Opioids and the Gastrointestinal Tract: The Role of Peripherally Active µ-Opioid Receptor Antagonists in Modulating Intestinal Permeability.

Opioid receptors are found throughout the gastrointestinal tract, including the large intestine. Many patients treated with opioids experience opioid-induced constipation (OIC). Laxatives are not effective in most patients, and in those who do initially respond, the efficacy of laxatives generally diminishes over time. In addition, OIC does not spontaneously resolve for most patients. However, complications of opioids extend far beyond simply slowing gastrointestinal transit. Opioid use can affect intestinal permeability through a variety of mechanisms. Toll-like receptors are a crucial component of innate immunity and are tightly regulated within the gut epithelium. Pathologic µ-opioid receptor (MOR) and toll-like receptor signaling, resulting from chronic opioid exposure, disrupts intestinal permeability leading to potentially harmful bacterial translocation, elevated levels of bacterial toxins, immune activation, and increased cytokine production. Peripherally active MOR antagonists, including methylnaltrexone, are effective at treating OIC. Benefits extend beyond simply blocking the MOR; these agents also act to ameliorate opioid-induced disrupted intestinal permeability. In this review, we briefly describe the physiology of the gastrointestinal epithelial border and discuss the impact of opioids on gastrointestinal function. Finally, we consider the use of peripherally active MOR antagonists to treat disrupted intestinal permeability resulting from opioid use and discuss the potential for improved morbidity and mortality in patients treated with methylnaltrexone for opioid-induced bowel disorders.

Virtual Reality Improves Symptoms of Functional Dyspepsia: Results of a Randomized, Double-Blind, Sham-Controlled, Pilot Study.

INTRODUCTION: We investigated the efficacy and safety of virtual reality (VR) for functional dyspepsia. METHODS: Patients were randomized 2:1 between active vs sham VR. Symptoms were assessed using the Patient Assessment of Gastrointestinal Disorders-Symptom Severity Index (PAGI-SYM) over 2-week. RESULTS: Patients in the active VR group had greater numerical improvement in PAGI-SYM scores (mean difference -0.7; P < 0.001) compared with sham VR (mean difference -0.4; P = 0.032). Active VR led to significant improvements for all PAGI-SYM subscales, except lower abdominal pain, whereas sham only improved heartburn/regurgitation and nausea/vomiting. Half of the total patients reported nonserious adverse effects, although only 1 patient withdrew from the study because of adverse effects. DISCUSSION: VR is safe and results in significant symptom improvement in functional dyspepsia. Larger trials are warranted.

Irritable bowel syndrome - less irritable, or better treatments?

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.

Gastroparesis: time for a paradigm change.

PURPOSE OF REVIEW: Gastroparesis (GP) is a syndrome defined by symptoms and delayed gastric emptying in the absence of mechanical obstruction. Typical symptoms include nausea, vomiting, abdominal pain, and early satiety. Only one medication is currently FDA-approved for the treatment of GP. This review highlights recent research findings pertaining to GP and provides evidence to support a change in the current GP diagnostic and treatment paradigm. RECENT FINDINGS: An analysis of GP trials over the past four decades demonstrates the power of placebo and the need to perform longer studies with clearly defined patient populations. Two studies highlight the need to evaluate patients with suspected GP carefully and to perform gastric emptying studies properly. The misdiagnosis of GP symptoms is reviewed, preceded by a discussion of whether GP should be considered a disorder of gut-brain interaction. Finally, new data on therapies that target the pylorus are highlighted. SUMMARY: Gastroparesis is frequently over-diagnosed and incorrectly diagnosed. Performing a proper gastric emptying study which adheres to standard protocol, and accurately interpreting the results in the context of the individual patient, are critical to making an accurate diagnosis of GP. The treatment paradigm needs to shift from simply aiming to accelerate gastric emptying to treating global symptoms of a chronic syndrome that may represent gut-brain dysfunction in many patients.

Updates in functional dyspepsia and bloating.

PURPOSE OF REVIEW: Functional dyspepsia and bloating are common gastrointestinal conditions that frequently lead to gastroenterology referral. Both disorders have a significant negative impact on patients' quality of life and the healthcare system. The purpose of this review is to highlight important new findings in the cause, pathophysiology and treatment of these two disorders. RECENT FINDINGS: Confocal laser endomicroscopy identified changes in epithelial barrier structure and function, providing important insights into the development of functional dyspepsia symptoms when combined with new observations of localized duodenal inflammation. Changes in the gut microbiome may be responsible for functional dyspepsia symptoms in some patients and may respond to gut-selective antibiotics. New data from the NIH-sponsored Gastroparesis Consortium confirmed that functional dyspepsia and gastroparesis are not distinct disorders but rather exist on a spectrum. Virtual reality may be a new therapeutic option for the treatment of functional dyspepsia. A novel questionnaire was developed and validated to assess symptoms, prevalence and impact in patients with bloating and distension. A meta-analysis identified medications to treat symptoms of bloating in patients with irritable bowel syndrome and constipation. SUMMARY: Advances in our understanding of the pathophysiology of functional dyspepsia and bloating are leading to important changes in medical therapies.

Diagnostic Evaluation of Gastric Motor and Sensory Disorders.

Disorders of gastric motor and sensory function affect 10%-20% of the world's population and adversely impact nutrition, quality of life, work productivity, and health care costs. Classifying these disorders can be challenging given the heterogeneity of symptom presentation, the presence of symptoms unexplained by endoscopic, radiographic and/or laboratory evaluation, and overlap with other luminal gastrointestinal disorders. Accurately diagnosing these highly prevalent disorders relies upon an understanding of epidemiology and risk factors, the ability to take a careful clinical history focused on symptoms, and the presence of predisposing medical, surgical, and psychological conditions. A variety of diagnostic studies are now available to assess gastric motor function and identify maladaptive relaxation, accommodation, and abnormal sensation. FDA-approved treatment options are limited and thus many patients undergo a series of empirical treatment trials that target individual symptoms, often without much benefit. This article provides updated recommendations for identifying and classifying the most common gastric motor and sensory disorders using currently accepted diagnostic tests, and provides a brief supplemental overview on treatment options. "Things sweet to taste prove in digestion sour." -Shakespeare, Richard II, 1595.

Gastroparesis.

PURPOSE OF REVIEW: This review highlights recent research advances regarding the pathophysiology and treatment of gastroparesis. RECENT FINDINGS: Differences in brain activity have been identified on functional MRI imaging in gastroparesis patients with nausea. Abdominal pain is common in patients with gastroparesis and does not correlate with the severity of gastric emptying delay, though may be associated with depression and anxiety. Autonomic dysfunction may play an important role in the pathophysiology of gastroparesis. There is increasing sentiment that gastroparesis should be considered a part of the same spectrum of gastric neuromuscular disorders. The risk of tardive dyskinesia with metoclopramide has likely been significantly overestimated historically. Endoscopic BoTox injection of the pylorus and gastric electrical stimulation remain controversial treatments for gastroparesis. New, highly selective 5-hydroxytryptamine 4 (5-HT4) agonists appear safe and may be effective in improving symptoms of gastric emptying. Long-term data assessing the use of gastric peroral endoscopic myotomy (G-POEM) for the treatment of refractory gastroparesis suggest durable clinical improvement. SUMMARY: Altered central processing and autonomic dysfunction may be important factors in the pathogenesis of gastroparesis. While the risk of tardive dyskinesia appears much lower than historically advertised, there is increasing hope for novel therapeutics with the advent of new 5-HT4 agonists, neurokinin-1 receptor (N1KR) antagonists, and G-POEM.

Diagnosing Small Intestinal Bacterial Overgrowth: A Comparison of Lactulose Breath Tests to Small Bowel Aspirates.

BACKGROUND: Duodenal aspiration (DA) and lactulose breath tests (LBT) are commonly performed to diagnose small intestinal bacterial overgrowth (SIBO). There are no data directly comparing these tests. AIMS: To investigate the agreement between DA and LBT for the diagnosis of SIBO. METHODS: A retrospective cohort study of adult patients who underwent a LBT and a DA at a tertiary care center over 9 years was assembled. LBT was considered positive if the hydrogen baseline or peak change measurement was ≥ 20 ppm, and/or if the methane baseline or peak change was ≥ 10 ppm. DA was considered positive if > 100,000 cfu/mL of gram-negative flora was identified on culture, and contaminated if > 100,000 cfu/mL of gram-positive flora was identified. RESULTS: A total of 106 patients were evaluated; 81 (76.4%) were female; the mean age was 53.4 ± 15.9 years. 21 patients (19.8%) had evidence of contamination on DA. 14 (16.5%) patients had a positive DA result. Patients with diabetes mellitus and those with PPI use were more likely to have a positive DA (94.4% vs. 71.4%, p = 0.007; 62% vs. 28.6%, p = 0.021, respectively). 33 (31.1%) patients had a positive LBT. Patients with a history of small bowel resection were more likely to have a positive LBT (12.1% vs. 1.4%, p = 0.016). DA and LBT results agreed in 54 patients (63.5%; kappa = - 0.02), indicating poor agreement. CONCLUSIONS: The agreement between LBT and DA in evaluation for SIBO was poor. LBT may be favorable to DA, as LBT is safer, cheaper, and less likely to yield a contaminant result.

Gastroparesis and functional dyspepsia: different diseases or different ends of the spectrum?

PURPOSE OF REVIEW: This review assesses the relationship between gastroparesis and functional dyspepsia, in light of recent research assessing cause, pathophysiology and treatment. RECENT FINDINGS: The Gastroparesis Cardinal Symptom Index (GCSI) lacks the ability to readily distinguish functional dyspepsia from gastroparesis based on symptoms. Although prior studies found that the extent of delay in gastric emptying did not accurately predict severity of symptoms, when optimally measured, delayed gastric emptying may in fact correlate with gastroparesis symptoms. Enteric dysmotility may be an important risk factor for gastroparesis. Altered central processing may play a role in symptom generation for both gastroparesis and functional dyspepsia based on functional brain MRI. Treatment directed towards reducing low-grade inflammation and improving mucosal barrier function in the duodenum may represent a novel therapeutic target for functional dyspepsia, whereas gastric peroral endoscopy myotomy (G-POEM) remains a promising intervention for refractory gastroparesis. SUMMARY: Abnormalities on functional MRI of the brain have been identified in patients with functional dyspepsia and gastroparesis. Small bowel dysmotility and duodenal barrier dysfunction have been implicated in the pathophysiology of gastroparesis and functional dyspepsia, respectively. New treatments for functional dyspepsia may target low-grade duodenal inflammation and barrier dysfunction. The pylorus remains a target in gastroparesis.

Jackhammer Esophagus After Lung Transplantation: Results of a Retrospective Multicenter Study.

GOALS: We sought to determine the incidence of jackhammer esophagus (JE) after lung transplantation (LT) and identify potential risk factors for the development of JE after LT. BACKGROUND: JE is a rare esophageal motility disorder, and its pathophysiology remains unclear. Lung transplantation has been implicated as a potential risk factor for JE, but the incidence of JE after LT is unknown. STUDY: A retrospective cohort of adult patients who underwent LT at 2 tertiary care centers over 7.5 years was reviewed. Analysis was performed on patients who underwent a high-resolution esophageal manometry (EM) study before and after LT. JE was defined according to the latest Chicago classification, version 3.0. RESULTS: A total of 57 patients without JE identified on pre-LT EM also underwent an EM study after LT. Fifteen (25.4%) were found to have new JE after LT. Patients with newly diagnosed JE after LT were older (61.3±5.3 y vs. 51.6±15.6 y; P=0.02) and more often had chronic obstructive pulmonary disease (COPD; 47.6% vs. 16.6%; P=0.03) compared with those without COPD. There was a trend toward increased risk for JE among female individuals (60% vs. 33.3%; P=0.07) and those with shorter surgical anastomosis times (75.8±12.2 min vs. 84.4±14.3; P=0.06). There was no significant difference between body mass index, opioid use, pretransplant EM findings, surgical ischemic time, occurrence of gastroparesis, or measured post-LT outcomes between the 2 groups. CONCLUSIONS: JE occurs not uncommonly in patients after LT. Older age and COPD pre-LT may be significant risk factors.

Colonic Stool Burden a Useful Surrogate for Slow Transit Constipation as Determined by a Radiopaque Transit Study.

OBJECTIVES: Plain film abdominal x-ray (AXR) is frequently used in the evaluation of constipation, but studies assessing the association between stool burden on AXR and colonic transit have been limited. We sought to investigate the relationship between colonic stool burden and slow transit constipation, as determined by a radiopaque marker (ROM) transit study. METHODS: A retrospective cohort population was assembled, consisting of adult patients with chronic constipation who underwent testing with both a ROM study and anorectal manometry at 2 tertiary care centers over 5 years. Stool burden was graded by 2 independent observers, with colonic transit being assessed by the Hinton method. RESULTS: Of 361 patients, 145 (40.3%) had slow transit constipation, and women were more likely than men to have slow transit constipation (42.3% vs 26.5%, P = 0.04). The mean stool burden scores by observer 1 and observer 2 for patients with slow transit constipation were significantly higher than the mean stool burden scores for patients with normal transit constipation (8.1 ± 1.6 vs 6.9 ± 1.9, P < 0.0001; 8.5 ± 1.5 vs 5.8 ± 1.6, P < 0.0001). The Pearson correlation coefficient for the stool burden score and number of remaining ROMs was 0.31 (moderate) for observer 1 (P < 0.0001) and 0.62 (strong) for observer 2 (P < 0.0001), whereas the Pearson correlation coefficient for interrater reliability of the stool burden score was 0.58 (P < 0.0001), indicating a strong correlation. The ideal score cutoff for both observers was 7, with moderate agreement by Cohen's kappa (0.43, P < 0.0001). CONCLUSIONS: Stool burden assessment on AXR may be a reliable alternative ROM study in the assessment of colonic transit.

Practical Perspectives in the Treatment of Nausea and Vomiting.

Nausea and vomiting result from complex interactions between afferent and efferent pathways of the gastrointestinal tract, central nervous system, and autonomic nervous system. Afferent pathways from the vagus nerve, vestibular system, and chemoreceptor trigger zone project to nucleus tractus solitarius, which in turn relays signals to the central pattern generator to initiate multiple downstream pathways resulting in symptoms of nausea and vomiting. There is increasing evidence that the central pathway of chronic nausea is different from that of acute nausea and vomiting-and closely resembles that of neuropathic pain. This improved understanding of chronic nausea has resulted in a paradigm shift with regard to management strategy. Although conventional therapies such as antiemetics and prokinetics are commonly used to manage acute nausea and vomiting, they are historically not as effective in treating chronic nausea. Recently, neuromodulator agents, such as tricyclic antidepressants, gabapentin, olanzapine, mirtazapine, and benzodiazepines, and cannabinoids have been shown to be efficacious in the treatment of nausea and vomiting, and may be useful in the treatment of chronic symptoms. There is a need to study these agents, especially in the management of chronic functional nausea. Improved understanding of the central and peripheral circuitry of nausea and vomiting symptoms will allow for enhanced utilization of the currently available medications, and the development of novel therapeutic options.

A Comparison of the Rate of Gastrointestinal Bleeding in Patients Taking Non-Vitamin K Antagonist Oral Anticoagulants or Warfarin.

OBJECTIVES: Early reports suggested that the risk of gastrointestinal bleeding (GIB) was higher for patients on non-vitamin K antagonist oral anticoagulants (NOACs) than for those on warfarin. We compared the incidence of GIB in our patients on NOACs with those on warfarin. METHODS: We used our VA pharmacy database to identify patients taking NOACs (dabigatran, rivaroxaban, and apixaban) or warfarin between January 2011 and June 2015, and used the VistA system to identify those who were hospitalized for GIB. We included only patients with clinically significant GIB, defined as documented GI blood loss with a hemoglobin drop ≥2 g/dl, hemodynamic instability, and/or need for endoscopic evaluation, angiography, or surgery. RESULTS: We identified 803 patients on NOACs and 6,263 on warfarin. One hundred and fifty-eight patients on warfarin had GIB (2.5%), compared with only five patients (0.6%) on NOACs (odds ratio=4.13; 95% confidence interval: 1.69-10.09). Blood transfusion for GIB was significantly more common in patients on warfarin than on NOACs (64.6% vs. 20%, P=0.04). Within 90 days of GIB hospitalization, 12 patients (7.6%) in the warfarin group died, whereas there were no deaths in the NOAC group. CONCLUSIONS: In our patients, the incidence of GIB for those on warfarin was more than four times that for those on NOACs. Blood transfusions for GIB were more common in warfarin patients, and no NOAC patients died of GIB. In contrast to early reports, our findings suggest that the risk of GIB and subsequent complications is considerably lower for patients on NOACs than for patients on warfarin.

Patent foramen ovale in liver transplant recipients does not negatively impact short-term outcomes.

AIM: Patent foramen ovale (PFO) is a common atrial septal defect that is largely asymptomatic and often undiagnosed. The impact of a PFO in patients undergoing liver transplantation (LT) is unknown. OBJECTIVE: Assess the impact of PFO and physiologic intrapulmonary shunt (IPS) on the perioperative outcomes of patients who underwent LT. METHODS: We performed a retrospective, intention-to-treat analysis of patients with PFO and controls without PFO who underwent LT at Mayo Clinic in Florida between 2008 and 2013. Patients with physiologic IPS were also analyzed. The cohorts were compared for baseline characteristics, length of stay in the intensive care unit (ICU), postoperative oxygen requirements, 30-d cerebrovascular accidents, and mortality. RESULTS: Of the 935 patients who underwent LT, 10.4% had proven PFO by pre-LT echocardiogram. Control patients (n = 101) were statistically older than PFO and IPS (n = 56) patients, but similar in sex, BMI, Model for End-stage Liver Disease score, American Society of Anesthesiologist score, and left ventricular ejection fraction. PFO and IPS patients had similar length of stay in the ICU, mechanical ventilation times, post-LT oxygen requirements, and 30-d mortality compared to controls. Subgroup analysis showed similar outcomes for large PFO and IPS patients to controls. CONCLUSIONS: The presence of PFO did not have a negative impact on perioperative LT outcomes.

Double-balloon enteroscopy and outcomes in patients older than 80.

BACKGROUND: double-balloon enteroscopy (DBE) is becoming more commonly used for investigation of small bowel pathology. Currently, there are limited data to describe its safety and efficacy in the population over age 65. AIM: to investigate the indications, findings and outcomes of DBE performed in patients older than 80, as well as the correlation between DBE and prior capsule endoscopy (CE) findings. METHODS: we retrospectively reviewed our large DBE database, including procedures from January 2006 to September 2012. Patients aged 80 or older at the time of DBE were included in the study. The indications, findings, outcomes and diagnostic yield of DBE were calculated by frequency analysis. RESULTS: two hundred and fifteen DBEs were performed in 130 patients aged 80 or older. The mean age was 83.6 ± 3.03 years (range: 80-94). Twelve patients (9.2%) were assigned an American Society of Anaesthesiologists score of II prior to procedure, 102 patients (78.4%) were assigned a score of III and 16 patients (12.3%) were given a score of IV. The most common indication for DBE was obscure gastrointestinal bleeding (N = 204, 94.9%). One hundred and fourteen patients (87.7%) underwent CE prior to DBE, and correlation between findings of CE and DBE occurred in 74.6% of these patients. The overall diagnostic yield of DBE was 77.2% (N = 166). There were no immediate post-procedural complications or failed procedures. CONCLUSION: DBE is a safe and effective technique for investigation of the small bowel in patients aged 80 and older. Age alone should not be a contraindication to performing DBE when clinically indicated.

Leaky Gut Syndrome: Myths and Management.

Leaky gut syndrome is a condition widely popularized in the lay literature, although it is not currently accepted as a formal medical diagnosis. Multiple gastrointestinal symptoms are ascribed to leaky gut syndrome, including diarrhea, bloating, distension, abdominal pain, and dyspeptic symptoms of early satiety, nausea, and postprandial fullness. The etiology and pathophysiology of leaky gut syndrome are multifactorial; a preceding gastrointestinal infection, inflammatory bowel disease, and certain medications may be relevant factors in some patients. The diagnosis of leaky gut syndrome is problematic. Although patients are frequently informed that the diagnosis can be readily made using results from blood work or stool studies, no validated test currently exists to make this diagnosis. Patients report a variety of myths about the etiology, diagnosis, and treatment of leaky gut syndrome, which can cause alarm and can frequently lead to expensive, unnecessary tests and unproven, sometimes dangerous treatments. This article reviews some of the most common myths about leaky gut syndrome and provides data from the scientific literature to correct these statements. Management strategies, based on data, are provided when available.