,Personalized Medicine Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences , Tehran, Iran
| |
Collapse
|
|
29
|
Liu R, Staller K. Update on Eluxadoline for the Treatment of Irritable Bowel Syndrome with Diarrhea: Patient Selection and Perspectives. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:1391-1400. [PMID: 32308371 PMCID: PMC7153999 DOI: 10.2147/dddt.s216056] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Accepted: 02/09/2020] [Indexed: 12/15/2022]
Abstract
Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder characterized by chronic abdominal pain associated with changes in bowel habits. It is the most common GI problem seen by gastroenterologists. IBS is a heterogenous disorder encompassing a spectrum of underlying mechanisms and clinical presentations. The pathophysiology of diarrhea-predominant form of IBS (IBS-D) remains poorly understood, and current available therapeutic options for IBS-D are limited. Eluxadoline is a novel, locally acting mixed μ- and κ-opioid receptor agonist and δ-receptor antagonist approved by the Food and Drug Administration (FDA) for treatment of adults with IBS-D. Data from two phase III clinical trials showed that approximately 25–30% of the eluxadoline-treated patients achieved composite clinical response, defined by a reduction of abdominal pain and improvement in stool consistency. Patients who achieve composite response during the first month of therapy were significantly more likely to demonstrate sustained clinical response. The most common adverse events reported with eluxadoline use were constipation, nausea and abdominal pain. The risk of abuse, dependence, or withdrawal is low. Serious adverse events associated with eluxadoline include sphincter of Oddi spasm (SOS) and pancreatitis particularly in patients without a gallbladder. Development of pancreatitis is likely secondary to SOS, but it remains unclear why pancreatitis occurs so quickly after initial doses. This adverse event profile helps guide proper selection of IBS-D patients for eluxadoline use, with important contraindications including absence of a gallbladder, biliary duct obstruction or sphincter of Oddi dysfunction, alcoholism, history of pancreatitis, or structural diseases of the pancreas. With the recent clinical trials demonstrating its efficacy, eluxadoline provides an additional option to the few existing pharmacologic interventions available for IBS-D. In this review, we discuss the drug development, efficacy and safety of eluxadoline, as well as selection criteria for identifying appropriate candidates for this medication.
Collapse
Affiliation(s)
- Rebecca Liu
- Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Kyle Staller
- Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.,Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
30
|
Current US Food and Drug Administration-Approved Pharmacologic Therapies for the Treatment of Irritable Bowel Syndrome with Diarrhea. Adv Ther 2020; 37:83-96. [PMID: 31707713 DOI: 10.1007/s12325-019-01116-z] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Indexed: 02/07/2023]
Abstract
Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by abdominal pain and alterations in stool form and/or frequency, leading to reduced quality of life. Pharmacologic agents currently approved by the US Food and Drug Administration for treatment of IBS with diarrhea (IBS-D) in adults are the nonsystemic antibiotic rifaximin, the mixed µ- and κ-opioid receptor agonist/δ-opioid antagonist eluxadoline, and the selective serotonin 5-HT3 antagonist alosetron (the last of which is indicated only in women with severe IBS-D refractory to conventional therapy). Both eluxadoline and alosetron are administered as chronic daily therapies; rifaximin is given as a 2-week course of treatment with repeat courses administered as needed for symptom recurrence. Presumed mechanisms of action of rifaximin include modulation of the gut microbiota, anti-inflammatory activity, normalization of visceral hypersensitivity, and reduction in intestinal permeability. Eluxadoline targets opioid receptors in the gastrointestinal (GI) tract, resulting in decreased GI motility, fluid secretion, and visceral pain perception. Alosetron antagonizes serotonergic afferent neural signals and also slows GI motility. The efficacy and safety of these agents have been investigated in several rigorous clinical trials, and it has been demonstrated that they improve global and individual IBS symptoms. This review highlights the pivotal efficacy and safety data of the three pharmacologic agents currently indicated in the USA for the management of IBS-D in adults.Funding: Salix Pharmaceuticals.
Collapse
|
|
31
|
Munjal A, Dedania B, Cash BD. Current and emerging pharmacological approaches for treating diarrhea-predominant irritable bowel syndrome. Expert Opin Pharmacother 2019; 21:63-71. [PMID: 31738621 DOI: 10.1080/14656566.2019.1691524] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Introduction: Irritable bowel syndrome with diarrhea (IBS-D) is among the most common functional gastrointestinal (GI) disorders and is associated with impaired quality of life, increased health-care utilization, and significant costs to patients and society. The treatment of IBS is typically hierarchal with initial therapies consisting of dietary and lifestyle modifications. Pharmacotherapy with over-the-counter and prescription medications is also commonly used for symptomatic control in the course of therapy.Areas covered: Three medications are approved by the United States Food and Drug Administration (FDA) for IBS-D, with all of them demonstrating efficacy in randomized, placebo-controlled trials. In this review, the authors discuss the clinical trial data applicable to the current FDA approved IBS-D therapies as well as review data related to new and emerging therapies for this condition.Expert opinion: Clinicians should be familiar with emerging therapies for IBS-D as they may provide benefit to some IBS-D patients. The exact mechanisms of action of many of the emerging agents for IBS-D remain unknown. Despite substantial differences and limitations in the design and quality of supporting studies, there is an increasing body of evidence suggesting that emerging agents may promote meaningful symptom improvement in patients with IBS-D.
Collapse
Affiliation(s)
- Akhil Munjal
- Division of Internal Medicine, University of Texas Health Science Center, McGovern Medical School, Houston, TX, USA
| | - Bhavtosh Dedania
- Division of Gastroenterology, University of Texas Health Science Center, McGovern Medical School, Houston, TX, USA
| | - Brooks D Cash
- Division of Gastroenterology, University of Texas Health Science Center, McGovern Medical School, Houston, TX, USA
| |
Collapse
|
|
32
|
Barros LL, Farias AQ, Rezaie A. Gastrointestinal motility and absorptive disorders in patients with inflammatory bowel diseases: Prevalence, diagnosis and treatment. World J Gastroenterol 2019; 25:4414-4426. [PMID: 31496621 PMCID: PMC6710178 DOI: 10.3748/wjg.v25.i31.4414] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 07/04/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases (IBD), Crohn`s disease and ulcerative colitis, are chronic conditions associated with high morbidity and healthcare costs. The natural history of IBD is variable and marked by alternating periods of flare and remission. Even though the use of newer therapeutic targets has been associated with higher rates of mucosal healing, a great proportion of IBD patients remain symptomatic despite effective control of inflammation. These symptoms may include but not limited to abdominal pain, dyspepsia, diarrhea, urgency, fecal incontinence, constipation or bloating. In this setting, commonly there is an overlap with gastrointestinal (GI) motility and absorptive disorders. Early recognition of these conditions greatly improves patient care and may decrease the risk of mistreatment. Therefore, in this review we describe the prevalence, diagnosis and treatment of GI motility and absorptive disorders that commonly affect patients with IBD.
Collapse
Affiliation(s)
- Luísa Leite Barros
- Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo 05403-000, Brazil
| | - Alberto Queiroz Farias
- Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo 05403-000, Brazil
| | - Ali Rezaie
- Division of Gastroenterology, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA 90048, United States
| |
Collapse
|
|
33
|
Shahid Z, Packard E, Groff A, Jain R. Eluxadoline-induced pancreatitis occurring in an adult man without a prior cholecystectomy. BMJ Case Rep 2019; 12:12/8/e231185. [DOI: 10.1136/bcr-2019-231185] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Eluxadoline is a novel medication that was approved in the USA in 2015 for the treatment of diarrhoea-predominant irritable bowel syndrome. Due to its unique mechanism of action as both an opioid agonist and antagonist, it has been placed as a schedule IV controlled substance. Since its approval, there have been several cases of eluxadoline-induced pancreatitis reported in the literature. The majority of patients who presented with eluxadoline-induced pancreatitis were reported to have had a prior cholecystectomy. Due to this, the Food and Drug Administration released a warning in 2017 that eluxadoline should no longer be used in patients who do not have a gall bladder. We present a rare case of an adult man without prior cholecystectomy who presented with severe mid-epigastric pain and was found to have eluxadoline-induced pancreatitis.
Collapse
|
|
34
|
|
|
35
|
Response to Lai. Am J Gastroenterol 2019; 114:1177-1178. [PMID: 31205133 DOI: 10.14309/ajg.0000000000000312] [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: 12/11/2022]
|
|
36
|
Abstract
PURPOSE OF REVIEW Irritable bowel syndrome (IBS) is a functional GI disorder that affects a large percentage of the population and presents a significant socio-economic burden on the society. In this article, we reviewed the evidence supporting various pharmacological treatment options for IBS. RECENT FINDINGS Rifaximin, eluxadoline, and alosetron have demonstrated that they reduce symptom severity improving quality of life in patients with IBS-diarrhea. Ramosetron is a promising agent in development. Peppermint oil has also demonstrated a positive impact on some symptoms of IBS. For IBS with constipation, traditional laxatives have failed to demonstrate significant benefit. However, lubiprostone, linaclotide, and plecanatide have demonstrated improvement of IBS with constipation in large, placebo-controlled trials. Tenapanor, a sodium/hydrogen exchanger 3 inhibitor, appears to be a promising treatment option in the pipeline. There are multiple pharmacologic agents with a variety of mechanisms that have demonstrated efficacy in IBS with diarrhea and constipation. There are no established pharmacologic agents for IBS with a mixed bowel pattern. There is a promising pipeline for additional novel therapies for IBS.
Collapse
Affiliation(s)
- Akhil Munjal
- Department of Internal Medicine, University of Texas Health Science Center at Houston/McGovern Medical School, 6431 Fannin Street, Houston, TX, 77030, USA
| | - Bhavtosh Dedania
- Division of Gastroenterology, University of Texas Health Science Center at Houston/McGovern Medical School, 6431 Fannin Street, MSB 4.234, Houston, TX, 77030, USA
| | - Brooks Cash
- Division of Gastroenterology, University of Texas Health Science Center at Houston/McGovern Medical School, 6431 Fannin Street, MSB 4.234, Houston, TX, 77030, USA.
| |
Collapse
|
|
37
|
Lacy BE, Harris LA, Chang L, Lucak S, Gutman C, Dove LS, Covington PS, Lembo A. Impact of patient and disease characteristics on the efficacy and safety of eluxadoline for IBS-D: a subgroup analysis of phase III trials. Therap Adv Gastroenterol 2019; 12:1756284819841290. [PMID: 31019552 PMCID: PMC6466471 DOI: 10.1177/1756284819841290] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Accepted: 02/14/2019] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Irritable bowel syndrome with diarrhea (IBS-D) is a prevalent gastrointestinal (GI) disorder with a varied presentation, often overlapping with other GI and non-GI disorders. Eluxadoline is a locally active mixed µ- and κ-opioid receptor agonist and δ-opioid receptor antagonist approved for the treatment of IBS-D in adults. As IBS-D is a heterogeneous disease, factors such as patient demographics, symptom severity, and symptom pattern history can potentially inform treatment selection. METHODS Here, we report additional prospectively planned analyses of two large double-blind, placebo-controlled studies (IBS-3001 and IBS-3002) enrolling patients meeting Rome III criteria for IBS-D. Patients were randomized 1:1:1 to receive placebo or eluxadoline 75 mg or 100 mg twice daily. Efficacy (abdominal pain, stool consistency, and composite, simultaneous improvement in both) and safety were assessed for prospectively defined patient subgroups stratified by age, sex, race, presence of comorbidities, and baseline disease characteristics. RESULTS Across all age, sex, race, comorbidity, and disease characteristic subgroups, a greater proportion of patients were composite responders with both eluxadoline doses as compared with placebo, including patients with a history of depression or a history of gastroesophageal reflux disease. Among patients aged ⩾65 years, a greater proportion of patients receiving eluxadoline 75 mg were composite, abdominal pain, and stool consistency responders compared with those receiving 100 mg. The proportion of patients with at least one adverse event was slightly higher in patients aged ⩾65 years and also in female patients. CONCLUSIONS This analysis suggests that eluxadoline is effective in treating IBS-D across a range of commonly encountered patient types. In contrast to the overall population, patients aged ⩾65 years demonstrated a greater proportion of responders at the lower approved 75 mg eluxadoline dose.
Collapse
Affiliation(s)
- Brian E. Lacy
- Division of Gastroenterology and Hepatology,
Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA
| | | | - Lin Chang
- University of California, Los Angeles, CA,
USA
| | - Susan Lucak
- Weill Cornell Medical Center, New York, NY,
USA
| | | | - Leonard S. Dove
- Former employees of Furiex Pharmaceuticals,
Inc., an affiliate of Allergan plc, Madison, NJ, USA
| | - Paul S. Covington
- Former employees of Furiex Pharmaceuticals,
Inc., an affiliate of Allergan plc, Madison, NJ, USA
| | - Anthony Lembo
- Beth Israel Deaconess Medical Center, Boston,
MA, USA
| |
Collapse
|
|
38
|
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.
Collapse
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
| |
Collapse
|
|
39
|
Ng QX, Soh AYS, Lim DY, Yeo WS. Agomelatine, a novel therapeutic option for the management of irritable bowel syndrome. J Clin Pharm Ther 2018; 43:752-756. [PMID: 30014556 DOI: 10.1111/jcpt.12749] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 06/08/2018] [Accepted: 06/27/2018] [Indexed: 12/12/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE Irritable bowel syndrome (IBS) is a complex and chronic, relapsing gastrointestinal condition that affects more than 10% of the population worldwide. There is a pressing need for new therapeutic strategies in the management of IBS. Increasing research has shed light on the modulatory functions of melatonin on pain, local inflammation and motility in the gastrointestinal tract. However, melatonin's effects are limited by its extensive first-pass metabolism and short half-life. COMMENT Agomelatine, a naphthalene analog of melatonin, is a novel melatonergic drug with a longer half-life and a comparatively greater affinity for MT1 and MT2 melatonin receptors than melatonin itself. Agomelatine also shows serotonin 5-HT3 receptor antagonist activity, which is theoretically of benefit for patients with IBS with diarrhoea (IBS-D) as it regulates gastrointestinal motility and visceral sensory mechanisms. Although only one clinical study of agomelatine use in patients with IBS exists, we believe that agomelatine is a safe and efficacious multimodal agent with untapped potential in the management of IBS. WHAT IS NEW AND CONCLUSION Numerous comorbidities are associated with IBS, including chronic pain syndromes and psychiatric disorders. Coupled with its antidepressant actions, agomelatine could serve as an effective adjunct therapeutic. Agomelatine should be considered in our therapeutic armamentarium for IBS management.
Collapse
Affiliation(s)
- Qin Xiang Ng
- National University Hospital, National University Health System, Singapore City, Singapore
| | - Alex Yu Sen Soh
- National University Hospital, National University Health System, Singapore City, Singapore
| | | | - Wee-Song Yeo
- National University Hospital, National University Health System, Singapore City, Singapore
| |
Collapse
|
|
40
|
Lacy BE. Review article: an analysis of safety profiles of treatments for diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther 2018; 48:817-830. [PMID: 30194692 PMCID: PMC6667996 DOI: 10.1111/apt.14948] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 04/27/2018] [Accepted: 07/28/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is multifactorial in nature, and a wide range of therapies is available to manage symptoms of this common disorder. AIM To provide an overview of the safety of interventions that may be used to manage patients with diarrhoea-predominant IBS (IBS-D). METHODS Medline and Embase database searches (through 02 May 2018) to identify clinical studies that evaluated treatment safety and/or efficacy in adults with IBS-D. RESULTS IBS-D treatments include dietary modification, probiotics, serotonin receptor antagonists, opioid receptor agonists and antagonists, nonsystemic antibiotics, bile acid sequestrants, antidepressants, and complementary and alternative therapies. These treatments vary in administration frequency (eg, daily; short-course therapy) and target various pathophysiologic factors. Safety profiles vary considerably by treatment among IBS-D therapies. The number needed to harm (defined as the number of patients treated to encounter an adverse event) was lowest (worse) for antidepressants (8.5) and highest (best) for probiotics (35), and the number needed to harm (defined as the number of patients who discontinued due to an adverse event) was lowest for tricyclic antidepressants (9) and highest for rifaximin (8971). Notable safety concerns with IBS-D treatments include pancreatitis with eluxadoline, ischaemic colitis and serious complications of constipation with alosetron, and cardiac adverse events with loperamide and tricyclic antidepressants. Treatment decisions need to account for medication risks and adverse events for each patient. CONCLUSIONS Multiple treatment options are now available for patients with IBS-D. However, the safety profiles of these agents vary widely by number needed to harm value. Providers should consider both safety and efficacy of a specific intervention when determining how best to manage patients' IBS-D symptoms.
Collapse
Affiliation(s)
- Brian E. Lacy
- Section of GastroenterologyMayo ClinicJacksonvilleFlorida
| |
Collapse
|
|
41
|
Abel JL, Carson RT, Andrae DA. The impact of treatment with eluxadoline on health-related quality of life among adult patients with irritable bowel syndrome with diarrhea. Qual Life Res 2018; 28:369-377. [PMID: 30267294 PMCID: PMC6373309 DOI: 10.1007/s11136-018-2008-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/17/2018] [Indexed: 12/17/2022]
Abstract
Purpose Irritable bowel syndrome with diarrhea (IBS-D) significantly impacts health-related quality of life (HRQOL). This post hoc analysis of two phase III trials evaluated the effects of eluxadoline treatment on disease-specific HRQOL among patients with IBS-D. Methods Adult patients meeting Rome III criteria for IBS-D were randomized to oral eluxadoline (75 mg or 100 mg) or placebo twice daily in two phase III clinical trials for 52 weeks (IBS-3001) and 26 weeks (IBS-3002). The Irritable Bowel Syndrome Quality of Life (IBS-QOL) questionnaire assessed disease-specific HRQOL throughout the study. Changes from baseline to Week 26 in IBS-QOL total and subscale scores were analyzed using an analysis of covariance model. Percentages of IBS-QOL responders with ≥ 14- and 20-point changes were evaluated for IBS-QOL total and subscale scores. A longitudinal mixed-effects model was fitted to evaluate mean IBS-QOL total scores. A cumulative distribution function for change from baseline to Week 26 in IBS-QOL total score was plotted. Results Mean changes from baseline to Week 26 for the IBS-QOL total and all subscale scores were significantly higher for patients treated with eluxadoline (both doses) compared to placebo. A significantly greater proportion of eluxadoline-treated patients were responders compared to placebo. Mean and mixed-effects model estimated mean IBS-QOL total scores were consistently higher for eluxadoline versus placebo over 52 weeks. Conclusions Compared to placebo, twice-daily eluxadoline treatment significantly improved HRQOL among patients with IBS-D in two phase III trials.
Collapse
|
|
42
|
Chang C. Short-course therapy for diarrhea-predominant irritable bowel syndrome: understanding the mechanism, impact on gut microbiota, and safety and tolerability of rifaximin. Clin Exp Gastroenterol 2018; 11:335-345. [PMID: 30288076 PMCID: PMC6160288 DOI: 10.2147/ceg.s167031] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Irritable bowel syndrome (IBS) is a common gastrointestinal (GI) disorder characterized by abdominal pain that occurs with defecation or alterations in bowel habits. Further classification is based on the predominant bowel habit: constipation-predominant IBS, diarrhea-predominant IBS (IBS-D), or mixed IBS. The pathogenesis of IBS is unclear and is considered multifactorial in nature. GI dysbiosis, thought to play a role in IBS pathophysiology, has been observed in patients with IBS. Alterations in the gut microbiota are observed in patients with small intestinal bacterial overgrowth, and overgrowth may occur in a subset of patients with IBS. The management of IBS includes therapies targeting the putative factors involved in the pathogenesis of the condition. However, many of these interventions (eg, eluxadoline and alosetron) require long-term, daily administration and have important safety considerations. Agents thought to modulate the gut microbiota (eg, antibiotics and probiotics) have shown potential benefits in clinical studies. However, conventional antibiotics (eg, neomycin) are associated with several adverse events and/or the risk of bacterial antibiotic resistance, and probiotics lack uniformity in composition and consistency of response in patients. Rifaximin, a nonsystemic antibiotic administered as a 2-week course of therapy, has been shown to be safe and efficacious for the treatment of IBS-D. Rifaximin exhibits a favorable benefit-to-harm ratio when compared with daily therapies for IBS-D (eg, alosetron and tricyclic antidepressants), and rifaximin was not associated with the emergence of bacterial antibiotic resistance. Thus, short-course therapy with rifaximin is an appropriate treatment option for IBS-D.
Collapse
Affiliation(s)
- Christopher Chang
- New Mexico VA Health Care System, Division of Gastroenterology and Hepatology, Albuquerque, NM, USA,
- Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA,
| |
Collapse
|
|
43
|
Bonifacio L, Hunt TL, McIntyre G, Dove LS, Covington PS. Evaluation of Eluxadoline Effect on Cardiac Repolarization. Clin Pharmacol Drug Dev 2018; 7:727-736. [PMID: 29659201 PMCID: PMC6175186 DOI: 10.1002/cpdd.453] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Accepted: 01/31/2018] [Indexed: 12/17/2022]
Abstract
This study evaluated the effects of eluxadoline, a mixed μ‐opioid receptor (OR) and κ‐OR agonist and δ‐OR antagonist, on cardiac repolarization. This evaluator‐blinded, placebo‐ and positive‐controlled, 4‐period crossover study randomized healthy men and women to single oral doses of eluxadoline (therapeutic dose 100 mg or supratherapeutic dose 1000 mg), moxifloxacin 400 mg, or placebo. QT data were corrected using individual custom correction (QTcI). The primary endpoint was the change from baseline in QTcI intervals (ΔQTcI) between eluxadoline and placebo (ΔΔQTcI). An upper bound of the 95% confidence interval around ΔΔQTcI of 10 milliseconds was considered clinically significant. Concentration–QTc data were analyzed using a repeated‐measures, mixed‐effects linear model. Sixty‐four volunteers were treated, and 58 completed the study. Assay sensitivity was demonstrated with moxifloxacin (noted by ΔΔQTcI of 11.94 milliseconds). The maximum ΔΔQTcI for eluxadoline 1000 mg was 4.10 milliseconds 1 hour postdose (1‐sided 95% upper confidence bound, 5.81 milliseconds), and for eluxadoline 100 mg was 1.20 milliseconds at 0.5 hours postdose (1‐sided 95% upper confidence bound, 2.91 milliseconds). Primary ΔΔQTcI results were confirmed using Fridericia's formula for QTc. Categorical, morphological, and concentration–QTc analyses were consistent with the primary and secondary findings. There were no significant gender effects on ΔΔQTcI values. The most common adverse events were contact dermatitis and nausea (12.5% each) and dizziness (10.9%); adverse events were more frequent in the eluxadoline 1000 mg group. In conclusion, eluxadoline, at therapeutic or supratherapeutic doses, did not significantly prolong QT intervals, and was safe and generally well tolerated in this study population.
Collapse
Affiliation(s)
| | | | | | | | - Paul S Covington
- Former employee of Furiex Pharmaceuticals, Inc., an affiliate of Allergan plc, Madison, NJ, USA
| |
Collapse
|
|
44
|
Hyun JJ, Kozarek RA. Sphincter of Oddi dysfunction: sphincter of Oddi dysfunction or discordance? What is the state of the art in 2018? Curr Opin Gastroenterol 2018; 34:282-287. [PMID: 29916850 DOI: 10.1097/mog.0000000000000455] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
PURPOSE OF REVIEW To review important manuscripts published over the previous 2 years relative to sphincter of Oddi dysfunction (SOD). RECENT FINDINGS The long-term outcomes of the Evaluating Predictors and Interventions of SOD (EPISOD) trial further substantiated results from the initial EPISOD study, reinforcing that neither endoscopic retrograde cholangiopancreatography-manometry nor endoscopic sphincterotomy are appropriate for SOD type III. Pain management in the latter patients has reverted to neuromodulating agents, and recent studies have suggested a role for duloxetine and potentially acupuncture. The functional role of the sphincter of Oddi has been reiterated with a report demonstrating a higher clinically significant pancreatic fistula rate in distal pancreatectomy patients treated with higher doses of postoperative narcotics. Moreover, the injection of periampullary botulinum toxin preoperatively has been shown to decrease these fistulas in a pilot trial. Additional studies have reinforced that eluxadoline can cause sphincter of Oddi spasm and pancreatitis. In contrast to approaching patients with acute relapsing pancreatitis using endoscopic retrograde cholangiopancreatography and manometry, previous and current studies suggest that endoscopic ultrasound should be done first and the role of SOD in idiopathic acute relapsing pancreatitis remains controversial. Finally, there remain widespread disparities in practice patterns in the approach to patients currently classified as SOD type II. SUMMARY In contrast to historical manuscripts which stress the classical definitions of three types of SOD and their consequences, more recent manuscripts on this topic have focused on improving surgical outcomes based on the physiologic role of sphincter of Oddi, as well as the pharmacologic causes and treatments of SOD. The simplistic view that SOD, however it has been diagnosed, requires biliary or dual sphincterotomy is just that, simplistic and potentially misguided.
Collapse
Affiliation(s)
- Jong Jin Hyun
- Digestive Disease Institute, Virginia Mason Medical Center, Seattle, Washington, USA
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Richard A Kozarek
- Digestive Disease Institute, Virginia Mason Medical Center, Seattle, Washington, USA
| |
Collapse
|
|
45
|
Maev IV, Kucheravy YA, Tsukanov VV, Eremnia EY, Andreev DN, Abdulhakov SR, Akhmedov VA, Batskov SS, Vasyutin AV, V'yuchnova ES, Ivanchenko DN, Luzina EV, Krapivnaya OV, Onuchina EV, Osipenko MF, Simanenkov VI, Tonkih YL, Khomeriki NM, Shklyaev AE, Akimov AV, Sokolov KA. Effectiveness of mebeverine in patients with post-cholecystectomy gastrointestinal spasm: results of prospective observational program "odyssey". TERAPEVT ARKH 2018; 90:40-47. [PMID: 30701938 DOI: 10.26442/terarkh201890840-47] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
AIM To assess the effectiveness of mebeverine 200 mg BID in patients with post-cholecystectomy gastrointestinal spasm not requiring surgical treatment. MATERIALS AND METHODS 218 patients were included in 16 clinical centers in 14 cities in Russia. All patients had post-cholecystectomy gastrointestinal spasms, not requiring surgical treatment and received mebeverine (Duspatalin®) 200 mg BID. The observational assessment period lasted from the moment of their inclusion into the study up to 6 weeks post inlusion. The therapy results were evaluated using visual analog scales (GPA and 11-point numeric rating scale) by patient self-assessment of the dynamics of spasm/discomfort and other post-cholecystectomic gastrointestinal symptoms after 2 and 6 weeks of treatment. Gastrointestinal Quality of Life Index (GIQLI) was used to assess patient quality of life. RESULTS All 218 patients completed the 2-week mebeverine treatment course, 101 of them finished the 6-week course ("prolonged population"). Significant positive changes in the relief of abdominal pain and dyspepsia were noted as well as normalization of stool frequency and consistency. A more marked change in values was observed during prolonged (up to 6 weeks) therapy. Both 2-week and 6-week mebeverine courses led to a normalization of patient quality of life. After 6 week therapy, an effect of mebeverine on the quality of life 91% of patients was observed comparable to cholecystectomy itself, speficially related to the quality of life subscore 'symptoms'. CONCLUSION The results of our study demonstrate that mebeverine (Duspatalin®) therapy leads to an effective elimination of clinical symptoms associated with post-cholecystectomy GI-spasm disorders, like abdominal pain, symptoms of dyspepsia and stooldisorders. A more marked change in values was observed during prolonged (up to 6 weeks) therapy.
Collapse
Affiliation(s)
- I V Maev
- A.I. Yevdokimov Moscow State University of Medicine and Dentistry, Ministry of Health of Russia, Moscow, Russia
| | - Yu A Kucheravy
- A.I. Yevdokimov Moscow State University of Medicine and Dentistry, Ministry of Health of Russia, Moscow, Russia
| | - V V Tsukanov
- Federal Research Centre "Krasnoyarsk Science Centre" of the Siberian Branch of Russian Academy of Science"(FRC KSC SB RAS), Scientific Research Institute of medical problems of the North (SRI MPN), Krasnoyarsk, Russia
| | - E Yu Eremnia
- N.P. Ogarev National Research Mordovia State University, Saransk, Russia
| | - D N Andreev
- A.I. Yevdokimov Moscow State University of Medicine and Dentistry, Ministry of Health of Russia, Moscow, Russia
| | - S R Abdulhakov
- Kazan State Medical Univesity, Ministry of Health of Russia, Kazan, Russia
- Kazan Federal University, Kazan, Russia
| | - V A Akhmedov
- Omsk State Medical Univesity, Ministry of Health of Russia, Omsk, Russia
| | - S S Batskov
- А.М. Nikiforov All-Russian Center for Emergency and Radiation Medicine, Russian Ministry for Emergency Situations, Saint-Petersburg, Russia
| | - A V Vasyutin
- Federal Research Centre "Krasnoyarsk Science Centre" of the Siberian Branch of Russian Academy of Science"(FRC KSC SB RAS), Scientific Research Institute of medical problems of the North (SRI MPN), Krasnoyarsk, Russia
| | - E S V'yuchnova
- A.I. Yevdokimov Moscow State University of Medicine and Dentistry, Ministry of Health of Russia, Moscow, Russia
| | - D N Ivanchenko
- Rostov State Medical University, Ministry of Health of Russia, Rostov-on-Don, Russia
| | - E V Luzina
- Chita State Medical Academy, Ministry of Health of Russia, Chita, Russia
| | - O V Krapivnaya
- Road Clinical Hospital at Khabarovsk-1 station of ОАО RzhD, Khabarovsk, Russia
| | - E V Onuchina
- Irkutsk State Medical Academy for Postgraduate Education - affiliated branch of Russian Medical Academy of Continuous Professional Training, Ministry of Health of Russia, Irkutsk, Russia
| | - M F Osipenko
- Novosibirsk State Medical University, Ministry of Health of Russia, Novosibirsk, Russia
| | - V I Simanenkov
- I.I. Mechnikov North-Western State Medical University, Ministry of Health of Russia, Saint-Petersburg, Russia
| | - Yu L Tonkih
- Federal Research Centre "Krasnoyarsk Science Centre" of the Siberian Branch of Russian Academy of Science"(FRC KSC SB RAS), Scientific Research Institute of medical problems of the North (SRI MPN), Krasnoyarsk, Russia
| | - N M Khomeriki
- Hospital of Pushchino Scientific Center, Pushchino, Russia
| | - A E Shklyaev
- Izhevsk State Medical Academy, Ministry of Health of Russia, Izhevsk, Russia
| | | | | |
Collapse
|
|
46
|
Garcia-Gonzalez F, Faghih M, Singh V. Letter: eluxadoline-associated acute pancreatitis-myth or reality? Aliment Pharmacol Ther 2018; 48:490-491. [PMID: 30588698 DOI: 10.1111/apt.14846] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- F Garcia-Gonzalez
- Gastroenterology and Hepatology, Johns Hopkins Hospital and Health System, Baltimore, MD, USA.,Division of Gastroenterology, Johns Hopkins Hospital, Baltimore, MD, USA
| | - M Faghih
- Division of Gastroenterology, Johns Hopkins Hospital, Baltimore, MD, USA
| | - V Singh
- Division of Gastroenterology, Johns Hopkins Hospital, Baltimore, MD, USA
| |
Collapse
|
|
47
|
Arasteh P, Maharlouei N, Eghbali SS, Amini M, Lankarani KB, Malekzadeh R. A Comprehensive Look at Irritable Bowel Syndrome and its Associated Factors Considering the Rome IV Criteria: A Penalized Smoothly Clipped Absolute Deviation Regression Approach in the Pars Cohort Study. Middle East J Dig Dis 2018; 10:149-159. [PMID: 30186578 PMCID: PMC6119837 DOI: 10.15171/mejdd.2018.104] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 06/19/2018] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND After the introduction of the Rome IV criteria for the diagnosis of irritable bowel syndrome (IBS), studies on the clinical significance of the new criteria in the settings of a large study has been scarce. Objective: Herein we used the infrastructures provided by one the largest cohort studies in Iran to evaluate the epidemiological features related to IBS. METHODS A total of 9264 participants, were enrolled in the initial registry. Diagnosis of IBS was done using the Rome IV criteria. Individuals with IBS were compared with a control group. Since the study included a large sample size of patients, we used the penalized smoothly clipped absolute deviation (SCAD) regression analysis to construct a model for the evaluation of factors associated with IBS. RESULTS Overall, data of 9163 participants entered the final analysis. In total, 1067 (11.6%) individuals were diagnosed with IBS, among which 57 (5.3%) were diarrhea dominant (IBS-D), 380 (35.6%) were constipation dominant (IBS-C), and 630 (59%) did not mention having any of the two (IBS-U). In the regression model, back pain/arthralgia (OR: 1.98, 95% CI: 1.65 - 2.40), insomnia (OR: 1.65, 95% CI: 1.40 - 1.93), depression (OR: 1.64, 95% CI: 1.38 - 1.95), female sex (OR: 1.58, 95% CI: 1.27 - 1.96), anxiety (OR: 1.43, 95% CI: 1.21 - 1.69), and being married (OR: 1.23, 95% CI: 1.03 - 1.48), were associated with higher rates of IBS. We found that IBS prevalence displays a peak at the age of 41 years for both men and women. CONCLUSION The present study provides a background for follow-up studies to be conducted in order to evaluate causality between IBS and some major diseases such as liver disease. We also found that opium use, although not statistically significant, in addition to sex, education, back/joint pain, depression, insomnia, anxiety, and marital status might be a contributing factor in IBS.
Collapse
Affiliation(s)
- Peyman Arasteh
- Department of MPH, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Najmeh Maharlouei
- Health Policy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyed Sajjad Eghbali
- Department of Pathology and Lab Medicine, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Mitra Amini
- Clinical Education Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Kamran B. Lankarani
- Health Policy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Malekzadeh
- Digestive Oncology Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
48
|
Gawron AJ, Bielefeldt K. Risk of Pancreatitis Following Treatment of Irritable Bowel Syndrome With Eluxadoline. Clin Gastroenterol Hepatol 2018; 16:378-384.e2. [PMID: 28804032 DOI: 10.1016/j.cgh.2017.08.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Revised: 08/01/2017] [Accepted: 08/04/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The Food and Drug Administration approved eluxadoline for the treatment of diarrhea-predominant irritable bowel syndrome despite cases of pancreatitis in early stage trials. We investigated the frequency of pancreatitis attributed to eluxadoline in postmarketing surveillance. METHODS We extracted reports on eluxadoline submitted to the Federal Adverse Event Reporting System from January through September 2016. We collected data on patient age and sex, event date, reporting entity (consumer, physician, pharmacist, legal worker, or other), medications, dosages, presumed role in the event (coinciding, primary, or secondary suspect), treatment indication, and outcome (death, life threatening, hospitalization, disability, or other).We compared data for eluxadoline with data from antidiarrheals, oxycodone, and rifaximin using the κ2 test, Kruskal-Wallis rank test, and analysis of variance; findings with P < .05 were considered statistically significant. RESULTS Pancreatitis accounted for 16.4% of the 597 reports of adverse events linked to eluxadoline; 53 cases required hospitalization. Pancreatitis was listed as treatment complication of other agents in significantly lower proportions of cases (loperamide, 0.3%; diphenoxylate, 0.4%; oxycodone, 0.2%; rifaximin, 0.5%), with 75% of these submissions not considering the agent as causal. CONCLUSIONS In an analysis of reports on eluxadoline submitted to the Federal Adverse Event Reporting System, we confirmed a previously reported risk of pancreatitis associated with eluxadoline. The need for hospitalization in at least half of these instances and a recent report of 2 fatalities should prompt reassessments of the agent's risk-benefit ratio.
Collapse
Affiliation(s)
- Andrew J Gawron
- Gastroenterology Section, George E. Wahlen VA Medical Center, Salt Lake City, Utah; Division of Gastroenterology, Hepatology, and Nutrition, University of Utah, Salt Lake City, Utah; Salt Lake City Specialty Care Center of Innovation, Salt Lake City, Utah
| | - Klaus Bielefeldt
- Gastroenterology Section, George E. Wahlen VA Medical Center, Salt Lake City, Utah.
| |
Collapse
|
|
49
|
Szigethy E, Knisely M, Drossman D. Opioid misuse in gastroenterology and non-opioid management of abdominal pain. Nat Rev Gastroenterol Hepatol 2018; 15:168-180. [PMID: 29139482 PMCID: PMC6421506 DOI: 10.1038/nrgastro.2017.141] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Opioids were one of the earliest classes of medications used for pain across a variety of conditions, but morbidity and mortality have been increasingly associated with their chronic use. Despite these negative consequences, chronic opioid use is increasing worldwide, with the USA and Canada having the highest rates. Chronic opioid use for noncancer pain can have particularly negative effects in the gastrointestinal and central nervous systems, including opioid-induced constipation, narcotic bowel syndrome, worsening psychopathology and addiction. This Review summarizes the evidence of opioid misuse in gastroenterology, including the lack of evidence of a benefit from these drugs, as well as the risk of harm and negative consequences of opioid use relative to the brain-gut axis. Guidelines for opioid management and alternative pharmacological and nonpharmacological strategies for pain management in patients with gastrointestinal disorders are also discussed. As chronic pain is complex and involves emotional and social factors, a multimodal approach targeting both pain intensity and quality of life is best.
Collapse
Affiliation(s)
- Eva Szigethy
- Departments of Psychiatry and Medicine, University of Pittsburgh, 3708 Fifth Avenue, Pittsburgh, Pennsylvania 15213, USA
| | - Mitchell Knisely
- School of Nursing, University of Pittsburgh, 3500 Victoria Street, Pittsburgh, Pennsylvania 15261, USA
| | - Douglas Drossman
- Center for Functional GI & Motility Disorders, University of North Carolina, Bioinformatics Building, 130 Mason Farm Road, Chapel Hill, North Carolina 27599, USA
- Drossman Gastroenterology PLLC, 901 Kings Mill Road, Chapel Hill, North Carolina 27517, USA
| |
Collapse
|
|
50
|
Chedid V, Vijayvargiya P, Camilleri M. Advantages and Limitations of the Federal Adverse Events Reporting System in Assessing Adverse Event Reporting for Eluxadoline. Clin Gastroenterol Hepatol 2018; 16:336-338. [PMID: 29155353 PMCID: PMC5816691 DOI: 10.1016/j.cgh.2017.11.025] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Revised: 11/08/2017] [Accepted: 11/11/2017] [Indexed: 02/07/2023]
Affiliation(s)
- Victor Chedid
- Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota
| | - Priya Vijayvargiya
- Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota
| | - Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota
| |
Collapse
|