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BACKGROUND: Olorinab is a highly selective, peripherally acting, full agonist of cannabinoid receptor 2. This study assessed the efficacy and safety of olorinab to treat abdominal pain in patients with irritable bowel syndrome with diarrhea (IBS-D) and constipation (IBS-C). METHODS: CAPTIVATE was a phase 2b, randomized, double-blind, placebo-controlled, parallel-group trial. Eligible participants aged 18-70 years with IBS-C and IBS-D diagnosed per Rome IV received olorinab 10 mg, 25 mg, or 50 mg three times daily (TID) or placebo TID for 12 weeks. The primary endpoint was the change in patient-reported average abdominal pain score (AAPS) from baseline to Week 12. KEY RESULTS: A total of 273 participants were randomized to receive olorinab 10 mg (n = 67), olorinab 25 mg (n = 67), olorinab 50 mg (n = 69), or placebo (n = 70). Although a treatment response was observed across all groups, the weekly change in average AAPS from baseline to Week 12 was not significantly different between placebo and any olorinab dose. In a prespecified subgroup analysis of participants with a baseline AAPS ≥6.5, olorinab 50 mg (n = 35) significantly improved AAPS compared with placebo (n = 30) (p = 0.014). Adverse event rates were comparable between olorinab and placebo and there were no reported serious adverse events or deaths. CONCLUSION AND INFERENCES: Although olorinab was well-tolerated and improved weekly AAPS, the primary endpoint was not met. However, in participants with moderate-to-severe pain at baseline (AAPS ≥6.5), olorinab 50 mg significantly improved weekly AAPS compared with placebo. CLINICALTRIALS: gov: NCT04043455. ispartof: NEUROGASTROENTEROLOGY AND MOTILITY vol:35 issue:5 ispartof: location:England status: published

BACKGROUND Abdominal pain is a bothersome and lifestyle limiting symptom in patients with functional bowel disorders. It is associated with decreased quality of life in affected individuals, as well as significant annual healthcare expenditure. Knowledge of specific factors that predict improvement in abdominal pain in those with functional bowel disorders is thus far limited. METHODS Consecutive patients presenting for outpatient care at a major academic medical center between October 2017 and March 2020 completed an electronic symptom survey prior to initial clinic visit, and again after 3 months. The Rome IV questionnaires for functional dyspepsia, irritable bowel syndrome, functional constipation, and functional diarrhea were all included. Additionally, all subjects completed the Patient Reported Outcomes Measurement Information System Anxiety, Depression, and sleep disturbance questionnaires. Patients with a diagnosis of a Rome IV functional gastrointestinal disorder without any organic cause for symptoms were identified based on both chart review as well as survey response data. Univariable and multivariable analysis was used to assess predictors of improved abdominal pain after 3 months. KEY RESULTS 180 patients with a mean age of 45.3 years were included in the final analysis. 78.3% of patients were female, and 77.2% met Rome IV criteria for irritable bowel syndrome. On multivariable analysis, improvement in constipation and diarrhea were both independent predictors of improved abdominal pain after 3 months. CONCLUSIONS AND INFERENCES Improvement in constipation and diarrhea both predicted improvement in abdominal pain, suggesting that addressing these factors is central to the management of abdominal pain in functional gastrointestinal disorders.

BACKGROUND Abdominal bloating is common in functional gastrointestinal disorders (FGID). To better characterize this patient population, we evaluated clinical and psychological characteristics of bloating and analyzed their differences by bloating severity. METHODS Patients with FGIDs evaluated at a single academic outpatient referral gastroenterology clinic were surveyed. Bloating severity was classified as minimal, moderate or severe. Symptom-specific questionnaires were used to evaluate bowel habits, abdominal bloating, depression, anxiety, somatization and sleep disturbance. Associations between bloating severity, clinical characteristics and FGID subtypes were analyzed in univariate and multivariate modeling. KEY RESULTS Of 612 FGID patients included (78% female, mean age of 44 ± 16.5 years), bloating was reported as minimal in 231(37.8%), moderate in 217(35.4%), or severe in 164(26.8%). Patients with severe bloating were more likely to be female, younger, and have co-existing functional dyspepsia than those with minimal bloating (p

Background Recurring abdominal pain is a characteristic and often unpredictable and debilitating symptom of irritable bowel syndrome with diarrhea (IBS‐D). Measuring the effects of IBS‐D treatments on abdominal pain remains a significant challenge in clinical trials. Here, we aimed to examine the effect of eluxadoline through various post hoc analyses. Methods Data from two eluxadoline Phase 3 trials were pooled over 26 weeks, comparing eluxadoline 100 mg twice daily to placebo. Worst abdominal pain (WAP) was measured daily on a 0‐10 scale. WAP responder criteria were prospectively defined as a ≥30% improvement in daily WAP score on ≥50% of days. Pairwise, two‐sided Cochran‐Mantel‐Haenszel tests assessed treatment effects. Cumulative distribution functions were used to plot WAP response rates using variations on the response criteria. Key results Of 1615 patients with IBS‐D (66% female, mean age 46 years), 806 received eluxadoline and 809 received placebo; 48.3% and 44.0% were WAP responders (≥30% improvement), respectively (P value not significant). When the response threshold was increased to 50% daily WAP improvement from baseline, a significantly greater percentage of eluxadoline‐treated patients versus placebo‐treated patients were WAP responders (38.7% vs 32.5%, respectively; P = .009). At Week 26, average WAP changes from baseline were −3.4 and −3.0 points, respectively (P = .002). Conclusions and Inferences Despite small effect sizes, eluxadoline demonstrated consistent and sustained improvement in WAP compared to placebo across a range of prospective and post hoc analyses. Assessing WAP response across a range of measures is important for fully understanding a treatment's efficacy., Pooled data, cumulative distribution function: percentage of patients who were worst abdominal pain responders based on achieving various levels of pain improvement compared to baseline over weeks 1‐26, while keeping the ≥50% of days criterion constant.

Background This manuscript summarizes consensus reached by the International Anorectal Physiology Working Group (IAPWG) for the performance, terminology used, and interpretation of anorectal function testing including anorectal manometry (focused on high‐resolution manometry), the rectal sensory test, and the balloon expulsion test. Based on these measurements, a classification system for disorders of anorectal function is proposed. Methods Twenty‐nine working group members (clinicians/academics in the field of gastroenterology, coloproctology, and gastrointestinal physiology) were invited to six face‐to‐face and three remote meetings to derive consensus between 2014 and 2018. Key recommendations The IAPWG protocol for the performance of anorectal function testing recommends a standardized sequence of maneuvers to test rectoanal reflexes, anal tone and contractility, rectoanal coordination, and rectal sensation. Major findings not seen in healthy controls defined by the classification are as follows: rectoanal areflexia, anal hypotension and hypocontractility, rectal hyposensitivity, and hypersensitivity. Minor and inconclusive findings that can be present in health and require additional information prior to diagnosis include anal hypertension and dyssynergia. Conclusions and Inferences This framework introduces the IAPWG protocol and the London classification for disorders of anorectal function based on objective physiological measurement. The use of a common language to describe results of diagnostic tests, standard operating procedures, and a consensus classification system is designed to bring much‐needed standardization to these techniques., This document summarizes consensus reached by the International Anorectal Physiology Working Group (IAPWG) for the performance of anorectal function testing and introduces a consensus classification for disorders of anorectal function based on objective, physiological measurement.

Background Functional gastrointestinal disorders (FGIDs) are among the most common outpatient diagnoses in pediatric primary care and gastroenterology. There is limited data on the inpatient burden of childhood FGIDs in the USA. The aim of this study was to evaluate the inpatient admission rate, length of stay (LoS), and associated costs related to FGIDs from 1997 to 2009. Methods We analyzed the Kids’ Inpatient Sample Database (KID) for all subjects in which constipation (ICD-9 codes: 564.0–564.09), abdominal pain (ICD-9 codes: 789.0–789.09), irritable bowel syndrome (IBS) (ICD-9 code: 564.1), abdominal migraine (ICD-9 code: 346.80 and 346.81) dyspepsia (ICD-9 code: 536.8), or fecal incontinence (ICD-codes: 787.6–787.63) was the primary discharge diagnosis from 1997 to 2009. The KID is the largest publicly available all-payer inpatient database in the USA, containing data from 2 to 3 million pediatric hospital stays yearly. Key Results From 1997 to 2009, the number of discharges with a FGID primary diagnosis increased slightly from 6 348 537 to 6 393 803. The total mean cost per discharge increased significantly from $6115 to $18 058 despite the LoS remaining relatively stable. Constipation and abdominal pain were the most common FGID discharge diagnoses. Abdominal pain and abdominal migraine discharges were most frequent in the 10–14 year age group. Constipation and fecal incontinence discharges were most frequent in the 5–9 year age group. IBS discharge was most common for the 15–17 year age group. Conclusions & Inferences Hospitalizations and associated costs in childhood FGIDs have increased in number and cost in the USA from 1997 to 2009. Further studies to determine optimal methods to avoid unnecessary hospitalizations and potentially harmful diagnostic testing are indicated.

Summary Background Irritable bowel syndrome (IBS) is one of the most common out-patient diagnoses in primary care and gastroenterology. There are limited data on the rate and costs associated with in-patient discharges for IBS. Aim To estimate the incidence and costs of hospital discharges for IBS in the United States. Methods We analysed the National Inpatient Sample database for all subjects in which IBS (ICD-9 code: 564.1) was the principal discharge diagnosis from 1997 to 2010. The National Inpatient Sample contains data from approximately 8 million hospital stays each year. Our findings reflected patient and hospital characteristics like geographical region and bed size. Results In 1997, there were 11 433 patients with a principal discharge diagnosis of IBS as compared to 12 842 in 2010 (P > 0.9, GoF test). The mean length of stay for IBS also remained the same between 1997 and 2010 at 3.7 ± 0.1 days. However, during this period, the mean hospital charges per hospitalization increased by 207.8% from $6873 ± 198 in 1997 to $21 153 ± 598 in 2010 (P

SummaryBackground While the Crohn's disease activity index (CDAI) is the gold standard for defining clinical endpoints in Crohn's disease (Crohn's) clinical trials, its ability to distinguish symptoms due to inflammation from those that are non-inflammatory has been questioned. Aim To compare CDAI scores in patients with Crohn's and those with Irritable Bowel Syndrome (IBS). Methods This was a prospective, cross-sectional cohort study of 91 patients with either Crohn's (n = 44) or IBS (n = 47). Total CDAI and individual component scores were recorded and comparisons were made between Crohn's and IBS patients. Results Mean CDAI scores were higher in the IBS patients (183 vs. 157, P = 0.1). Sixty-two per cent (n = 29) of IBS patients had CDAI scores greater than 150. Mean CDAI haematocrit score (35.9 vs. 23.0, P = 0.02) and CRP level (6.8 vs. 2.0, P = 0.002) were higher in the Crohn's group. Analysis of CDAI sub-scores demonstrated that IBS patients had significantly higher pain (mean 1.7 vs. 0.8, P = 0.0007) and well-being scores (mean 1.2 vs. 0.8, P = 0.04) relative to patients with Crohn's. Specifically evaluating patients with CDAI greater than 150 (n = 51), IBS patients had higher pain sub-scores (mean 2.4 vs. 1.4, P = 0.002), whereas patients with Crohn's had higher CRP (mean 8.4 vs. 1.8, P = 0.001). Conclusions Our study demonstrates that the CDAI does not discriminate patients with symptoms due to active Crohn's from patients with IBS. Patients with IBS can have CDAI scores in the clinically meaningful range. Objective measures, such as CDAI haematocrit score and CRP, are more specific markers of inflammation.

Chronic constipation (CC) is widely prevalent in the Western world, with a significant negative impact on quality of life, yet new and effective pharmacological and non-pharmacological treatment options have only recently emerged. The article by Tack and colleagues in the current issue of NGM is timely with the recent introduction of the serotonin type 4 receptor agonist prucalopride in Europe and wider acceptance of anorectal biofeedback for patients with pelvic floor dyssynergia. This Editorial (i) highlights the importance of identifying patients with pelvic floor dysfunction who are candidates for pelvic floor retraining programs and (ii) discusses the potential limitations of the 5-HT4 agonist, prucalopride, as an early option in the treatment algorithm for CC.

Aliment Pharmacol Ther 2010; 32: 1275–1291 Summary Background There is uncertainty about how to measure patient-reported outcomes (PROs) in IBS. The Food and Drug Administration (FDA) emphasizes that PROs must be couched in a conceptual framework, yet existing IBS PROs were not based on such a framework. Aim To perform qualitative analyses to inform a new conceptual framework for IBS symptoms. Methods Following FDA guidance, we searched the literature for extant IBS questionnaires. We then performed interviews in IBS patients to learn about the illness experience in their own words. We cultivated vocabulary to inform a conceptual framework depicted with domains, sub-domains, and item categories, per FDA guidance. Results We identified 13 questionnaires with items encompassing 18 symptoms. We recruited 123 IBS patients for cognitive interviews. Major themes included: pain and discomfort are different – asking about discomfort is nonspecific and should be avoided in future PROs; bowel urgency is multifaceted – PROs should measure bowel immediacy, controllability, and predictability; and PROs should divide bloating into how it feels vs. how it looks. Symptom experience may be determined by 35-item categories within five domains: (i) pain; (ii) gas/bloat; (iii) diarrhoea; (iv) constipation; and (v) extraintestinal symptoms. Conclusions We applied FDA guidance to develop a framework that can serve as the foundation for developing a PRO for IBS clinical trials.

Aliment Pharmacol Ther 2010; 32: 1192–1202 Summary Background Although irritable bowel syndrome (IBS) is a multisymptom disorder, abdominal pain drives illness severity more than other symptoms. Despite consensus that IBS trials should measure pain to define study entry and determine efficacy, the optimal method of measuring pain remains uncertain. Aim To determine whether combining information from multiple pain dimensions may capture the IBS illness experience more effectively than the approach of measuring ‘pain predominance’ or pain intensity alone. Methods Irritable bowel syndrome patients rated dimensions of pain, including intensity, frequency, constancy, predominance, predictability, duration, speed of onset and relationship to bowel movements. We evaluated the impact of each dimension on illness severity using multivariable regression techniques. Results Among the pain dimensions, intensity, frequency, constancy and predictability were strongly and independently associated with illness severity; the other dimensions had weaker associations. The clinical definition of ‘pain predominance’, in which patients define pain as their most bothersome symptom, was insufficient to categorize patients by illness severity. Conclusions Irritable bowel disease pain is multifaceted; some pain dimensions drive illness more than others. IBS trials should measure various pain dimensions, including intensity, constancy, frequency and predictability; this may improve upon the customary use of measuring pain as a unidimensional symptom in IBS.

Aliment Pharmacol Ther 2010; 32: 29–42 Summary Background There appears to be a significant placebo response rate in clinical trials for gastro-oesophageal reflux disease. Little is known about the determinants and the circumstances associated with placebo response in the treatment of gastro-oesophageal reflux disease (GERD). Aims To estimate the magnitude of the placebo response rate in randomized controlled trials for GERD and to identify factors that influence this response. Methods A meta-analysis of randomized, double-blind, placebo-controlled trials, published in English language, which included >20 patients with GERD, treated with either a proton pump inhibitor or H2-receptor antagonist for at least 2 weeks. Medline, Cochrane and EMBASE databases were searched, considering only studies that reported a global response for ‘heartburn’. Results A total of 24 studies included 9989 patients with GERD. The pooled odds ratio (OR) for response to active treatment vs. placebo was 3.71 (95% CI: 2.78–4.96). The pooled estimate of the overall placebo response was 18.85% (range 2.94%–47.06%). Patients with erosive oesophagitis had a non-significantly lower placebo response rate than patients without it (11.87% and 18.31%, respectively; P = 0.246). Placebo response was significantly lower in studies of PPI therapy vs. studies of H2 RAs (14.51% vs. 24.69%, respectively; P = 0.05). Conclusions The placebo response rate in randomized controlled trials for GERD is substantial. A lower placebo response was associated with the testing of PPIs, but not the presence of erosive oesophagitis.

Background and objective Helicobacter pylori infects the mucus layer of the human stomach and causes peptic ulcers and adenocarcinoma. We have previously shown that H. pylori accumulates photoactive porphyrins making the organism susceptible to inactivation by light, and that small spot endoscopic illumination with violet light reduced bacterial load in human stomachs. This study assessed the feasibility and safety of whole-stomach intra-gastric violet phototherapy for the treatment of H. pylori infection. Study design/materials and methods A controlled, prospective pilot trial was conducted using a novel light source consisting of laser diodes and diffusing fibers to deliver 408-nm illumination at escalating total fluences to the whole stomach. Eighteen adults (10 female) with H. pylori infection were treated at three U.S. academic endoscopy centers. Quantitative bacterial counts were obtained from biopsies taken from the antrum, body, and fundus, and serial urea breath tests. Results The largest reduction in bacterial load was in the antrum (>97%), followed by body (>95%) and fundus (>86%). There was a correlation between log reduction and initial bacterial load in the antrum. There was no dose-response seen with increasing illumination times. The urea breath test results indicated that the bacteria repopulated in days following illumination. Conclusion Intra-gastric violet light phototherapy is feasible and safe and may represent a novel approach to eradication of H. pylori, particularly in patients who have failed standard antibiotic treatment. This was a pilot study involving a small number of patients. Further research is needed to determine if phototherapy can be effective for eradicating H. pylori.

Summary Background A genetic contribution has been proposed for irritable bowel syndrome (IBS) and gastro-oesophageal reflux disease (GERD), but is controversial. No twin data exist for dyspepsia. Aim To determine the relative contribution of genetic factors in GERD, dyspepsia (upper abdominal pain) and IBS. Methods A total of 986 twin pairs (from initial mail-out response 51%). Both members completed validated symptom and psychological questionnaires; 481 monozygotic pairs [mean (s.d.) age 53 ± 5.8 years] and 505 dizygotic pairs (mean age 54 ± 5.6 years). Results Prevalence of IBS, dyspepsia and GERD was 12%, 10% and 20%, respectively. Polychoric correlation for monozygotic twins for IBS (0.47) and GERD (0.44) were both substantially larger than those for dizygotic twins (0.17 and −0.37, respectively). Polychoric correlation was slightly lower in monozygotic than dizygotic twins for dyspepsia. Genetic modelling confirmed the independent additive genetic effects in GERD and IBS but not dyspepsia. Estimates of genetic variance were 22% for IBS, 13% for GERD and 0% for dyspepsia, but adjusting for anxiety and depression removed the statistical significance for IBS and GERD. Conclusions There is a genetic contribution to GERD and IBS but not dyspepsia; this may be mediated by the hereditability of anxiety and depression.

Background: Despite the apparent high placebo response rate in randomized placebo-controlled trials (RCT) of patients with irritable bowel syndrome (IBS), little is known about the variability and predictors of this response. Objectives: To describe the magnitude of response in placebo arms of IBS clinical trials and to identify which factors predict the variability of the placebo response. Methods: We performed a meta-analysis of published, English language, RCT with 20 or more IBS patients who were treated for at least 2 weeks. This analysis is limited to studies that assessed global response (improvement in overall symptoms). The variables considered as potential placebo modifiers were study design, study duration, use of a run-in phase, Jadad score, entry criteria, number of office visits, number of office visits/study duration, use of diagnostic testing, gender, age and type of medication studied. Findings: Forty-five placebo-controlled RCTs met the inclusion criteria. The placebo response ranged from 16.0 to 71.4% with a population-weighted average of 40.2%, 95% CI (35.9–44.4). Significant associations with lower placebo response rates were fulfilment of the Rome criteria for study entry (P = 0.049) and an increased number of office visits (P = 0.026). Conclusions: Placebo effects in IBS clinical trials measuring a global outcome are highly variable. Entry criteria and number of office visits are significant predictors of the placebo response. More stringent entry criteria and an increased number of office visits appear to independently decrease the placebo response.

Background Attention to and perception of physical sensations and somatic states can significantly influence reporting of complaints and symptoms in the context of clinical care and randomized trials. Although anxiety and high neuroticism are known to increase the frequency and severity of complaints, it is not known if other personality dimensions or genes associated with cognitive function or sympathetic tone can influence complaints. Genetic variation in catechol-O-methyltransferase (COMT) is associated with anxiety, personality, pain, and response to placebo treatment. We hypothesized that the association of complaint reporting with personality might be modified by variation in the COMT val158met genotype. Methods We administered a standard 25-item complaint survey weekly over 3-weeks to a convenience sample of 187 irritable bowel syndrome patients enrolled in a placebo intervention trial and conducted a repeated measures analysis. Results We found that complaint severity rating, our primary outcome, was negatively associated with the personality measures of conscientiousness (β = −0.31 SE 0.11, P = 0.003) and agreeableness (β = −0.38 SE 0.12, P = 0.002) and was positively associated with neuroticism (β = 0.24 SE 0.09, P = 0.005) and anxiety (β = 0.48 SE 0.09, P

BACKGROUND The epidemiology of chronic constipation (CC) skews toward female predominance, yet men make up an important component of those suffering from CC. We sought to determine whether there are sex-specific differences in symptoms and physiologic parameters on anorectal manometry (ARM). METHODS We performed a case-control analysis of sequential men and age-matched women (2:1 ratio) presenting for ARM as part of the evaluation of CC. We collected physiologic parameters derived from 3D high-resolution ARM in addition to the ROME III constipation module and the Pelvic Floor Distress Inventory 20 (PFDI-20) questionnaires. We analyzed univariate, sex-specific differences in ARM physiologic parameters and PFDI-20 parameters and adjusted for putative confounders using multivariate logistic regression. KEY RESULTS Our study enrolled 80 men and 165 age-matched women. Men had a higher median sphincter resting pressure (81.2 vs 75.2 mm Hg, P=.01) and mean squeeze pressure (257.0 vs 170.5 mm Hg, P

Background Dyssynergic defecation (DD) results from inadequate relaxation of the pelvic floor on attempted defecation. The prevalence of DD in patients with chronic constipation (CC) is not certain. Aims of this study are to estimate the prevalence of abnormal findings associated with DD across testing modalities in patients referred for physiological testing for CC. Methods Systematic search of MEDLINE, EMBASE and PUBMED databases were conducted. We included full manuscripts reporting DD prevalence in CC, and specific findings at pelvic floor diagnostic tests. Random effects models were used to calculate pooled DD prevalences (with 95% CI) according to individual tests and specific findings. Key Results A total of 79 studies on 7581 CC patients were included. The median prevalence of any single abnormal finding associated with DD was 37.2%, ranging from 14.9% (95% CI 7.9–26.3) for absent opening of the anorectal angle (ARA) on defecography to 52.9% (95% CI 44.3–61.3) for a dyssynergic pattern on ultrasound. The prevalence of a dyssynergic pattern on manometry was 47.7% (95% CI 39.5–56.1). The prevalence of DD was similar across specialty and geographic area as well as when restricting to studies using Rome criteria to define constipation. Conclusions & Inferences Dyssynergic defecation is highly prevalent in CC and is commonly detected across testing modalities, type of patient referred, and geographical regions. We believe that the lower prevalence of findings associated with DD by defecography supports use of manometry and balloon expulsion testing as an initial evaluation for CC.

Background Our objective was to evaluate the performance of the Food and Drug Administration (FDA) Responder Endpoint for clinical trials in IBS-C, using data from two large Phase 3 clinical trials of linaclotide. The FDA interim endpoint requires that, for 50% of trial weeks, patients report ≥30% decrease in Abdominal Pain at its worst and (in the same week) an increase in Complete Spontaneous Bowel Movements (CSBMs) of ≥1 from baseline. Methods Anchor-based methodology was used to estimate thresholds of clinically meaningful change using symptom-specific patient rating of change questions (PRCQs) and symptom severity questions. The diagnostic accuracy of the FDA Responder Endpoint was assessed using sensitivity/specificity-based methods. Key Results Using anchor-based methods, the estimates of the clinically meaningful improvement thresholds for Abdominal Pain ranged from 25.9% to 32.4% and thresholds for increase in weekly CSBM rate ranged from 1.4 to 1.6 CSBMs per week. Compared with the symptom-specific PRCQs for patient rating of relief, the FDA Responder Endpoint has a sensitivity of 60.7%, a specificity of 93.5%, and an accuracy of 82.0%. Changing the number of weeks required to be a responder or the percentage improvement in the Abdominal Pain criteria did not result in notable improvement in the accuracy of the FDA Responder Endpoint. Conclusions & Inferences The FDA Responder Endpoint for IBS-C clinical trials represents clinically meaningful improvements in IBS-C symptoms for patients with excellent specificity and reasonable sensitivity.