Review document of the Spanish Association of Neurogastroenterology and Motility on the management of opioid-induced constipation.

Opioid induced constipation is a rising problem due to the progressive increment in the prescription of opioids. By contrast to functional constipation, opioid-induced constipation is not a functional gut disorder, but a side effect of the use of opioids. Opioids produce constipation due to a decrease in gastrointestinal motility and a reduction in the gastrointestinal secretions. The treatment of OIC focuses on three basic pillars: optimizing opioid drug indication, preventing constipation onset, and treating it if it occurs. As with any other cause of constipation, lifestyle adjustments and laxatives should be the first-line treatment in the pharmacological management of OIC. Osmotic laxatives such as polyethylene glycol (PEG) are the agents of choice. PEG is inert and is neither fermented nor absorbed in the gastrointestinal tract. Furthermore, it has broad clinical applicability due to its favourable safety profile. If first-line treatments fail, peripheral mu receptor antagonists (PAMORA) are the drugs of choice. They reduce the peripheral effects of OIC with minimal potential to diminish analgesia or induce centrally mediated withdrawal syndrome. Different PAMORA are available in the market, both for oral and subcutaneous administration, with demonstrated efficacy for management of OIC in different clinical trials.

When symptoms are more than reflux.

45 year-old male patient with history of heartburn and regurgitation of non-acid food in the immediate postprandial period, with no symptomatic improvement after anti-acid treatment. The patient underwent an upper endoscopy that was unremarkable. A high-resolution impedance manometry (HRIM) was performed according to Chicago Protocol 4.0, as well as an additional solid test meal, with findings of rumination syndrome (RS) (figure 1). The study was completed with a 24-hour impedance pH monitoring that showed, in the immediate postprandial period, episodes of reflux that reached the proximal sensor followed by a normal swallow (figure 2). Abdominophrenic biofeedback was started with clinical improvement and anti-acid treatment was maintained at once a day. Discussion: RS is diagnosed by a complete clinical history, using the Rome IV or DSM-5 criteria (figure 3). Due to lack of knowledge of the disease and the fact that regurgitation can be present in other conditions including gastroesophageal reflux disease and achalasia, most patients undergo multiple tests and visit several physicians before reaching the diagnosis1. The gold standard investigation for RS, in cases where there are diagnostic doubts, is HRIM with solid meal administration, that shows a sudden increase in intragastric pressure > 30 mmHg concurrent with a drop in impedance and both simultaneous lower and upper esophageal sphincter relaxation, that may or may not be followed by re-swallowing food2. Rumination episodes can appear spontaneously (type 1) or may be preceded by a reflux episode (type 2) or a supragastric belch (type 3)3. 24-hour impedance pH monitoring cannot confirm de diagnosis, but during rumination, in the majority of episodes, the refluxed material reaches the proximal esophagus2.

Achalasia: diagnostic delay and manometric characteristics with high-resolution solid-state and perfusion equipment.

INTRODUCTION: The early diagnosis of achalasia requires a high degree of clinical suspicion, and delays in diagnosis are frequent. High-resolution oesophageal manometry (HRM) is the gold standard for its diagnostic confirmation. There are two HRM systems, perfusion and solid-state, which allow its classification into three subtypes: I, or classical; II, or with pan-oesophageal pressurization; and III, or spastic. OBJECTIVE: To determine the clinical and manometric characteristics of the three subtypes with high-resolution perfusion and solid-state equipment and the time of evolution until diagnosis. METHODS: This was a multicentre, observational, retrospective study of patients from the INTEGRA database of the Spanish Association of Neurogastroenterology and Motility who were diagnosed with primary achalasia confirmed by HRM, who fell under the Chicago Classification v3.0, and who had not been treated. RESULTS: The study included 110 patients (subtype I, N = 14; subtype II, N = 73; subtype III, N = 23). The HRM equipment was perfusion for 49 and solid-state for 61. The mean age was 61.8 ± 14 years (age range 44-81), the age was lower in subtype II, and the sex distribution was similar. The time of clinical evolution until diagnosis was > 12 months (51.6%), subtype II being the one that was diagnosed earlier and the most often (66.3%). Dysphagia was the most frequent symptom (90.5%). According to the comparative analysis by high-resolution perfusion and solid-state oesophageal manometry equipment, the baseline pressure of the lower oesophageal sphincter was higher in the solid-state oesophagus, but the difference was not statistically significant. The median integrated relaxation pressure at 4 seconds (IRP4) was similar (21 mmHg) between the perfusion and solid-state measurements. We describe the ranges of IRP4 in achalasia patients with both systems and confirm the possibility of achalasia even when IRP4 is within the normal range. CONCLUSIONS: Achalasia in our environment has a significant diagnostic delay. No significant differences were observed in the oesophagogastric junction between the two groups diagnosed with perfusion and solid-state equipment.

Asociación Española de Neurogastroenterología y Motilidad (ASENEM) updated review on the management of functional abdominal pain. / Documento de puesta al día de la Asociación Española de Neurogastroenterología y Motilidad (ASENEM) sobre el manejo del dolor abdominal funcional.

Functional abdominal pain is a disorder in which central and peripheral sensitization processes converge, leading to hypersensitivity and allodynia. Differential diagnosis is made with organic digestive, renal, gynecological, endocrine, or neurological diseases. Treatment should be individualized for each patient. In cases of debilitating pain, therapy combining drugs with different mechanisms of action can be initiated, while in less severe cases, therapy with a progressive introduction of drugs based on clinical response is advised. The first line includes general lifestyle advice and antispasmodic substances, like peppermint oil, anticholinergic/antimuscarinic, and calcium channels antagonists. In the second line of treatment, neuromodulating agents are added. Finally, when these measures fail, third-line treatments such as gabapentine and atypical antipsychotics are considered. Psychological interventions should be considered if specialized therapists are available to manage these disorders.

Development of a core outcome set for therapeutic studies in eosinophilic esophagitis (COREOS).

BACKGROUND: End points used to determine treatment efficacy in eosinophilic esophagitis (EoE) have evolved over time. With multiple novel therapies in development for EoE, harmonization of outcomes measures will facilitate evidence synthesis and appraisal when comparing different treatments. OBJECTIVE: We sought to develop a core outcome set (COS) for controlled and observational studies of pharmacologic and diet interventions in adult and pediatric patients with EoE. METHODS: Candidate outcomes were generated from systematic literature reviews and patient engagement interviews and surveys. Consensus was established using an iterative Delphi process, with items voted on using a 9-point Likert scale and with feedback from other participants to allow score refinement. Consensus meetings were held to ratify the outcome domains of importance and the core outcome measures. Stakeholders were recruited internationally and included adult and pediatric gastroenterologists, allergists, dieticians, pathologists, psychologists, researchers, and methodologists. RESULTS: The COS consists of 4 outcome domains for controlled and observational studies: histopathology, endoscopy, patient-reported symptoms, and EoE-specific quality of life. A total of 69 stakeholders (response rate 95.8%) prioritized 42 outcomes in a 2-round Delphi process, and the final ratification meeting generated consensus on 33 outcome measures. These included measurement of the peak eosinophil count, Eosinophilic Esophagitis Histology Scoring System, Eosinophilic Esophagitis Endoscopic Reference Score, and patient-reported measures of dysphagia and quality of life. CONCLUSIONS: This interdisciplinary collaboration involving global stakeholders has produced a COS that can be applied to adult and pediatric studies of pharmacologic and diet therapies for EoE and will facilitate meaningful treatment comparisons and improve the quality of data synthesis.

Practical approach to irritable bowel syndrome-diarrhea beyond low-FODMAP diet.

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by abdominal pain and altered defecation, usually accompanied by abdominal bloating or distension. The integrated model of bidirectional interaction between the central, autonomic, enteric nervous system, the microbiome, and the gut barrier allows a better understanding of the pathophysiology of IBS, as well as consideration of potential therapeutic strategies. IBS with predominant diarrhea (IBS-D) represents a therapeutic challenge. Dietary changes or restrictions are most commonly used by patients in an attempt at symptom control. Therefore, a number of diets, especially low-FODMAP diet, have increasingly gained interest as a therapy for IBS-D or mixed IBS. However, this kind of diet, while effective, is not exempt of problems. It is therefore necessary that other therapeutic options be considered while bearing pathophysiological mechanisms and general symptom management in mind.

Irritable bowel syndrome and basal serum tryptase: correlation between subtype, severity, and comorbidities. A pilot study.

INTRODUCTION: the activation of mast cells causes alterations in epithelial and neuromuscular function and is involved in visceral hypersensitivity and dysmotility in gastrointestinal functional disorders. OBJECTIVES: primary: to evaluate differences in basal serum tryptase (BST) between patients with irritable bowel syndrome (IBS) and healthy controls. Secondary: BST depending on IBS subtype (diarrhea: IBS-D; constipation: IBS-C), comorbidities and correlation with IBS severity and quality of life. MATERIAL AND METHODS: a prospective control-case study in IBS patients (Rome IV criteria). BST (ImmunoCAP-Phadia, Sweden®), IBS Severity Score (IBSSS), pain, bloating and flatulence analogue scales, IBS quality of life (IBSQOL), and patient health status (PHQ-9) were determined. BST is the primary variable to achieve the primary endpoint. RESULTS: thirty-two patients were included, 21 (65.6 %) with IBS-D and 11 (34.4 %) with IBS-C; 32 controls were also included. Mean IBSSSS: 326.6 (± 71.4), IBSQOL: 76 (± 20.3), and PHQ9: 10.2 (± 5.9). BST was 4.8 ± 2.6 in IBS and 4.7 ± 2.6 in controls (p = 0.875). There were no differences in BST between IBS subtypes (4.7 ± 2.9 in IBS-D and 5 ± 1.8 in IBS-C; p = 0.315) or IBS severity (p = 0.662). However, BST was higher in patients with IBS and extraintestinal comorbidities compared to other patients and controls (p = 0.029). This subgroup also has more severe bloating (p = 0.021). There was no correlation between BST, quality of life (p = 0.9260), and health status (p = 0.3985). CONCLUSION: BST does not discriminate between IBS patients and controls. However, BST was higher in patients with IBS with extraintestinal comorbidities, which had more severe bloating. This finding is worthy of investigation.

Budesonide Orodispersible Tablets Maintain Remission in a Randomized, Placebo-Controlled Trial of Patients With Eosinophilic Esophagitis.

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder. Swallowed topical-acting corticosteroids are effective in bringing active EoE into remission. However, it is not clear whether these drugs are effective for long-term maintenance of remission. METHODS: We performed a double-blind trial to compare the efficacy and safety of 2 dosages of a budesonide orodispersible tablet (BOT) vs placebo in maintaining remission of EoE. Maintenance of remission was defined as absence of clinical and histologic relapse and no premature withdrawal for any reason. Two hundred and four adults with EoE in clinical and histologic remission, from 29 European study sites, were randomly assigned to groups given BOT 0.5 mg twice daily (n = 68), BOT 1.0 mg twice daily (n = 68), or placebo twice daily (n = 68) for up to 48 weeks. RESULTS: At end of treatment, 73.5% of patients receiving BOT 0.5 mg twice daily and 75% receiving BOT 1.0 mg twice daily were in persistent remission compared with 4.4% of patients in the placebo group (P < .001 for both comparisons of BOT with placebo). Median time to relapse in the placebo group was 87 days. The frequency of adverse events was similar in the BOT and placebo groups. Morning serum levels of cortisol were in the normal range at baseline and did not significantly change during treatment. Four patients receiving BOT developed asymptomatic, low serum levels of cortisol. Clinically manifested candidiasis was suspected in 16.2% of patients in the BOT 0.5 mg group and in 11.8% of patients in the BOT 1.0 mg group; all infections resolved with treatment. CONCLUSIONS: In a phase 3 trial, up to 48 weeks of treatment with BOT (0.5 mg or 1.0 mg twice daily) was superior to placebo in maintaining remission of EoE. Both dosages were equally effective and well tolerated. EudraCT number; 2014-001485-99; ClinicalTrials.gov number, NCT02434029.

Diagnostic and therapeutic challenges in the management of obstructive defecation.

Chronic constipation is a very common disease in daily clinical practice with a significant deterioration in quality of life that increases when associated with obstructive defecation. For this reason, we believe that the case presented here can improve our knowledge of these problems.

Risk of COVID-19 transmission in esophageal, anorectal manometry and 24-hour impedance-pH monitoring.

BACKGROUND: the impact of the COVID-19 pandemic has led to the interruption of most manometry or impedance-pH monitoring studies. The risk of restarting activities is unknown. OBJECTIVE: assess the risk of SARS-CoV-2 virus infection, both to patients and healthcare workers, in relation to esophageal and anorectal functional tests during the pandemic without protective measures. METHOD: a questionnaire was designed to determine whether patients and healthcare workers had COVID-19, confirmed by either a test or compatible symptoms, after functional studies were performed from January until March 2020. RESULTS: the survey was answered by 263 (92.9 %) patients. Four (1.52 %) patients had confirmed COVID-19 in the two weeks after the functional test (adjusted rate 8.34 cases per 1,000 [95 % CI -0.06-16.74], OR 0.84 [95 % CI: 0.83-0.85], p < 0.001) and no patient after anorectal manometry. Another five had only compatible symptoms, for a total of nine patients (3.42 %) (adjusted rate 27.50 cases/1,000 [95 % CI: 7.27-47.74], OR 2.84 [95 % CI: 2.81-2.87]). In the total study period, 18.25 % had confirmed COVID-19 or compatible symptoms. The average number of days between the procedure and the first day of symptoms was progressively shortened (January: 56 days, February: 33 days, March: 10.5 days). Two of ten healthcare workers (20 %) had confirmed COVID-19. CONCLUSIONS: the risk of COVID-19 infection when performing functional tests is low and more related to the evolution of the pandemic rather than to the procedure itself. The small number of healthcare workers included in the study does not allow a definitive conclusion to be drawn on their risk of infection.

Efficacy of Budesonide Orodispersible Tablets as Induction Therapy for Eosinophilic Esophagitis in a Randomized Placebo-Controlled Trial.

BACKGROUND & AIMS: Swallowed topical-acting corticosteroids are recommended as first-line therapy for eosinophilic esophagitis (EoE). Asthma medications not optimized for esophageal delivery are sometimes effective, although given off-label. We performed a randomized, placebo-controlled trial to assess the effectiveness and tolerability of a budesonide orodispersible tablet (BOT), which allows the drug to be delivered to the esophagus in adults with active EoE. METHODS: We performed a double-blind, parallel study of 88 adults with active EoE in Europe. Patients were randomly assigned to groups that received BOT (1 mg twice daily; n = 59) or placebo (n = 29) for 6 weeks. The primary end point was complete remission, based on clinical and histologic factors, including dysphagia and odynophagia severity ≤2 on a scale of 0-10 on each of the 7 days before the end of the double-blind phase and a peak eosinophil count <5 eosinophils/high power field. Patients who did not achieve complete remission at the end of the 6-week double-blind phase were offered 6 weeks of open-label treatment with BOT (1 mg twice daily). RESULTS: At 6 weeks, 58% of patients given BOT were in complete remission compared with no patients given placebo (P < .0001). The secondary end point of histologic remission was achieved by 93% of patients given BOT vs no patients given placebo (P < .0001). After 12 weeks, 85% of patients had achieved remission. Six-week and 12-week BOT administration were safe and well tolerated; 5% of patients who received BOT developed symptomatic, mild candida, which was easily treated with an oral antifungal agent. CONCLUSIONS: In a randomized trial of adults with active EoE, we found that budesonide oral tablets were significantly more effective than placebo in inducing clinical and histologic remission. Eudra-CT number 2014-001485-99; ClinicalTrials.gov ID NCT02434029.

Obstructed defecation syndrome: a diagnostic and therapeutic challenge.

Obstructed defecation syndrome produces constipation with anal blockage and a feeling of incomplete evacuation, due to either anatomic and functional causes. This is a complex and multifactorial entity due to diverse etiological factors that may coexist in many patients. Therefore, a diagnostic approach requires structural and functional assessment. The concordance between findings of diagnostic tests is suboptimal, thus an individualized analysis is mandatory in each patient. Therapeutic strategies require the best understanding of anatomic and functional aspects. Consequently, this entity is a diagnostic and therapeutic challenge.

High-resolution and high-definition anorectal manometry: rediscovering anorectal function.

Anorectal motor and functional disorders are common among the general population. Anorectal manometry allows the study of anorectal motor activity both at rest and mimicking different physiological situations. High-resolution anorectal manometry (HR-ARM) and high-definition anorectal manometry (HD-ARM) are increasingly used in clinical practice. In comparison with the conventional technique, HR-ARM and HD-ARM catheters provide a higher number of recording points because of their many, closely packed circumferential sensors. This allows time-space visualization (topographic or 2-3-plane mode) as spatially continuous measurements are obtained by interpolation between near sensors. HR-ARM and HD-ARM allow a more standardized, reproducible technique, and a better assessment and understanding of the functional anatomy of the sphincter complex. Newer specific parameters are now being developed for use with these systems. They are being currently assessed by multiple research teams, and many of them remain unavailable for clinical practice as of today. However, they provide highly relevant information, which is now prompting a redefinition of anorectal anatomy and physiology. The goal of the present review was to describe the currently available HR-ARM and HD-ARM techniques, to discuss the normal values so far reported, and to analyze the newer parameters that may be assessed with these techniques, and which will likely be highly useful for clinical practice in the upcoming future.

Esophageal motor disorders are frequent during pre and post lung transplantation. Can they influence lung rejection?

BACKGROUND: lung transplantation (LTx) is a viable option for most patients with end-stage lung diseases. Esophageal motor disorders (EMD) are frequent in candidates for LTx, but there is very little data about changes in esophageal motility post-LTx. AIM: the aim of our study was to assess esophageal motor disorders by high resolution manometry (HRM) both pre-LTx and six months post-LTx in patients with and without organ rejection. STUDY: HRM (Manoscan®) was performed in 57 patients both pre-LTx and six months post-LTx. HRM plots were analyzed according to the Chicago classification 3.0. RESULTS: EMD were found in 33.3% and in 49.1% of patients pre-LTx and post-LTx, respectively, and abnormal peristalsis was more frequently found post-LTx (p = 0.018). Hypercontractile esophagus was frequently found post-LTx (1.8% and 19.3% pre-LTx and post-LTx, respectively). Esophagogastric junction (EGJ) morphology changed significantly pre-LTx and post-LTx; type I (normal) was more frequent post-LTx (63-2% and 82.5% respectively, p = 0.007). EMD were more frequent post-LTx in both the non-rejection and rejection group, although particularly in the rejection group (43.2% and 69.2% respectively, p = 0.09). EMD such as distal spasm, hypercontractile esophagus and EGJ outflow obstruction were also observed more frequently post-LTx in the rejection group. CONCLUSION: significant changes in esophageal motility were observed pre-LTx and particularly post-LTx; hypercontractile esophagus was a frequent EMD found post-LTx. EMD were more frequent in the group of patients that experienced organ rejection compared to the non-rejection group. EMD leading to an impaired esophageal clearance should be considered as an additional factor that contributes to LTx failure.

Consensus document on exclusion diets in irritable bowel syndrome (IBS).

This paper summarizes the contents of a consensus document on exclusion diets in irritable bowel disease that was developed by a task force from SEPD, FEAD, SENPE, FESNAD, SEÑ, SEEN, SEGHNP, SEDCA and ADENYD. The complete document is available at the SEPD website. Irritable bowel syndrome is a highly prevalent functional digestive disorder where, in addition to drugs, therapy includes diet and acquisition of healthy habits as basic elements for its control. In order to facilitate dietary counseling for these patients in daily practice, the present consensus document on the role of exclusion diets was developed. To this end, consensus opinions were collected from various experts in the national scientific societies aiming at establishing recommendations applicable to the health care of patients with irritable bowel syndrome.

Practical aspects of high resolution esophageal manometry.

High resolution esophageal manometry (HRM) is currently under development as can be seen in the various Chicago classifications. In order to standardize criteria in certain practical aspects with limited scientific evidence, the First National Meeting for Consensus in High Resolution Manometry of the Spanish Digestive Motility Group took place, bringing together a wide group of experts. The proposals were based on a prior survey composed of 47 questions, an exhaustive review of the available literature and the experience of the participants. Methodological aspects relating to the poorly defined analysis criteria of certain new high resolution parameters were discussed, as well as other issues previously overlooked such as spontaneous activity or secondary waves. Final conclusions were drawn with practical applications.

Questionnaires for the diagnosis of gastroesophageal reflux disease: are they really useful?

Gastroesophageal reflux disease (GERD) is a major medical complaint both in primary care and gastroenterology clinics. This is partly due to the condition's high prevalence, which in developed countries is estimated to be 10-20%. Its initial diagnosis, however, remains controversial. The Montreal definition of GERD is widely accepted, and both heartburn and regurgitation are therein considered the syndrome's typical symptoms. However, in the DIAMOND study only 49% of patients with GERD surprisingly reports these symptoms as major causes of disability (40%) heartburn, 9% regurgitation).

How useful is esophageal high resolution manometry in diagnosing gastroesophageal junction disruption: causes affecting this disruption and its relationship with manometric alterations and gastroesophageal reflux.

BACKGROUND: High-resolution manometry (HRM) is a breakthrough in the morphological study of the gastroesophageal junction (GEJ) and its degrees of disruption. OBJECTIVES: a) Assessment of risk factors involved in the disruption of the GEJ in patients with gastroesophageal reflux (GER) symptoms; b) the relationship between the type of GEJ and GER demonstrated by 24 hours pH-monitoring; and c) identification of the alterations in the manometric parameters related to the morphology of the GEJ. METHODS: One hundred and fifteen patients with symptoms of GER studied with HRM and classified by the type of GEJ (type I: Normal; type II: Sliding; type III: Hiatal hernia). Twenty four hour pH-monitoring without proton pump inhibitors was performed in all of them. Epidemiological aspects, manometric parameters (Chicago 2012 classification) and the pH-monitoring results were evaluated. RESULTS: Age (OR 1.033 [1.006-1.060]; p = 0.16), BMI (OR 1.097 [1.022-1.176]; p = 0. 01) and abdominal perimeter (OR 1.034 [1.005-1.063]; p = 0.0215) were independent risk factors for the GEJ type III (area under the curve 0.70). Disruption of the GEJ was associated with a lower resting pressure (p = 0.006), greater length (p < 0.001) and greater esophageal shortening (p < 0.001). Abnormal acidic reflux was found in the total period (p = 0.015), standing (p = 0.022) and supine (p = 0.001) in patients with GEJ type II and III with respect to type I. CONCLUSIONS: Increased age, overweight and central obesity pose a higher risk of GEJ type III (hiatal hernia). The greater disruption of the GEJ is associated with lower resting pressure, esophageal shortening, and higher acid exposure in the pH-monitoring.

Transcultural adaptation and validation of the "Adult Eosinophilic Esophagitis Quality of Life Questionnaire" into Spanish.

BACKGROUND: The "Adult Eosinophilic Esophagitis Quality of Life (EoE-QoL-A) Questionnaire" was developed in English as a valid, reliable, and disease-specific health-related QoL measure.This research aims to adapt and validate this questionnaire for Spanish-speaking patients. PATIENTS AND METHODS: A multicenter, observational, prospective study was conducted at 8 Spanish hospitals. The cultural adaptation of the original EoE-QoL-A questionnaire was undertaken through a standardized 3-phase procedure: 1. Translation; 2. Retrotranslation; and 3. Pilot study. Patients completed the Hospital Anxiety and Depression Scale (HADS), the Short Form (SF)-12, the Brief Illness Perception Questionnaire (BIPQ), and the adapted EoE-QoL-A, with a retest 3 months later.Statistical analysis included construct validity, internal consistency, criterion validity, and reproducibility. RESULTS: One hundred and seventy adult EoE patients (73.5 % male; aged 33.5 ± 11.4-y) were included in the study.With regard to internal validity, all Cronbach alpha values were > 0.75. A significant correlation between items assessed in the SF-12, BIPQ and EoE-QoL-A questionnaires (p < 0.001) was observed. Correlations with the HADS were stronger for anxiety than for depression levels. Anxiety related to disease diagnosis and choking were the most affected dimensions; less affected were the dimensions related to eating, social, and emotional development. Intraclass correlation coefficients between the test and retest assessments were acceptable for all questionnaires, with the highest values (0.73-0.84) calculated for the EoE-QoL-A Spanish version. CONCLUSION: The Spanish version of the EoE-QoL-A is a reliable, valid, and responsive questionnaire. Diagnosis and choking anxiety were the most affected dimensions in the health-related QoL in adult EoE patients.