Transient Lower Esophageal Sphincter Research Articles

Laparoscopic sleeve gastrectomy and esophageal motility

Laparoscopic sleeve gastrectomy (LSG) is becoming popular between the bariatric procedures. There are few studies available in the literature about LSG impact on esophageal motility, with debatable results. Technically, it modifies the anatomy of the esophago-gastric junction; it can damage the phreno-esophageal ligament and decrease the lower esophageal sphincter pressure that will predispose to reflux. Gastroesophageal reflux disease (GERD) is already common in obese patients due to frequent hiatal hernia, high intraabdominal pressure, increased transient lower esophageal sphincter relaxations (TLESR), altered esophageal motility and poor esophageal clearance. LSG can worsen gastroesophageal reflux disease, but also the weight loss achieved after it and the decrease of acid production in the small gastric pouch will probably reduce the GERD symptoms. Dysphagia and odynophagia were reported after sleeve gastrectomy, but usually associated with anatomical narrowing of the gastric sleeve, caused by esophageal dismotility or secondary to diabetes mellitus, low tiamine level, the use of opioids and non-steroidal anti-inflammatory drugs, even hypothyroidism. In addition to upper GI tract endoscopy, high-resolution esophageal manometry (HRM) should be required for all patients planning to undergo a LSG, and in the follow-up period according to the contractility pattern.

Rectal distention increases the frequency and duration of transient lower esophageal sphincter relaxations in anesthetized dogs– a putative rectoesophageal reflex

Introduction: The esophagus is subject to frequent reflux of gastric contents as a normal phenomenon during episodes of transient lower esophageal sphincter relaxation (tLESR), responsible too, for pathologic reflux. However, pathologic reflux is mostly associated with reflux of acid contents. Distending the stomach provokes an increase in frequency of tLESR. Objective: To investigate the effect of distending the rectum on the tLESR and possible involved pathways. Methods: Forty four (Protocol: 096/07) street dogs were selected and divided into respective protocols: Rectal distention (RD), Gastric distention (GD), RD+GD, Atropine+RD, Hexamethonium+RD, Baclofen+RD, Bilateral Pudendal nerve section+RD and Spinal cord transection+RD. We determined and compared the tLESR of each group and subjected data to statistical analysis. Values of p<0.05 were regarded as statistically significant. Results: RD provoked a significant increase in the tLESR just as GD, with RD+GD provoking the highest value of tLESR. This increase in tLESR due to RD was prevented in A+RD, B+RD, Bilateral Pudendal nerve section+RD and Spinal cord transection+RD but not Hexamethonium+RD protocols. Conclusion: RD is a significant inducer of an increase in tLESR with participation of muscharinic and GABAβ, sensitive and spinal cord neurons, but not nicotinic receptors.

Cannabis Use in Patients Presenting to a Gastroenterology Clinic: Associations with Symptoms, Endoscopy Findings, and Esophageal Manometry

Recreational cannabis use is increasing with its legalization in many states. Animal studies suggest cannabis can reduce transient lower esophageal sphincter relaxations (TLESRS), reflux and vomiting, while human studies report conflicting findings. There are currently no large studies investigating gastrointestinal symptoms in patients with chronic cannabis use. This was a retrospective case-control study including patients who presented to an outpatient Gastroenterology office, with documented cannabis use. Their main presenting complaint, demographics, frequency and duration of cannabis use, endoscopic and high-resolution esophageal manometry (HREM) with impedance findings were recorded. Cannabis users were more likely to complain of abdominal pain (25% vs. 8%, p < 0.0001), heartburn (15% vs. 9%, p < 0.0001), and nausea & vomiting (7% vs. 1%, p < 0.0001). They were also more likely to have findings of esophagitis (8% vs. 3%, p = 0.0002), non-erosive gastritis (30% vs. 15%, p = 0.0001) and erosive gastritis (14% vs. 3%, p < 0.0001) on upper endoscopy. Cannabis users were more likely to have impaired esophageal bolus clearance (43% vs. 17%, p = 0.04) and a hypertensive lower esophageal sphincter (LES) (29% vs. 7%, p = 0.04). This study is the largest to date evaluating GI complaints of patients with chronic recreational cannabis use. Our results suggest that cannabis use may potentiate or fail to alleviate a variety of GI symptoms which goes against current knowledge.

Sa1091 - Effect of Citalopram on Esophageal Motility in Healthy Subjects. Implications for Transient Lower Esophageal Sphincter Relaxations, Dysphagia and Globus Pharyngeus

Sa1091 - Effect of Citalopram on Esophageal Motility in Healthy Subjects. Implications for Transient Lower Esophageal Sphincter Relaxations, Dysphagia and Globus Pharyngeus

Regulation of transient lower esophageal sphincter relaxation in the pathogenesis of gastroesophageal reflux disease

Regulation of transient lower esophageal sphincter relaxation in the pathogenesis of gastroesophageal reflux disease

Su1083 Effect of a Carbonated Beverage on Transient Lower Esophageal Sphincter Relaxations (TLESR). A Study in Healthy Volunteers

Su1083 Effect of a Carbonated Beverage on Transient Lower Esophageal Sphincter Relaxations (TLESR). A Study in Healthy Volunteers

Primary Peristalsis and Esophagogastric Junction (EGJ) Pressure Following a Transient Lower Esophageal Sphincter Relaxation (TLESR) Are Accompanied by a Forceful Contraction

Primary Peristalsis and Esophagogastric Junction (EGJ) Pressure Following a Transient Lower Esophageal Sphincter Relaxation (TLESR) Are Accompanied by a Forceful Contraction

Use and overuse of proton pump inhibitors

In 2009, an editorial by Putman focused on the dramatic increase in the use of proton pump inhibitors (PPIs) in infants [1]. Considering the increasing evidence that PPIs offer little benefit for most of the symptoms for which they are prescribed, Putman strongly highlighted the need for a serious effort to curtail their empiric use. The editorial was linked to a study by Orenstein et al, which detected no difference in efficacy between lansoprazole and placebo for symptoms attributed to gastroesophageal reflux disease (GERD) in infants [2]. A very recent review on the effects of PPIs on irritability and crying in infants confirmed the conclusion that these drugs do not offer relief from these symptoms for which they are commonly prescribed [3]. After all, it has recently been pointed out that volume rather than acid is often the key promoter of reflux-associated symptoms in infants. Distension-induced increase in gastric wall tension has been associated with high rates of transient lower esophageal sphincter relaxations and is considered one of the main mechanisms contributing to postprandial GER [4]. Despite all these evidences on PPIs uneffectiveness for many of the symptoms for which they are commonly prescribed, the rate of their prescriptions have exponentially increased over the last years. The latest combined NASPGHAN/ESPGHAN guidelines already in 2009 highlighted the need to distinguish physiologic GER events from GERD, limiting for the latter the use of PPIs [5]. However, a 2012 European survey carried out by our study group showed that only 1.8% of pediatricians reported a complete adherence to the guideline recommendations in their clinical practice. The most relevant violation of the guideline recommendations concerned the prescription of unnecessary acid suppressive medications [6] (Figure ​(Figure1).1). In order to inquire into the reasons why pediatricians did not follow the guideline recommendations, we performed another trial with the same pediatricians undergoing specific training on the guidelines being supervised in their clinical practice. As a result, trained pediatricians showed a significantly higher compliance with the international guidelines and infants with unexplained crying and distressed behaviour or with uncomplicated recurrent regurgitation and vomiting who were unproperly prescribed PPIs decreased dramatically [7]. Besides these data on PPI overuse, recent studies highlighted the occurrence of several adverse effects related to their assumption, such as a higher risk of bronchoalveolar lavage culture positivity and gastric bacterial overgrowth, food allergy, Clostridium difficile infection, gastric polyps and nodules [8-12]. Figure 1 Rates of pediatricians over-prescribing PPIs in the different European countries

The most common errors in the management of gastroesophageal reflux

Gastro-Esophageal Reflux (GER) occurs in more than two-thirds of otherwise healthy children and is one of the major reason for referral to paediatricians; in fact, a quarter of all paediatric visits in the first six months of life [1] and numerous accesses to the paediatric gastroenterologist services are secondary to GER. GER is defined as the passage of gastric contents into the esophagus and is different from gastroesophageal reflux disease (GERD), which includes all the symptoms and/or complications associated with GER [2]. GER is considered a physiological normal process which occurs several times a day in healthy infants, children and adults. GER is usually associated with transient lower esophageal sphincter relaxations independent from swallowing, which allow the passage of gastric contents into the esophagus. Episodes of GER in healthy adults tend to occur after meals, lasting less than three minutes and usually do not cause symptoms. Although we know less on the normal physiology of newborns and infants, regurgitation is the most visible symptom and tends to occur daily in 50% of all infants with a peak incidence between 4 and 6 months of life [3]. For the majority of paediatric patients (especially in infants), the clinical history and the objective appraisal, in the absence of danger signals, are sufficient to reliably diagnose a not complicated GER and initiate conservative treatment strategies; in general, the diagnostic tests are not always necessary. The reliability of the symptoms to make the clinical diagnosis of GERD is higher in children younger than 8 years, reporting heartburn: only in this case, the doctor can make a diagnosis of Gastro Esophageal Reflux Syndrome and give an indication for therapy [4]. To date, no single symptom or set of symptoms can be trusted, and then used to diagnose GERD in children or to predict which patients are more likely to respond to therapy [2]. The only exception is the child (age> 8y.o.) reporting a history of long-term heartburn with or without vomiting. The new ESPGHAN/NASPGHAN guidelines [2] describe different treatment options for the treatment of infants / children with GER and GERD. In particular, they emphasized the changes in lifestyle, because it can effectively reduce the symptoms of both infants and children. They are based on a combination of changes of milk formulas and positional therapy. In infants with GER, it can be effective the changes to the mother's diet if children are breastfed, change the formula in use, reducing the volume of the single meal associated with an increased frequency of feedings. In particular, the guidelines stress that the allergy to milk proteins may have a clinical presentation similar to GERD. A strategy of nutritional intervention involves the use of thickened formulas that are able to decrease the regurgitation. A recent meta-analysis has shown that the anti regurgitation formula have the following functions: a) increase the number of infants without regurgitation; b) reduce the number of episodes of regurgitation and vomiting daily; c); increase the weight recovery of the infant, d) although they do not change the 24 hours pH study [4].

Mo1910 Acid Infusion Into the Stomach Does Not Affect the Number of Meal-Induced Transient Lower Esophageal Sphincter Relaxations (TLESR)

Mo1910 Acid Infusion Into the Stomach Does Not Affect the Number of Meal-Induced Transient Lower Esophageal Sphincter Relaxations (TLESR)

PO-0133 Gastroesophageal Reflux In Infants And Osteophatic Manipolative Treatment: An Alternative Therapy?

Background and aims Several study have been reported that modifying vagus nerve control of transient lower esophageal sphincter relaxation can induce improvement of gastroesophageal reflux disease (GERD). Our aim was to evaluate the efficacy of osteophatic treatment (OMT) in infants with GERD. Methods We enrolled 40 infants (M/F:24/16), age ranged 1–18 months (median 4 month) attending for persistent reflux. Each patient performed I-GERQ-R questionnaire and ultrasonography of the gastro-esophageal junction before and after treatment. The ultrasound score was 0 to 3 on the basis of severity of reflux (number of reflux episodes in 10 min). Moreover each patient did an osteophatic treatment consisting in an extensive physical examination, to evaluate TART parameters (T = tissue texture changes; A = asimmetry; R = restriction of motion; T = tenderness). Then, a specific therapeutic intervention was chosen, treating only the parts of the body presenting greater TART modifications. Results All the somatic dysfunctions observed before OMT (at the scale 32/40 patients, the condyles 36/40 patients, the occipito-mastoid suture 36/40 patients; the stomach 22/40 patients, the small epiploon 30/40 patients) disappeared after treatment. The average score of I GERQ-R questionnaire before and after treatment was 22.7 ± 4.7 and 17.2 ± 4.5 respectively (p Conclusion OMT could be considered as an alternative treatment in infants with gastroesophageal reflux. Further data are needed to confirm our hyphothesis.

Mechanisms of Acid Reflux and How Refluxed Acid Extends Proximally in Patients with Non-Erosive Reflux Disease

Background/Aims: The mechanisms that cause acid reflux in patients with non-erosive reflux disease (NERD), including those that determine how acid extends proximally, are not yet clear. Methods: Concurrent esophageal manometry and pH monitoring were performed for 3 h after a meal in 13 patients with NERD, 12 with mild reflux esophagitis (RE), and 13 healthy subjects (HS). Results: Transient lower esophageal sphincter (LES) relaxation (TLESR) was the major mechanism of acid reflux in all three groups. LES pressure did not differ between the groups. At 2 cm above the LES, there were no differences between the three groups in the number of TLESR-related acid reflux episodes, rate of TLESRs and rate of acid reflux during TLESR. However, at 7 cm above the LES, the rate of acid reflux during TLESRs was significantly higher in patients with NERD (mean ± SEM 42.3 ± 4.8) than in those with mild RE (28.0 ± 3.8) and HS (10.8 ± 2.5). Conclusions: TLESRs are the sole motor events underlying acid reflux episodes in patients with NERD. Acid extends proximally more readily in patients with NERD than in HS and those with mild RE.

Nicotinic receptor subtypes mediating relaxation of the normal human clasp and sling fibers of the upper gastric sphincter.

Proper function of the gastro-esophageal high pressure zone is essential for the integrity of the antireflux barrier. Mechanisms include tonic contractions and the decreased tone during transient lower esophageal sphincter relaxations. We characterized the pharmacology of nicotinic receptors mediating relaxations of the human upper gastric sphincter (clasp and sling fibers) using currently available subtype selective nicotinic antagonists in tissue from organ transplant donors. Donors with either a history of gastro-esophageal reflux disease or histologic evidence of Barrett's esophagus were excluded. Clasp and sling muscle fiber strips were used for one of three paradigms. For paradigm 1, each strip was exposed to carbachol, washed, exposed to nicotinic antagonists then re-exposed to carbachol. In paradigm 2, strips were exposed to a near maximally effective bethanechol concentration then nicotine was added. Strips then were washed, exposed to nicotinic antagonists then re-exposed to bethanechol followed by nicotine. In paradigm 3, strips were exposed to bethanechol then choline or cytisine. 100 μM methyllycaconitine has no inhibitory effects on relaxations, eliminating homomeric α7 subtypes. Subtypes composed of α4β2 subunits are also eliminated because choline acts as an agonist and dihydro-beta-erythroidine is ineffective. Because mecamylamine blocks the relaxations and both choline and cytisine act as agonists in both clasp and sling fibers, the nicotinic receptor subtypes responsible for these relaxations could be composed of α3β4β2, α2β4, or α4β4 subunits.

14 Identification of Transient Lower Esophageal Sphincter Relaxation (TLESR) in High Resolution Manometry Combined With Impedance (HRM-Z): Toward a Consensus Definition

14 Identification of Transient Lower Esophageal Sphincter Relaxation (TLESR) in High Resolution Manometry Combined With Impedance (HRM-Z): Toward a Consensus Definition

Esophageal motility abnormalities in gastroesophageal reflux disease.

Esophageal motility abnormalities are among the main factors implicated in the pathogenesis of gastroesophageal reflux disease. The recent introduction in clinical and research practice of novel esophageal testing has markedly improved our understanding of the mechanisms contributing to the development of gastroesophageal reflux disease, allowing a better management of patients with this disorder. In this context, the present article intends to provide an overview of the current literature about esophageal motility dysfunctions in patients with gastroesophageal reflux disease. Esophageal manometry, by recording intraluminal pressure, represents the gold standard to diagnose esophageal motility abnormalities. In particular, using novel techniques, such as high resolution manometry with or without concurrent intraluminal impedance monitoring, transient lower esophageal sphincter (LES) relaxations, hypotensive LES, ineffective esophageal peristalsis and bolus transit abnormalities have been better defined and strongly implicated in gastroesophageal reflux disease development. Overall, recent findings suggest that esophageal motility abnormalities are increasingly prevalent with increasing severity of reflux disease, from non-erosive reflux disease to erosive reflux disease and Barrett's esophagus. Characterizing esophageal dysmotility among different subgroups of patients with reflux disease may represent a fundamental approach to properly diagnose these patients and, thus, to set up the best therapeutic management. Currently, surgery represents the only reliable way to restore the esophagogastric junction integrity and to reduce transient LES relaxations that are considered to be the predominant mechanism by which gastric contents can enter the esophagus. On that ground, more in depth future studies assessing the pathogenetic role of dysmotility in patients with reflux disease are warranted.

Electroacupuncture at PC6 or ST36 Influences the Effect of Tacrine on the Motility of Esophagus.

Aim. To investigate the mechanisms of gastrointestinal side effects of tacrine, and find treatment methods with electroacupuncture (EA). Methods. Twenty-five healthy cats were randomly divided into 5 groups: gastric-distention group (model group), tacrine group (cholinesterase inhibitor), tacrine + sham acupoint group (control group), tacrine + PC6 (neiguan) group, and tacrine + ST36 (zusanli) group, with 5 cats in each group. Saline 2 mL i.p. was given 30 min before gastric distention in model group. Tacrine 5.6 mg/kg i.p. was given 30 minutes before gastric distention in the other groups. Tacrine + sham acupoint group (control group), tacrine + PC6 group, and tacrine + ST36 group received EA at corresponding acupoints during gastric distention. The frequency of TLESRs and LESP were recorded by using a perfused sleeve assembly. Results. Compared with the model group, tacrine significantly increased the frequency of gastric distention-induced TLESR (P < 0.05) but did not influence the rate of common cavity during TLESR. Tacrine significantly increased the LESP, which could not remain during gastric distention. EA at PC6 could decrease the frequency of TLESR and maintain the increase of LESP, but EA at ST36 did not have these effects. Conclusion. Tacrine can significantly increase the gastric distention-induced transient lower esophageal sphincter relaxations (TLESRs). Electroacupuncture (EA) at PC6 may reverse the above side effect.

Longitudinal muscle of the esophagus

The muscularis propria of the esophagus is organized into circular and longitudinal muscle layers. The function of the longitudinal muscle and its role in bolus propulsion are not clear. The goal of this review is to summarize what is known of the role of the longitudinal muscle in health, as well as in sensory and motor disorders of the esophagus. Simultaneous manometry and ultrasound imaging reveal that, during peristalsis, the two muscle layers of the esophagus contract in perfect synchrony. On the contrary, during transient lower esophageal sphincter (LES) relaxation, longitudinal muscle contracts independent of the circular muscle. Recent studies have provided novel insights into the role of the longitudinal muscle in LES relaxation and descending relaxation of the esophagus. In certain diseases (e.g. some motility disorders of the esophagus), there is discoordination between the two muscle layers, which likely plays an important role in the genesis of dysphagia and delayed esophageal emptying. There is close temporal correlation between prolonged contractions of the longitudinal muscles of the esophagus and esophageal 'angina-like' pain. Novel techniques to record longitudinal muscle contraction are reviewed. Longitudinal muscles of the esophagus play a key role in the physiology and pathophysiology of esophageal sensory and motor function. Neuro-pharmacologic controls of circular and longitudinal muscle are different, which provides an opportunity for the development of novel pharmacological therapies in the treatment of esophageal sensory and motor disorders.

Tu1787 Primary Peristalsis and Esophagigastric Junction (EGJ) Pressure, Following a Transient Lower Esophageal Sphincter Relaxation (TLESR), Are Accompanied by a Forceful Contraction

Background: A TLESR is a major mechanism of acid reflux in healthy subjects and patients with reflux esophagitis and we have noticed that the amplitude of primary peristalsis and EGJ pressure, following a TLESR, is accompanied by a forceful contraction, when compared with before a TLESR. The aim of this study is to investigate whether or not primary peristalsis and EGJ pressure, when accompanied by a forceful contraction and following a TLESR, is a characteristic finding of a TLESR. Methods: 10 healthy subjects underwent esophageal high-resolution manometry with a 21-lumen perfused assembly, which monitored pressure in the pharynx, the upper esophageal sphincter, the esophageal body, LES and the proximal stomach. The EGJ was evaluated using ten side holes, spaced at 1-cm intervals. Recordings were then taken, in the sitting position, for 1 hour after a meal (692 kcal, 33 % fat). A TLESR is defined as previously described. Data were analyzed, using Trace! Software (Dr. G.S Hebbard, The Royal Melbourne Hospital, Australia). The contractile integral (CI) of the distal esophageal segment (D-CI: volume of the domain above 20 mmHg), excluding the EGJ segment, was measured both before and after a TLESR, and the CI of the EGJ (EGJCI) (volume of the domain above 0 mmHg), was measured for 8 seconds after primary peristalsis reached the EGJ, both before and after a TLESR. Results: 56 TLESRs were measured during the study. The D-CI (1603 mmHg s cm (1177-2120), median (interquartile range)) following a TLESR was significantly greater than before a TLESR (484 (323-1079)) and more than a 50% increase of D-CI in 35 (62.5%) of the 56 TLESRs was observed. The EGJCI (790 (465-1009)) following a TLESR was significantly greater than before a TLESR (238 (186-308)) and more than a 50% increase in the EGJ-CI in 48 (85.7%) of the 56 TLESRs was observed. Conclusions: The D-CI and the EGJ-CI following a TLESR, were significantly greater than before a TLESR and this tendency was evident in the EGJ-CI, although it can, at times, be difficult to evaluate a TLESR. If the focus is on a forceful contraction of primary peristalsis or on the EGJ, it may be easier to detect and evaluate a TLESR.

Gastroesophageal Reflux Disease in Neonates and Infants

Gastroesophageal reflux (GER) is defined as the involuntary retrograde passage of gastric contents into the esophagus with or without regurgitation or vomiting. It is a frequently experienced physiologic condition occurring several times a day, mostly postprandial and causes no symptoms. These infants are also called 'happy spitters'. GER disease (GERD) occurs when reflux of the gastric contents causes symptoms that affect the quality of life or pathologic complications, such as failure to thrive, feeding or sleeping problems, chronic respiratory disorders, esophagitis, hematemesis, apnea, and apparent life-threatening events. About 70-85 % of infants have regurgitation within the first 2 months of life, and this resolves without intervention in 95 % of infants by 1 year of age. The predominant mechanism causing GERD is transient lower esophageal sphincter (LES) relaxation, which is defined as an abrupt decrease in LES pressure to the level of intragastric pressure, unrelated to swallowing and of relatively longer duration than the relaxation triggered by a swallow. Regurgitation and vomiting are the most common symptoms of infant reflux. A thorough history and physical examination with attention to warning signals suggesting other causes is generally sufficient to establish a clinical diagnosis of uncomplicated infant GER. Choking, gagging, coughing with feedings or significant irritability can be warning signs for GERD or other diagnoses. If there is forceful vomiting, laboratory and radiographic investigation (upper gastrointestinal series) are warranted to exclude other causes of vomiting. Irritability coupled with back arching in infants is thought to be a non-verbal equivalent of heartburn in older children. Other causes of irritability, including cow's milk protein allergy, neurologic disorders, constipation and infection, should be ruled out. The presentation of cow's milk protein allergy overlaps with GERD, and both conditions may co-exist in 42-58 % of infants. In these infants, symptoms decrease significantly within 2-4 weeks after elimination of cow's milk protein from the diet. For non-complicated reflux, no intervention is required for most infants. Effective parental reassurance and education regarding regurgitation and lifestyle changes are usually sufficient to manage infant reflux. Sandifer syndrome, apnea and apparent life-threatening events are the extraesophageal manifestations of GERD in infants. Pharmacotherapeutic agents used to treat GERD encompass antisecretory agents, antacids, surface barrier agents and prokinetics. Currently, North American Society for Pediatric Gasroenterology, Hepatology and Nutrition (NASPGHAN) and European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) practice guidelines concluded that there is insufficient evidence to justify the routine use of prokinetic agents. Esomeprazole (Nexium) is now approved in the US for short-term treatment of GERD with erosive esophagitis in infants aged from 1 to 12 months. Although Nissen fundoplication is now well established as a treatment option in selected cases of GERD in children, its role in neonates and young infants is unclear and is only reserved for selective infants who did not respond to medical therapy and have life-threatening complications of GERD.

Novel therapeutics for gastro–esophageal reflux symptoms

Approximately 20–30% of patients with gastro–esophageal reflux symptoms report inadequate symptom relief while on proton-pump inhibitor therapy. The mechanisms involved are failure of the antireflux barrier (transient lower esophageal sphincter relaxations), high proximal extent of the refluxate, esophageal hypersensitivity and impaired mucosal integrity. Persisting acid or nonacid reflux can be demonstrated in 40–50% of cases, suggesting that there is room for antireflux therapy in these patients. New antireflux compounds have been shown to decrease the occurrence of transient lower esophageal sphincter relaxations. The most promising classes of compounds are GABA type B agonists and metabotropic glutamate receptor 5 antagonists, which can reduce both reflux episodes and symptoms, but the development of these compounds has been abandoned for either safety issues or lack of efficacy. Esophageal hypersensitivity and impaired mucosal integrity may prove to be relevant therapeutic targets in the future.