An Overview of the Effects of Tenapanor on Visceral Hypersensitivity in the Treatment of Irritable Bowel Syndrome with Constipation.

Background: Patients with irritable bowel syndrome with constipation (IBS-C) experience persistent abdominal pain, a common symptom leading to greater healthcare utilization and reports of treatment non-response. Clinically significant improvements in abdominal pain were observed in clinical trials of tenapanor, a first-in-class inhibitor of sodium/hydrogen exchanger isoform 3 (NHE3), for the treatment of IBS-C in adults. Aim: This narrative review reports the current knowledge about visceral hypersensitivity as a mechanism for abdominal pain in patients with IBS-C and explores the published evidence for hypothesized mechanisms by which tenapanor may reduce visceral hypersensitivity leading to the observed clinical response of decreased abdominal pain. Findings: Abdominal pain is experienced through activation and signaling of nociceptive dorsal root ganglia that innervate the gut. These sensory afferent neurons may become hypersensitized through signaling of transient receptor potential cation channel subfamily V member 1 (TRPV1), resulting in reduced action potential thresholds. TRPV1 signaling is also a key component of the proinflammatory cascade involving mast cell responses to macromolecule exposure following permeation through the intestinal epithelium. Indirect evidence of this pathway is supported by observations of higher pain in association with increased intestinal permeability in patients with IBS. Tenapanor reduces intestinal sodium absorption, leading to increased water retention in the intestinal lumen, thereby improving gastrointestinal motility. In animal models of visceral hypersensitivity, tenapanor normalized visceromotor responses and normalized TRPV1-mediated nociceptive signaling. Conclusion: By improving gastrointestinal motility, decreasing intestinal permeability and inflammation, and normalizing nociception through decreased TRPV1 signaling, tenapanor may reduce visceral hypersensitivity, leading to less abdominal pain in patients with IBS-C. Therapies that have demonstrated effects on visceral hypersensitivity may be the future direction for meaningful abdominal pain relief for patients with IBS-C.

Plecanatide Improves Abdominal Bloating and Bowel Symptoms of Irritable Bowel Syndrome with Constipation.

BACKGROUND: Bloating is a bothersome symptom in irritable bowel syndrome with constipation (IBS-C). AIM: To evaluate plecanatide efficacy in patients with IBS-C stratified by bloating intensity. METHODS: Pooled phase 3 data (2 randomized, controlled IBS-C trials) from adults treated with plecanatide 3 mg or placebo for 12 weeks were analyzed. Patients were stratified post-hoc by baseline bloating severity (11-point scale: mild [≤ 5] and moderate-to-severe [> 5]). Assessments included change from baseline in bloating, abdominal pain, and complete spontaneous bowel movement (CSBM) frequency. Abdominal pain and bloating composite responders were defined as patients with ≥ 30% improvement from baseline in both bloating and abdominal pain at Week 12. RESULTS: At baseline, 1104/1436 patients with IBS-C (76.9%) reported moderate-to-severe bloating. In the moderate-to-severe bloating subgroup, plecanatide significantly reduced bloating severity versus placebo (least-squares mean change [LSMC]: - 1.7 vs - 1.3; P = 0.002), reduced abdominal pain (- 1.7 vs - 1.3; P = 0.006), and increased CSBM frequency (1.4 vs 0.8; P < 0.0001). In the mild bloating subgroup, significant improvements were observed with plecanatide versus placebo for abdominal pain (LSMC: - 1.3 vs - 1.0; P = 0.046) and CSBM frequency (2.0 vs 1.2; P = 0.003) but not bloating (- 0.9 vs - 0.8; P = 0.28). A significantly greater percentage of patients were abdominal pain and bloating composite responders with plecanatide versus placebo (moderate-to-severe bloating: 33.6% vs 26.8% [P = 0.02]; mild bloating: 38.4% vs 27.2% [P = 0.03]). CONCLUSION: Plecanatide treatment improved IBS-C abdominal and bowel symptoms, including in those who present with moderate-to-severe bloating.

Management of Constipation in Hospitalized Patients.

Constipation is frequently encountered in hospital settings and can have potentially serious consequences yet is often underrecognized and undertreated. Opioid-induced constipation is a common cause of constipation in hospitalized patients. Opioids induce constipation through agonistic effects on enteric µ-opioid receptors. This review aims to provide insight on the identification and management of constipation in inpatient settings, with a particular focus on opioid-induced constipation. Constipation assessment should be routinely initiated at hospital admission and can be facilitated by thorough symptom assessments; relevant patient history, including recent medication use; physical examination; and patient assessment tools developed to evaluate the impact of constipation. Management of opioid-induced constipation should begin with ensuring adequate hydration and electrolyte balance and encouraging patient mobilization. Other treatments may include laxatives, enemas, intestinal secretagogues, peripherally acting µ-opioid receptor antagonists, and manual disimpaction. Surgical intervention may be required for some patients as a salvage therapy in severe, refractory cases.

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.

Rifaximin Treatment for Individual and Multiple Symptoms of Irritable Bowel Syndrome With Diarrhea: An Analysis Using New End Points.

PURPOSE: Rifaximin is indicated for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults. The current aim was to evaluate rifaximin efficacy on individual and composite IBS-D symptoms using definitions not previously examined. METHODS: Phase III post hoc analyses of two randomized, double-blind, placebo-controlled trials and the open-label phase of a randomized, double-blind, placebo-controlled trial were conducted. Adults with IBS-D received a 2-week course of rifaximin 550 mg TID. Individual and composite responses for abdominal pain (mean weekly improvements from baseline of ≥30%, ≥40%, or ≥50%), bloating (mean weekly improvements from baseline of ≥1 or ≥2 points; or ≥30%, ≥40%, or ≥50%), stool consistency (mean weekly average stool consistency score <3 or <4), and urgency (improvement from baseline of ≥30% or ≥40% in percentage of days with urgency) for ≥2 of the first 4 weeks after treatment, and weekly for 12 weeks, were assessed. FINDINGS: Overall, 1258 patients from the double-blind trials (rifaximin [n = 624]; placebo [n = 634]) and 2438 from an open-label trial were analyzed. The percentage of bloating or urgency responders was significantly greater with double-blind rifaximin versus placebo (P ≤ 0.03). A significantly greater percentage of the double-blind group were composite abdominal pain and bloating responders versus placebo for all thresholds analyzed (P < 0.05). A significantly greater percentage of the double-blind group were tri-symptom composite end point responders (abdominal pain, bloating, and fecal urgency) versus placebo (P = 0.001). A significantly greater percentage of patients achieved response (≥30% composite tri-symptom threshold) with double-blind rifaximin versus placebo as early as 1 week posttreatment, with significance maintained through ≥5 weeks after treatment. Open-label results were consistent with those of the double-blind study. IMPLICATIONS: Rifaximin significantly improved multiple, concurrent IBS-D symptoms, using clinically relevant definitions of treatment response. Using a novel tri-symptom composite end point (ie, abdominal pain, bloating, fecal urgency), adults with IBS-D treated with a 2-week course of rifaximin were significantly more likely to be composite end point responders than those receiving placebo (≥30% or ≥40% threshold) for the three symptoms. Thus, rifaximin not only met current standard thresholds used for adjudication of responders in clinical trials but also achieved higher thresholds for many of these symptoms, suggesting potential for even more robust clinical improvements. CLINICALTRIALS: gov identifiers: NCT00731679, NCT00724126, and NCT01543178.

Nutrient Drink Test to Assess Gastric Accommodation in Cyclic Vomiting Syndrome: Single-blinded Parallel Grouped Prospective Study.

Background/Aims: Cyclic vomiting syndrome (CVS) is characterized by episodes of nausea and vomiting, separated by symptom-free intervals. The pathogenesis of CVS is poorly understood. Limited data exist on evaluating impaired gastric accommodation as a mechanistic means for symptoms. We aim to determine if CVS patients demonstrate impaired gastric accommodation applying a nutrient drink test (NDT) protocol. Methods: Through this single-blinded pilot clinical trial, patients with CVS per Rome IV critera and healthy controls were assessed for presence of impaired gastric accommodation by administering an established NDT protocol. Statistical analysis was performed, with data presented as medians and interquartile range. Results: Eleven CVS patients and 15 healthy controls participated in the study between January 2018 and October 2018. Median age was 42.0 years and 37.0 years; majority of subjects were female, 72.7% and 73.3%, respectively. Demographics were similar between CVS and healthy controls. Almost all healthy controls (93.3%) ingested the complete 500 mL protocol, whereas a smaller proportion (72.7%) were able to complete all 4 doses in the CVS group (P = 0.188). Post-prandial visual analogue scale scores of nausea and abdominal pain were found to be significantly higher in CVS patients compared to healthy controls. Conclusions: To our knowledge, this is the first NDT protocol in CVS evaluating the role of impaired gastric accommodation and hypersensitivity as a possible pathophysiologic mechanism. Findings from this study suggest the presence of gastric hypersensitivity in a subset of CVS patients. These results provide the foundational data necessary for future larger testing of NDT and diagnostic accuracy in CVS.

Gallbladder Dyskinesia.

Gallbladder dyskinesia is a functional disorder of the gastrointestinal tract, which can result in debilitating episodes of abdominal pain and associated symptoms. Key diagnostic criteria include a diminished gallbladder ejection fraction on scintigraphy and absence of other causes for the symptoms. Pathologic findings and follow-up suggest a distinct mechanistic basis for this condition. Unfortunately, the complexities of diagnosis and treatment combined with patient and provider preferences will likely continue to preclude randomized controlled studies to provide a clearer evidence-based management for this disorder. Patients meeting the clinical and diagnostic criteria for gallbladder dyskinesia should be referred for cholecystectomy, and most of these patients will have relief of their symptoms. A comprehensive preoperative discussion on expected outcomes needs to take place.

Episodic Memories Among Irritable Bowel Syndrome (IBS) Patients: An Important Aspect of the IBS Symptom Experience.

Objective: Some IBS patients possess detailed memories of the events surrounding their bowel symptom onset ("episodic memories"). In this exploratory study we sought to: (1) examine memory relationship with gastrointestinal (GI) symptom severity, extraintestinal symptoms, and mood; (2) qualitatively explore memory valence and content in IBS patients with or without episodic memories. Methods: Referral IBS patients n = 29; age 47.0± 2.2 years, 79.3% female) enrolled in this cross-sectional, mixed methods research study. Participants completed validated specific memory instruments [Autobiographical Memory Test (AMT), Sentence Completion for Events from the Past Test (SCEPT)] and relevant questionnaires [IBS symptoms 10-cm visual analog scale); SF-36 Health-related quality of life (HRQOL); Perley-Guze and PHQ-15/12: somatization; Beck Depression/Anxiety Inventories). Qualitative analysis examined the content and valence of general memories. Results: 14/29 (48.3%) of IBS subjects endorsed episodic memories of IBS symptom onset, often GI infections/enteritis (35.7%). Recall of the exact year (69%) and month (60%) of symptom onset were common. Episodic memories were associated with greater IBS symptom severity/bother, higher anxiety/depression, and poorer HRQOL. Though AMT and SCEPT memory specificity were not different based on episodic memories, overgeneralization to negatively-valenced cues in the AMT was associated with more severe IBS in those without episodic memory. Qualitative analysis revealed no observable differences in topic focus of IBS patients with and without episodic memories. Conclusions: IBS patients often endorse episodic memories associated with symptom onset, and this recall seems to associate with more severe symptoms. Overgeneralization responses to negative stimuli may lead to worse bowel symptoms in those without episodic memories. IBS memory specificity may associate with qualitative differences in processing psychosocial experiences and might be important to IBS pathophysiology.

A Narrative Review of Irritable Bowel Syndrome with Diarrhea: A Primer for Primary Care Providers.

Irritable bowel syndrome with diarrhea (IBS-D) is a chronic disorder of gut-brain interaction, characterized by recurrent abdominal pain in association with more frequent, loose stools. The pathophysiology of irritable bowel syndrome (IBS) includes disordered gut motility, alterations in gut microbiota, neural-hormonal system abnormalities, immune reactivity, and visceral hypersensitivity. Timely diagnosis of IBS-D can be achieved easily using clinical criteria. Formal IBS diagnosis is important for optimizing treatment and patient outcomes and facilitating patient access to appropriate educational resources. Yet, given the symptom overlap with other gastrointestinal conditions, diagnosis of IBS-D often is perceived to be challenging. Treatment of IBS includes both nonpharmacologic and pharmacologic options. Rifaximin, alosetron, and eluxadoline are effective treatments indicated for IBS-D, but have limited availability internationally. Dietary approaches may also be indicated for certain patients with IBS-D. Psychological interventions may be effective in treating abdominal pain alone and global symptoms in IBS. We describe use of these diverse therapies and provide an overview to facilitate the primary care provider's approach to distinguishing IBS-D from other conditions with symptom overlap.

Emerging therapies in the management of Irritable Bowel Syndrome (IBS).

INTRODUCTION: Irritable bowel syndrome (IBS) is a symptom-based disorder of chronic abdominal pain and altered bowel habits. The pathogenesis of IBS is multifactorial, leading to the potential for the development of diverse treatment strategies. This mechanistic heterogeneity suggests that available therapies will only prove effective in a subset of IBS sufferers. Current US Food and Drug Administration (FDA) approved therapies for IBS with diarrhea (IBS-D) and IBS with constipation (IBS-C) are reviewed. Limited symptom responses and side effect experiences lead to considerable patient dissatisfaction with currently available IBS treatments. Only a small percentage of IBS patients are on prescription therapies underscoring the potential market and need for additional therapeutic options. AREAS COVERED: Expanding on currently available therapies, the serotonergic and endogenous opioid receptor systems continue to be a focus of future IBS treatment development. Additional novel emerging therapies include the endogenous cannabinoid system, bile acid secretion and sequestration, and exploit our enhanced understanding of visceral sensory signaling and intestinal secretomotor function. EXPERT OPINION: While challenges remain for the future development of IBS therapies, the diverse etiologies underlying the disorder present an opportunity for novel therapies. Hence, great potential is anticipated for future IBS treatment options.

Mechanisms of Action of Current Pharmacologic Options for the Treatment of Chronic Idiopathic Constipation and Irritable Bowel Syndrome With Constipation.

Multiple therapeutic agents are currently available for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation. A better understanding of the mechanism of action of each treatment provides important insights into expected responses and is key to optimizing treatment outcomes. Some constipation treatments, such as stimulant laxatives, may increase bowel movement frequency but are ineffective at relieving, and may even exacerbate, abdominal symptoms. On the contrary, prescription treatments, such as the guanylyl cyclase-C agonists, for example, may improve bowel symptoms and reduce visceral hypersensitivity. This review summarizes the mechanisms of action of commonly used over-the-counter and prescription therapies for chronic idiopathic constipation and irritable bowel syndrome with constipation, outlining how these mechanisms contribute to the efficacy and safety of each treatment option.

Real-World Treatment Strategies to Improve Outcomes in Patients With Chronic Idiopathic Constipation and Irritable Bowel Syndrome With Constipation.

Chronic idiopathic constipation and irritable bowel syndrome with constipation are complex, overlapping conditions. Although multiple guidelines have informed healthcare providers on appropriate treatment options for patients with chronic idiopathic constipation and irritable bowel syndrome with constipation, little direction is offered on treatment selection. First-line treatment options usually include fiber and over-the-counter osmotic laxatives; however, these are insufficient for many individuals. When these options fail, prescription secretagogues (plecanatide, linaclotide, lubiprostone, and tenapanor [pending commercial availability]), or serotonergic agents (prucalopride and tegaserod) are generally preferred. Individuals experiencing concurrent abdominal pain and/or bloating may experience greater overall improvements from prescription therapies because these agents have been proven to reduce concurrent abdominal and bowel symptoms. Should initial prescription treatments fail, retrying past treatment options (if not adequately trialed initially), combining agents from alternative classes, or use of adjunctive therapies may be considered. Given the broad spectrum of available agents, therapy should be tailored by mutual decision-making between the patient and practitioner. Overall, patients need to be actively monitored and managed to maximize clinical outcomes.

Tegaserod: What's Old Is New Again.

Irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) are common gastrointestinal disorders imposing considerable impact on the quality of life and well-being of affected individuals. A paucity of evidence-based treatment options exist for CIC and IBS-C sufferers. Tegaserod, a 5-HT4 agonist, has a substantial body of preclinical and clinical study evidence to support its beneficial role in modulating sensorimotor function of the luminal gastrointestinal tract. Tegaserod was first approved for use by the U.S. Food and Drug Administration for the management of IBS-C and CIC in 2002 and 2004, respectively. Tegaserod enjoyed a successful uptake in the management of these disorders during its first several years of availability in the United States, but was later withdrawn from the market in 2007 over concerns related to adverse cardiovascular events. Since then, additional safety data has been generated, and following a resubmission and review by the Food and Drug Administration, in April 2019, tegaserod was once again approved for use in IBS-C under a more restricted labeling, confining use to women under 65 years of age without heart disease or additional cardiovascular risk factors. This review summarizes the regulatory journey of tegaserod and details the existing pharmacokinetic, physiologic, clinical, and safety data of tegaserod generated over the last 2 decades. The discussion also examines the future of tegaserod in the treatment of these constipation disorders, as well as its potential role in other related disorders of brain-gut interaction.

The Digital Rectal Examination: Appropriate Techniques for the Evaluation of Constipation and Fecal Incontinence.

Disorders of defecation, including constipation and fecal incontinence, are very common. The digital rectal examination (DRE) is a key component in the early evaluation of patients with these complaints. Confident performance of a DRE requires dedicated training for the clinician and hands-on experience with the technique. DRE can yield a diagnostic accuracy comparable to specialized physiologic tests, including anorectal manometry. This review will describe in detail the steps required to perform a thorough DRE evaluation, as well as the proper interpretation of observations. Thereafter, the current evidence-based findings supporting the value of DRE in defecatory disorders will be summarized.

Perceived sleep quality mediates the relationship between posttraumatic stress and somatic symptoms.

OBJECTIVE: Posttraumatic stress symptoms (PTSS) have been associated with increased somatic symptom expression. Sleep concerns have been associated with PTSS and somatic symptoms. Previous research suggests that sleep affects multiple domains of functioning including comorbid psychological and physical health concerns. The current study examines whether perceived sleep quality or sleep efficiency/duration may be mediating the relationship between PTSS and somatic symptoms in a trauma-exposed sample. METHOD: The sample consisted of 864 students, recruited from a large Midwestern university and compensated with research participation credit. Data were collected online over approximately 39 months (October 2015 through January 2019), and the pertinent scales examined in this study included Pittsburgh Sleep Quality Index, Posttraumatic Stress Disorder Checklist for Diagnostic and Statistical Manual of Mental Disorders, fifth edition, and Screening for Somatoform Symptoms-7. RESULTS: Of the 864 students, 668 participants identified as female (77.3%) and 540 identified as non-Hispanic White (62.5%), with an overall average age of 23.14 years (SD = 6.64). Mediation analyses indicated that the overall model examining global sleep quality complaints as a mechanism of the relationship between PTSS and somatic symptoms was significant, F(3, 860) = 193.97, R² = .40, p < .001, and that perceived sleep quality was found to be the only significant specific mediator (indirect effect = .21). Although females reported greater somatic severity, PTSS, and sleep concerns, models were significant, even after examining the influence of gender. CONCLUSIONS: Global sleep complaints are associated with both PTSS and somatic symptoms. Perceived sleep quality specifically mediated the relationship between PTSS and somatic symptoms, highlighting a potential intervention for improving physical health consequences in trauma-exposed individuals. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Increased Risk of Advanced Colonic Adenomas and Timing of Surveillance Colonoscopy Following Solid Organ Transplantation.

BACKGROUND: Detection and removal of colonic adenomatous polyps (CAP) decreases colorectal cancer (CRC) development, particularly with more or larger polyps or polyps with advanced villous/dysplastic histology. Immunosuppression following solid organ transplantation (SOT) may accelerate CAP development and progression compared to average-risk population but the benefit of earlier colonoscopic surveillance is unclear. AIMS: Study the impact of maintenance immunosuppression post-SOT on developmental timing, multiplicity and pathological features of CAP, by measuring incidence of advanced CAP (villous histology, size ≥ 10 mm, ≥ 3 polyps, presence of dysplasia) post-SOT and the incidence of newly diagnosed CRC compared to average-risk age-matched population. METHODS: Single-center retrospective cohort study of SOT recipients. RESULTS: 295 SOT recipients were included and were compared with 291 age-matched average-risk controls. The mean interval between screening and surveillance colonoscopies between SOT and control groups was 6.3 years vs 5.9 years (p = 0.13). Post-SOT maintenance immunosuppression mean duration averaged 59.9 months at surveillance colonoscopy. On surveillance examinations, SOT recipients exhibited more advanced (≥ 10 mm) adenomas compared to matched controls (9.2% vs. 3.8%, p = 0.034; adjusted OR 2.38; 95% CI 1.07-5.30). CONCLUSION: SOT recipients appear at higher risk for developing advanced CAP, suggesting that earlier surveillance should be considered.