Prokinetics-safety and efficacy: The European Society of Neurogastroenterology and Motility/The American Neurogastroenterology and Motility Society expert review.

BACKGROUND: Prokinetics are a class of pharmacological drugs designed to improve gastrointestinal (GI) motility, either regionally or across the whole gut. Each drug has its merits and drawbacks, and based on current evidence as high-quality studies are limited, we have no clear recommendation on one class or other. However, there remains a large unmet need for both regionally selective and/or globally acting prokinetic drugs that work primarily intraluminally and are safe and without systemic side effects. PURPOSE: Here, we describe the strengths and weaknesses of six classes of prokinetic drugs, including their pharmacokinetic properties, efficacy, safety and tolerability and potential indications.

Optimizing the Management Algorithm for Adults With Functional Constipation Failing a Fiber/Laxative Trial in General Gastroenterology: Cost-Effectiveness and Cost-Minimization Analysis.

INTRODUCTION: Anorectal function testing is traditionally relegated to subspecialty centers. Yet, it is an office-based procedure that appears capable of triaging care for the many patients with Rome IV functional constipation that fail empiric over-the-counter therapy in general gastroenterology, as an alternative to empirical prescription drugs. We aimed to evaluate cost-effectiveness of routine anorectal function testing in this specific population. METHODS: We performed a cost-effectiveness analysis from the patient perspective and a cost-minimization analysis from the insurer perspective to compare 3 strategies: (i) empiric prescription drugs followed by pelvic floor physical therapy (PFPT) for drug failure, (ii) empiric PFPT followed by prescription drugs for PFPT failure, or (iii) care directed by up-front anorectal function testing. Model inputs were derived from systematic reviews of prospective clinical trials, national cost data sets, and observational cohort studies of the impact of chronic constipation on health outcomes, healthcare costs, and work productivity. RESULTS: The most cost-effective strategy was upfront anorectal function testing to triage patients to appropriate therapy, in which the subset of patients without anal hypocontractility on anorectal manometry and with a balloon expulsion time of at least 6.5 seconds would be referred to PFPT. In sensitivity analysis, empiric PFPT was more cost effective than empiric prescription drugs except for situations in which the primary goal of treatment was to increase bowel movement frequency. If adopted, gastroenterologists would refer ∼17 patients per year to PFPT, supporting feasibility. DISCUSSION: Anorectal function testing seems to be an emergent technology to optimize cost-effective outcomes, overcoming testing costs by phenotyping care.

Optimizing the Utility of Anorectal Manometry for Diagnosis and Therapy: A Roundtable Review and Recommendations.

BACKGROUND & AIMS: Anorectal manometry (ARM) is a comprehensive diagnostic tool for evaluating patients with constipation, fecal incontinence, or anorectal pain; however, it is not widely utilized for reasons that remain unclear. The aim of this roundtable discussion was to critically examine the current clinical practices of ARM and biofeedback therapy by physicians and surgeons in both academic and community settings. METHODS: Leaders in medical and surgical gastroenterology and physical therapy with interest in anorectal disorders were surveyed regarding practice patterns and utilization of these technologies. Subsequently, a roundtable was held to discuss survey results, explore current diagnostic and therapeutic challenges with these technologies, review the literature, and generate consensus-based recommendations. RESULTS: ARM identifies key pathophysiological abnormalities such as dyssynergic defecation, anal sphincter weakness, or rectal sensory dysfunction, and is a critical component of biofeedback therapy, an evidence-based treatment for patients with dyssynergic defecation and fecal incontinence. Additionally, ARM has the potential to enhance health-related quality of life and reduce healthcare costs. However, it has significant barriers that include a lack of education and training of healthcare providers regarding the utility and availability of ARM and biofeedback procedures, as well as challenges with condition-specific testing protocols and interpretation. Additional barriers include understanding when to perform, where to refer, and how to use these technologies, and confusion over billing practices. CONCLUSIONS: Overcoming these challenges with appropriate education, training, collaborative research, and evidence-based guidelines for ARM testing and biofeedback therapy could significantly enhance patient care of anorectal disorders.

Up-Front Endoscopy Maximizes Cost-Effectiveness and Cost-Satisfaction in Uninvestigated Dyspepsia.

BACKGROUND & AIMS: Practice guidelines promote a routine noninvasive, non-endoscopic initial approach to investigating dyspepsia without alarm features in young patients, yet many patients undergo prompt upper endoscopy. We aimed to assess tradeoffs among costs, patient satisfaction, and clinical outcomes to inform discrepancy between guidelines and practice. METHODS: We constructed a decision-analytic model and performed cost-effectiveness/cost-satisfaction analysis over a 1-year time horizon on patients with uninvestigated dyspepsia without alarm features referred to gastroenterology. A RAND/UCLA expert panel informed model design. Four competing diagnostic/management strategies were evaluated: prompt endoscopy, testing for Helicobacter pylori and eradicating if present (test-and-treat), testing for H pylori and performing endoscopy if present (test-and-scope), and empiric acid suppression. Outcomes were derived from systematic reviews of clinical trials. Costs were informed by prospective observational cohort studies and national commercial/federal cost databases. Health gains were represented using quality-adjusted life years. RESULTS: From the patient perspective, costs and outcomes were similar for all strategies (maximum out-of-pocket difference of $30 and <0.01 quality-adjusted life years gained/year regardless of strategy). Prompt endoscopy maximized cost-satisfaction and health system reimbursement. Test-and-scope maximized cost-effectiveness from insurer and patient perspectives. Results remained robust on multiple one-way sensitivity analyses on model inputs and across most willingness-to-pay thresholds. CONCLUSIONS: Noninvasive management strategies appear to result in inferior cost-effectiveness and patient satisfaction outcomes compared with strategies promoting up-front endoscopy. Therefore, additional studies are needed to evaluate the drivers of patient satisfaction to facilitate inclusion in value-based healthcare transformation efforts.

Gastrointestinal Features of 22q11.2 Deletion Syndrome Include Chronic Motility Problems From Childhood to Adulthood.

OBJECTIVES: 22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal microdeletion syndrome and has a multisystemic presentation including gastrointestinal features that have not yet been fully described. Our aim was to examine lifetime gastrointestinal problems in a large cohort of patients with 22q11.2DS. METHODS: All patients followed in the 22q and You Center at the Children's Hospital of Philadelphia (n = 1421) were retrospectively screened for: 1) age ≥ 17 years, 2) documented chromosomal microdeletion within the 22q11.2 LCR22A-LCR22D region, and 3) sufficient clinical data to characterize the adult gastrointestinal phenotype. Gastrointestinal problems in childhood, adolescence, and adulthood were summarized. Statistical association testing of symptoms against other patient characteristics was performed. RESULTS: Included patients (n = 206; 46% female; mean age, 27 years; median follow-up, 21 years) had similar clinical characteristics to the overall cohort. Genetic distribution was also similar, with 96% having deletions including the critical LCR22A-LCR22B segment (95% in the overall cohort). Most patients experienced chronic gastrointestinal symptoms in their lifetime (91%), but congenital gastrointestinal malformations (3.5%) and gastrointestinal autoimmune diseases (1.5%) were uncommon. Chronic symptoms without anatomic or pathologic abnormalities represented the vast burden of illness. Chronic symptoms in adulthood are associated with other chronic gastrointestinal symptoms and psychiatric comorbidities ( P < 0.01) but not with deletion size or physiologic comorbidities ( P > 0.05). One exception was increased nausea/vomiting in hypothyroidism ( P = 0.002). CONCLUSIONS: Functional gastrointestinal disorders (FGIDs) are a common cause of ill health in children and adults with 22q11.2DS. Providers should consider screening for the deletion in patients presenting with FGIDs and associated comorbidities such as neuropsychiatric illness, congenital heart disease, and palatal abnormalities.

Effectiveness of Nutritional Ingredients on Upper Gastrointestinal Conditions and Symptoms: A Narrative Review.

Nutritional ingredients, including various fibers, herbs, and botanicals, have been historically used for various ailments. Their enduring appeal is predicated on the desire both for more natural approaches to health and to mitigate potential side effects of more mainstream treatments. Their use in individuals experiencing upper gastrointestinal (GI) complaints is of particular interest in the scientific space as well as the consumer market but requires review to better understand their potential effectiveness. The aim of this paper is to review the published scientific literature on nutritional ingredients for the management of upper GI complaints. We selected nutritional ingredients on the basis of mentions within the published literature and familiarity with recurrent components of consumer products currently marketed. A predefined literature search was conducted in Embase, Medline, Derwent drug file, ToXfile, and PubMed databases with specific nutritional ingredients and search terms related to upper GI health along with a manual search for each ingredient. Of our literature search, 16 human clinical studies including nine ingredients met our inclusion criteria and were assessed in this review. Products of interest within these studies subsumed the categories of botanicals, including fiber and combinations, and non-botanical extracts. Although there are a few ingredients with robust scientific evidence, such as ginger and a combination of peppermint and caraway oil, there are others, such as melatonin and marine alginate, with moderate evidence, and still others with limited scientific substantiation, such as galactomannan, fenugreek, and zinc-l-carnosine. Importantly, the paucity of high-quality data for the majority of the ingredients analyzed herein suggests ample opportunity for further study. In particular, trials with appropriate controls examining dose-response using standardized extracts and testing for specific benefits would yield precise and effective data to aid those with upper GI symptoms and conditions.

Can FLIP guide therapy in idiopathic esophagogastric junction outflow obstruction?

BACKGROUND: Esophagogastric junction outflow obstruction (EGJOO) has a variable disease course. Currently, barium swallow (BaS) and manometric parameters are used to characterize clinically significant EGJOO. The esophagogastric junction distensibility index (EGJ-DI) measured via functional lumen imaging probe (FLIP) can provide complementary information. Our aim was to assess symptom response in patients with EGJOO and an abnormal EGJ-DI after botulinum toxin (BT) treatment. METHODS: A prospective cohort study of adults with idiopathic EGJOO was performed from September 2019 to March 2021. Patients with dysphagia underwent upper endoscopy with FLIP. If the EGJ-DI was abnormally low, BT was injected. Data examined included demographics, medical history, endoscopic and FLIP findings, BaS, manometry, and Eckardt score (ES). ES improvement was assessed via paired samples t-test. Pearson's chi-square tests were used to assess for associations. RESULTS: Of the 20 patients, 75% had an abnormal EGJ-DI and underwent BT injections. Mean ES for patients with abnormal EGJ-DIs significantly improved from baseline to 1, 3, and 6 month follow-up (P-values: 0.01, 0.05, and 0.02, respectively). There was a significant association between an abnormal EGJ-DI with delayed bolus transit and presence of rapid drink challenge panesophageal pressurization on manometry: P = 0.03 and P = 0.03. CONCLUSION: This prospective study revealed that an abnormal EGJ-DI can guide BT as assessed via symptomatic response. Additionally, abnormal EGJ-DI measurements were significantly associated with other parameters used previously to determine clinically relevant EGJOO. Larger follow-up studies are warranted to further elucidate guidance for therapy in EGJOO.

Scleroderma and the Esophagus.

The gastrointestinal tract is the second largest organ system in the body and is often affected by connective tissue disorders. Scleroderma is the classic rheumatologic disease affecting the esophagus; more than 90% of patients with scleroderma have esophageal involvement. This article highlights esophageal manifestations of scleroderma, focusing on pathogenesis, clinical presentation, diagnostic considerations, and treatment options. In addition, this article briefly reviews the esophageal manifestations of other key connective tissue disorders, including mixed connective tissue disease, myositis, Sjogren syndrome, systemic lupus erythematosus, fibromyalgia, and Ehlers-Danlos syndrome.

Evaluating the Impact of Cost on the Treatment Algorithm for Chronic Idiopathic Constipation: Cost-Effectiveness Analysis.

INTRODUCTION: Chronic idiopathic constipation (CIC) is a common and burdensome illness. We performed a cost-effectiveness analysis of the US Food and Drug Administration-approved CIC drugs to evaluate and quantify treatment preferences compared with usual care from insurer and patient perspectives. METHODS: We evaluated the subset of patients with CIC and documented failure of over-the-counter (OTC) osmotic or bulk-forming laxatives. A RAND/UCLA consensus panel of 8 neurogastroenterologists informed model design. Treatment outcomes and costs were defined using integrated analyses of registered clinical trials and the US Centers for Medicare and Medicaid Services-supported cost databases. Quality-adjusted life years (QALYs) were calculated using health utilities derived from clinical trials. A 12-week time horizon was used. RESULTS: With continued OTC laxatives, CIC-related costs were $569 from an insurer perspective compared with $3,154 from a patient perspective (considering lost wages and out-of-pocket expenses). CIC prescription drugs increased insurer costs by $618-$1,015 but decreased patient costs by $327-$1,117. Effectiveness of CIC drugs was similar (0.02 QALY gained/12 weeks or ∼7 healthy days gained/year). From an insurer perspective, prescription drugs (linaclotide, prucalopride, and plecanatide) seemed less cost-effective than continued OTC laxatives (incremental cost-effectiveness ratio >$150,000/QALY gained). From a patient perspective, the cost-effective algorithm started with plecanatide, followed by choosing between prucalopride and linaclotide starting at the 145-µg dose (favoring prucalopride among patients whose disease affects their work productivity). The patient perspective was driven by drug tolerability and treatment effects on quality of life. DISCUSSION: Addressing costs at a policy level has the potential to enable patients and clinicians to move from navigating barriers in treatment access toward truly optimizing treatment choice.

Eosinophilic esophagitis: updates on key unanswered questions.

Eosinophilic esophagitis (EoE) is a clinicopathologic disease characterized by symptoms of esophageal dysfunction and esophageal eosinophilia. In the last decade, there has been a dramatic increase in its prevalence for reasons that are not completely understood. The underlying pathophysiology involves an antigen-mediated TH 2 immune response that draws eosinophils to the esophagus, causing mucosal inflammation, esophageal remodeling, and fibrosis. This ultimately leads to esophageal dysfunction that most commonly manifests as dysphagia. In this review, we will discuss updates on key questions regarding the diagnosis and treatment of EoE.

The functional lumen imaging probe in gastrointestinal disorders: the past, present, and future.

The functional lumen imaging probe (FLIP) is a diagnostic tool that utilizes impedance planimetry to allow the assessment of luminal diameter and distensibility. It has been used primarily in esophageal diseases, in particular, in the assessment of achalasia, esophagogastric junction outflow obstruction, and eosinophilic esophagitis (EoE). The usage and publications have increased over the past decade and it is now an essential tool in the armamentarium of the esophagologist. Indications are emerging outside of the esophagus, in particular with regard to gastroparesis. Our paper will review the history of FLIP, optimal current usage, data for key esophageal disorders (including achalasia, reflux, and EoE), data for nonesophageal disorders, and our sense as to whether FLIP is ready for prime time, as well as gaps in evidence and suggestions for future research.

Mucosal impedance for esophageal disease: evaluating the evidence.

Impedance has traditionally been employed in esophageal disease as a means to assess bolus flow and reflux episodes. Recent and ongoing research has provided new and novel applications for this technology. Measurement of esophageal mucosal impedance, via either multichannel intraluminal impedance catheters or specially designed endoscopically deployed impedance catheters, provides a marker of mucosal integrity. Mucosal impedance has been shown to segregate gastroesophageal reflux disease (GERD) and eosinophilic esophagitis from non-GERD controls and may play a role in predicting response to reflux intervention. More data are needed with regard to other esophageal subgroups, outcome studies, and functional disease. Our paper reviews the history of impedance in esophageal disease, the means of assessing baseline and mucosal impedance, data with regard to the newly developed mucosal impedance probes, the clinical utility of mucosal impedance in specific clinical conditions, and limitations in our existing knowledge, along with suggestions for future studies.

Low Yield of Cross-Sectional Imaging in Patients With Esophagogastric Junction Outflow Obstruction.

Esophagogastric junction outflow obstruction (EGJOO) is an abnormal finding on high-resolution manometry (HRM) characterized by an elevated median integrated relaxation pressure with some intact peristalsis.1 EGJOO is associated with heterogeneous symptoms, disease course, and response to treatment.1-4 It can be idiopathic or secondary with causes including malignancy, infiltrative disease, or structural etiology.1,3 Therefore, Chicago Classification of Esophageal Motility Disorders version 3.0 (CC v3.0) states a finding of EGJOO should prompt further investigation with cross-sectional imaging (CSI): endoscopic ultrasound (EUS) or computed tomography (CT) scan. However, there are limited data on the added yield of CSI to conventional modalities, namely esophagogastroduodenoscopy (EGD) and barium esophagram (BE). In previous studies, yield was small or unspecified.2,5-8 The aim of this study was to examine the yield of CSI for diagnosing secondary causes of EGJOO.

Popular Remedies for Esophageal Symptoms: a Critical Appraisal.

PURPOSE OF REVIEW: Popular remedies are of ongoing interest to patients experiencing common esophageal symptoms, particularly as typical pharmacologic interventions have been subject to increased scrutiny. Herein we summarize the available data regarding potential risks and benefits of several such remedies. RECENT FINDINGS: With emphasis on reflux and non-cardiac chest pain, research is ongoing into the clinical utility and diverse physiologic mechanisms underlying a variety of complementary and alternative modalities, including dietary manipulation, apple cider vinegar, melatonin, acupuncture, and various herbal products (rikkunshito, STW 5, slippery elm, licorice, and peppermint oil, among others). A substantial gap persists between anecdotal and empirical understandings of the majority of non-pharmacologic remedies for esophageal symptoms. This landscape of popular treatments nevertheless raises several interesting mechanistic hypotheses and compelling opportunities for future research.