ORIGINAL ARTICLES ALIMENTARY TRACT

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2012;10: ORIGINAL ARTICLES ALIMENTARY TRACT Baclofen Improves Symptoms and Reduces Postprandial Flow Events in Patients With Rumination and Supragastric Belching KATHLEEN BLONDEAU, VEERLE BOECXSTAENS, NATHALIE ROMMEL, RICHARD FARRÉ, STEPHANIE DEPEYPER, LIESELOT HOLVOET, GUY BOECKXSTAENS, and JAN F. TACK Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium See editorial on page 336. BACKGROUND & AIMS: In patients with clinically suspected rumination, esophageal impedance manometry differentiates episodes of rumination (involuntary straining with intragastric pressure increases) from aerophagia/supragastric belching. Treatment options are limited and focused on behavioral therapy. Baclofen, an agonist of the -aminobutyric acid B receptor, increases lower esophageal sphincter pressure and decreases swallowing rate. We investigated its effects in these patients. METHODS: High-resolution manometry-impedance recordings were taken from 12 patients (8 women; mean age, 45 years; range, years) with clinically suspected rumination or supragastric belching before and during treatment with baclofen (10 mg, 3 times daily). After 30 minutes of recordings, patients received a 1000-kcal solid meal; recordings were then continued for 1 hour. Patients were asked to register symptoms with an event marker. The number of symptoms registered and number and type of flow events were compared before and during treatment. RESULTS: An average of 20 symptom markers (range, 14 34) were recorded at baseline (10 [range, 4 25] for belching and 9 [range, 0 11] for regurgitation). This was significantly reduced to 6 (range, 2 22) (3 [range, 1 15] for belching and 1 [range, 0 13] for regurgitation) during baclofen treatment (P.01). The number of flow events (473 at baseline [42 reflux, 192 rumination, 188 supragastric belching, and 42 aerophagia]) was significantly reduced to 282 (32 reflux, 99 rumination, 123 supragastric belching, and 13 aerophagia) during baclofen therapy (P.02). The reduction in flow events correlated with the increase in lower esophageal sphincter pressure (r 0.62; P.03) and reduction in swallowing frequency (r 0.64; P.02). CONCLUSIONS: Baclofen is an effective treatment for patients with rumination or supragastric belching/aerophagia. Keywords: Clinical Trial; Esophagus; Stomach; LES. Rumination syndrome is characterized by the effortless, often repetitive regurgitation of recently ingested food into the mouth. 1 The regurgitated material can be chewed and swallowed again or is spat out. 2,3 In these patients, retrograde flow of gastric contents into the esophagus is due to a voluntary, although unintentional, act of contracting the abdominal muscles and subsequent increase in intragastric pressure (straining), pushing the gastric contents upward into the esophagus. 4,5 It is often stated that a reliable diagnosis of rumination syndrome can be made by recognizing typical elements in the history, in line with the diagnostic Rome criteria. 6 More recent studies have shown that clinically suspected rumination is not always confirmed during mechanistic studies that use postprandial stationary esophageal impedance monitoring and manometry, with regurgitation or supragastric belching present in large subgroups of patients. 4,7 Supragastric belching is an act during which air is either sucked into the esophagus by decreasing the intrathoracic pressure or pushed into the esophagus by contracting the pharyngeal muscles during glottis closure. Afterward the air is rapidly expelled, which might be initiated by abdominal straining. 8 Both rumination and excessive belching are troublesome symptoms that might have a severe impact on the patient s quality of life. 9 Thus far, treatment for rumination syndrome is based on behavioral modification, which uses diaphragmatic breathing to compete with the urge to ruminate, and which has been reported to be effective in more than half of the patients. 1 However, behavioral therapy is often difficult to organize, with a shortage of therapists familiar with this therapeutic approach. Furthermore, regurgitation and supragastric belching are unlikely to respond to diaphragmatic breathing. A recent report indicated that supragastric belching might respond to a different type of behavioral therapy; a speech pathologist s intervention, focusing on refraining from glottis closures and regaining control of the breathing pattern, was able to improve symptoms in more than half of the patients with supragastric belching. 10 The behavioral therapy approach to these disorders therefore is complex and requires very specific skills and dedication, which are unlikely to be widely available. Hence, a clear unmet need for other therapeutic approaches exists in rumination syndrome and related conditions. A key factor in the occurrence of rumination is an increase in intragastric pressure during straining that is able to overcome the lower esophageal sphincter (LES) pressure and that provides a driving force for the upward movement of gastric contents. A Abbreviations used in this paper: GABA, -aminobutyric acid; GERD, gastroesophageal reflux disease; HRM, high-resolution manometry; LES, lower esophageal sphincter; PPI, proton pump inhibitor; TLESR, transient lower esophageal sphincter relaxation by the AGA Institute /$36.00 doi: /j.cgh

2 380 BLONDEAU ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 4 low postprandial LES pressure or straining during transient LES relaxation (TLESR) is likely to be an underlying facilitating factor and could provide a target for a novel type of therapeutic approach. The -aminobutyric acid (GABA) B agonist baclofen has successfully been used for the treatment of gastroesophageal reflux disease (GERD). Baclofen reduces all types of reflux by increasing the basal LES pressure and reducing the number of TLESRs, the most important mechanism of regurgitation of gastric contents in patients with GERD. In addition to an enhanced LES function, baclofen reduces the swallowing frequency An increase of basal LES pressure and a decrease in swallowing frequency might be beneficial in patients with rumination and excessive belching, respectively. Our aim therefore was to conduct a pilot study to evaluate the effect of baclofen on symptoms and postprandial flow events in patients with clinically suspected rumination syndrome. Methods Patients We studied 16 patients (10 women; mean age, 43 years; range, years) with a clinical suspicion of rumination. All patients had undergone upper gastrointestinal endoscopy and empiric proton pump inhibitor (PPI) and prokinetic therapy without clear explanation of the symptoms and without beneficial symptomatic effect. Study Protocol All patients underwent stationary high-resolution manometry (HRM)-impedance recordings after an overnight fast. The manometry-impedance assembly (Medical Measurement Systems, Enschede, the Netherlands) consisted of 22 waterperfused pressure sensors and 7 impedance channels. Pressure and impedance signals were sampled at 50 Hz. The catheter was positioned with the high-definition zone in the LES region and impedance sensors, respectively, 5, 7, 9, 11, 13, 15, and 17 cm above the upper margin of the LES. After placement of the manometry-impedance catheter, patients remained in a bed in semirecumbent position. After 30 minutes of baseline recordings, patients received a 1000-kcal solid meal (meat loaf, mashed potatoes, applesauce, pudding, and a glass of milk). After the meal, recordings were continued for 1 hour. Patients were instructed to carefully record symptoms of regurgitation (upward movement of liquid contents in the esophagus) or belching by using the respective event marker throughout the entire recording period. After the baseline study, patients were treated with baclofen for 1 week (10 mg 3 times a day). This dose has been based on previous experience with the use of baclofen as monotherapy or add-on therapy in GERD ,14,15 At the end of the 1-week treatment, a second HRM-impedance recording was performed while on therapy. Patients were instructed to take the medication before the start of the recording. Analysis of Symptom Markers The number of times that patients pushed the belching or the regurgitation symptom marker was determined for each half hour of registration. Analysis of Flow Events HRM-impedance recordings were manually analyzed for flow events. The meal period was excluded from the analysis. Flow events were categorized as reflux, rumination, aerophagia, supragastric belching, gastric belching, or a combination of these when applicable. Gastroesophageal reflux was defined as a sequential orally progressing drop in impedance to less than 50% of the baseline values that starts in the most distal channel and propagates retrograde to at least the next more proximal measuring segment 16 (Figure 1A). Rumination was defined as a reflux episode Figure 1. (A) Example of a liquid reflux event as identified by HRM-impedance recording. The impedance signal shows a drop of 50% from the baseline, starting in the most distal channel and progressing in a retrograde fashion up to the most proximal channel. (B) Example of a rumination episode. The impedance recording shows a liquid reflux event that is associated with an increase in intragastric pressure (straining) on the HRM recording. The arrows indicate the direction of flow on the impedance tracings.

3 April 2012 BACLOFEN IMPROVES RUMINATION AND SUPRAGASTRIC BELCHING 381 Figure 2. (A) Example of a gastric belch. Impedance signal shows a rapid increase starting in the most distal channel and progressing in a retrograde way. (B) Example of a supragastric belch, which is characterized by a rapid increase in impedance starting in the most proximal channel and progressing in an aboral fashion. The air is rapidly expelled, which is characterized by a return of the impedance signal to the baseline value. Expulsion of air is associated with an increase in intragastric pressure (straining). (C) Example of an aerophagia episode. Combined HRM-impedance tracing shows a peristaltic pressure wave of a swallow that is associated with an increase in the impedance signal, indicating the presence of gas. The arrows indicate the direction of flow on the impedance tracings. that was associated with a transient increase in intragastric pressure (strain) occurring simultaneously with or preceding the flow event 5 (Figure 1B). Gastric belching was identified as a rapid increase in impedance in at least 2 consecutive impedance channels progressing in a retrograde fashion (Figure 2A). 16,17 Supragastric belching was defined as a rapid increase in impedance (3000 ohm/s or 1000-ohm increase in distal channel) progressing in an aboral fashion, followed by an immediate expulsion (impedance values returning to baseline in a retrograde way) (Figure 2B). Aerophagia was classified as a swallow together with a rapid impedance increase of 1000 ohm in the most distal channel (Figure 2C). 17 Analysis of Lower Esophageal Sphincter Pressure, Transient Lower Esophageal Sphincter Relaxations, and Swallowing Rate Basal LES pressure was measured at end-expiration relative to intragastric pressure and was determined as means of 1-minute periods every 15 minutes, provided that the measurement was stable and no TLESR or swallow occurred. The mean LES pressure was calculated for each 30-minute period. The number of TLESRs was evaluated during the postprandial period according to previously published guidelines. 18 The rate of spontaneous swallowing was determined by counting the pharyngeal pressure waves. Statistical Analysis The number of symptom markers and the number of flow events were compared before and during baclofen treatment by using a paired t test or Wilcoxon matched pairs test in case of nonparametric distribution (GraphPad Prism, LaJolla, CA). Spearman correlation was performed to correlate changes in symptoms, flow events, and pressure data. Results are expressed as median (25th 75th) percentile unless otherwise stated. Results Twelve patients (8 women; mean age, 45 years; range, years) were included in the final analysis. Four patients were excluded from the study because they refused the second HRM-impedance recording while on baclofen. Ten patients presented with predominant symptoms of regurgitation, whereas 2 patients presented with predominant symptoms of belching. Four of the 12 patients included in the final analysis reported side effects of sleepiness and difficulty to concentrate during baclofen treatment. Nevertheless, these adverse effects were mild, and all patients successfully completed the treatment period. Symptom Markers During baseline recording, patients pushed the symptom markers on average 20 times (range, 1434), with similar use of the belching and the regurgitation markers (10 [4 25] and 9 [0 11] events, respectively). Overall, the majority of markers registered by the patient corresponded to a flow event identified by HRM-impedance. Only 1.3% of the event markers were recorded before the meal period. The majority of markers (60.2%) were recorded during the first 30 minutes after the meal, whereas the remaining 38.5% of event markers were recorded minutes after the meal. During the recording while on baclofen treatment, patients recorded significantly fewer symptoms during the study (6 [2 22]/patient; P.01) (Figure 3). The number of symptom markers for regurgitation was significantly reduced from 9 (0 11) to 1 (0 13)/patient (P.01), whereas the number of symptom markers for belching was borderline significantly decreased from 10 (4 25) to 3 (1 15) per patient (P.06). In contrast to the baseline conditions, the majority of symptom markers were recorded minutes after the meal (54.5%), whereas 45% of the symptoms were registered during

4 382 BLONDEAU ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 4 the first 30 minutes after the meal and only 0.5% before the meal. We found no correlation between symptom improvement and patient demographics. Both during baseline conditions and during baclofen treatment, the majority of symptom markers corresponded to a flow event identified by HRM-impedance recordings. Overall, only 1.1% of all symptom markers registered by the patients did not correspond to a flow event on HRM-impedance. Both in baseline and treatment conditions, the majority of regurgitation markers corresponded to episodes of rumination (62.9%), whereas the majority of belching markers corresponded to episodes of supragastric belching (58.4%). Figure 4. Classification of the different types of flow events before and during baclofen treatment. Overall, baclofen significantly reduced the number of flow events from 464 to 282 (P.02). Nine of the 12 patients showed a reduction in event markers during baclofen treatment compared with baseline. Flow Events Overall, 473 flow events were identified from the HRMimpedance recordings (34 [17 43]/patient). All events were recorded during the postprandial period; no events were recorded before the meal. Sixty percent of all flow events occurred in the first 30 minutes after the meal, whereas the remaining 40% occurred minutes after the meal. Figure 4 shows the classification of flow events into different categories. Different types of flow events were found in all patients. On the basis of the most frequently occurring type of event, 1 patient had predominantly reflux events, 6 had predominantly rumination, 3 had supragastric belching, and 1 had aerophagia as a predominant pattern. One patient displayed equal amounts of supragastric belching and rumination events. The total number of flow events was significantly reduced from 473 to 282 (39.2%) during baclofen treatment (P.02) (Figure 5). As in baseline conditions, the majority of flow events (70.1%) occurred during the first 30 minutes after the meal. In the group of patients who had rumination episodes (n 8), a significant decrease in rumination events occurred during treatment with baclofen (18 [10 41] vs 4 [0 22] events; P.01). Episodes of supragastric belching occurred in 9 patients, and in these patients the number of supragastric belching episodes was reduced from 9 (1 18) at baseline to 1 (0 17) events while on baclofen, but this did not reach statistical significance (P.2). In the patient with aerophagia, the number of events was reduced from 41 at baseline to 9 while on baclofen treatment. We found no correlation between the reduction in flow events with baclofen and patient demographics (data not shown). Lower Esophageal Sphincter, Swallows, and Straining Events Overall, baclofen increased the LES pressure from 13.7 (8 14.3) mm Hg to 20 ( ) mm Hg, but this did not reach statistical significance (P.1). Baclofen increased LES pressure in 7 of 12 patients (12.2 [ ] mm Hg increase), whereas in the remaining 5 patients baclofen had no measurable effect on LES pressure. There was a significant correlation between the change in LES pressure and the percentage reduction of flow events identified on HRM-impedance recordings (r 0.62, P.03). Figure 3. The number of event markers, registered by the patient during the HRM-impedance recording, was significantly lower during baclofen treatment compared with baseline conditions. Figure 5. The number of postprandial flow events, identified from the HRM-impedance recording, was significantly lower during baclofen treatment compared with baseline (464 vs 28, P.02). A reduction in the number of flow events was observed in 9 of 12 patients.

5 April 2012 BACLOFEN IMPROVES RUMINATION AND SUPRAGASTRIC BELCHING 383 The number of TLESRs during the postprandial period was significantly reduced from 15 (9 19) in baseline conditions to 7 (6 15) during baclofen treatment (P.03). One patient was excluded from the analysis because of an extremely low LES pressure after the meal. A reduction in TLESRs was observed in 8 of 11 patients. There was no correlation between the change in TLESRs and the percentage change in total flow events (r 0.12, P.7) or rumination episodes (r 0.73, P.06) during baclofen treatment compared with baseline conditions. Straining episodes were detected in 11 of 12 patients. The number of strains was reduced from 32 (17 48) in baseline conditions to 17 (2 70) during baclofen treatment (P.1). A reduction of strains was observed in 9 of 11 patients. There was no correlation between the percentage reduction in straining episodes and the percentage reduction in flow events (r 0.3, P.4). The number of swallows in the postprandial hour was significantly reduced with baclofen treatment from 119 ( ) to 89 (59 138) (P.01). A significant correlation was found between the percentage of change in swallows and the percentage of change in flow events (r 0.64, P.02) after the meal. Discussion The GABA B agonist baclofen has been shown to increase the basal LES pressure and to reduce the number of TLESRs, resulting in reduction of acid and nonacid reflux in GERD patients The increase in LES function might be potentially beneficial in patients with rumination syndrome because it might increase the threshold to induce upward movement of liquid gastric contents or gas into the esophagus during straining. In addition to an improved LES function, baclofen decreases the swallowing frequency, which might positively affect aerophagia and supragastric belching. 15 In the current study we studied the effect of baclofen (1-week open-label treatment, 10 mg 3 times a day) on symptoms and postprandial flow events in patients with a clinical suspicion of rumination or supragastric belching. Our results showed that baclofen successfully reduced both symptoms and postprandial flow events, particularly in rumination but also in supragastric belching. The beneficial effect of baclofen treatment seems to be at least partially associated with an increase in basal LES pressure and reduced swallowing frequency. In addition, baclofen significantly reduced TLESRs and straining events, but this was not correlated to the improvement in flow events. Rumination syndrome refers to a clinical entity characterized by the effortless, often repetitive regurgitation of recently ingested food into the mouth. 2,3,19 Although rumination syndrome was originally described in children and in developmentally disabled patients, it is now well recognized that rumination syndrome occurs in patients of all ages and cognitive abilities. 20,21 Typically, the regurgitation in rumination is not preceded by nausea or retching. Although there is a typical symptom profile in patients with rumination, patients are often misdiagnosed as having GERD. In contrast to GERD, rumination is due to a voluntary, although not intentional, act of contracting the abdominal muscles that results in an increase of the intragastric pressure and as a consequence in the upward movement of gastric contents into the esophagus up to the mouth. 4,5,19 The pathophysiological mechanism underlying rumination is incompletely elucidated. Under normal circumstances, the LES in conjunction with the crural diaphragm acts as a barrier between the stomach and the esophagus, and this high-pressure zone should be overcome to allow the gastric contents to enter the esophagus. A low basal LES pressure or straining episodes during TLESRs might facilitate rumination. Besides rumination, belching can also be associated with a voluntary behavior. Both aerophagia (air swallowing) and supragastric belching have been identified as possible underlying causes of excessive belching in otherwise healthy adults. 8 Supragastric belching is characterized by a rapid influx of air in the esophagus that can be due to either a negative intraesophageal pressure (air sucking) or contraction of the pharyngeal muscles (air pushing). As in patients with rumination, the rapid expulsion of air is often initiated by straining. 8,17 In the current study we showed that treatment with baclofen (10 mg 3 times a day), a GABA B receptor agonist, successfully reduced both symptoms and postprandial rumination episodes. Overall, rumination episodes were reduced by 68% during baclofen treatment. Although a clear improvement of symptoms and flow events was observed during baclofen treatment, episodes of rumination and supragastric belching often occurred in the same patient, and the underlying mechanism remains incompletely elucidated. In agreement with previous studies, baclofen increased the LES pressure in 7 of 12 patients. Moreover, the degree of LES pressure increase was significantly correlated with the overall reduction of flow events. The latter finding suggests that an increase in LES pressure might at least partially contribute to improvement in patients with rumination and with excessive belching. In patients with GERD, the beneficial effect of baclofen is mainly due to the reduction of TLESRs, the most important mechanism of reflux in both healthy volunteers and patients with GERD. 10,14,15 It has been suggested that straining during TLESRs might be the mechanism underlying rumination. Although baclofen treatment significantly reduced the number of TLESRs in the current study, we could not observe a significant correlation between the reduction in TLESRs and the reduction in flow events, suggesting that reduction in TLESRs is not the main mechanism underlying the observed improvement in patients with rumination and belching after baclofen treatment. In addition to improvement of the LES function, baclofen reduces the swallowing frequency. 15 In particular in patients with aerophagia, a reduction of the swallowing will reduce the chance to ingest air, thereby leading to symptom improvement. In support of this hypothesis, we found a significant correlation between the reduction in swallowing frequency and the overall reduction of postprandial flow events, but because the current study included only 1 patient with predominant aerophagia, additional studies are needed. Our findings therefore suggest that symptom improvement and reduction of flow events during baclofen treatment might be related to enhanced LES function and/or reduced swallowing frequency. Nevertheless, HRM-impedance recordings during baclofen treatment also showed significantly less straining episodes compared with baseline conditions. Moreover, a number of patients showed significant reduction of symptoms and flow events in the absence of a marked measured effect of the drug on LES function. These findings suggest that baclofen has other effects that might contribute to reducing straining behavior. The reason for the straining in patients with rumination syndrome is unclear, and both psychological factors as well as attempts to relieve dyspeptic symptoms with belching, leading

6 384 BLONDEAU ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 4 to rumination behavior, have been suggested. 19 Given its central mechanisms of action, it is conceivable that baclofen might also affect the compulsive behavior of straining. 22 In addition, baclofen might affect primary vagal afferents, reducing mechanosensitivity of the proximal stomach after gastric distention. 23,24 The current study has some limitations; the most important one is the open-label treatment design. All patients were aware that they were treated with active medication, and therefore a placebo effect cannot be excluded. However, this limitation is partially overcome by analyzing objective flow events and manometry patterns as observed during HRM-impedance. Another limitation is the heterogeneous group of patients included in the current study. Both rumination and supragastric belching are relatively uncommon disorders, making patient recruitment challenging. Although we observed an overall reduction of postprandial flow events, the fact that rumination and supragastric belching episodes occurred often in the same patient made subclassifying patients into different groups difficult. Moreover, even when subclassifying patients on the basis of the predominant event type, the number of patients included was too small to identify the mechanisms underlying the effect of baclofen in this specific patient group. Finally, the magnitude of the clinical benefit of longer-term baclofen treatment and its efficacy compared with behavioral therapies remain to be studied. In conclusion, we showed that baclofen improves symptoms and postprandial flow events in patients with a clinical suspicion of rumination and supragastric belching. Our findings indicate that its effect might be at least partially related to an increase in LES pressure and a reduction of swallowing frequency. However, central effects of the drug, affecting patient s behavior or reducing gastric mechanosensitivity, might also contribute. A placebo-controlled trial seems warranted to confirm these beneficial effects in a large group of patients with rumination and supragastric belching. References 1. Tack J, Blondeau K, Boecxstaens V, et al. Review article: the pathophysiology, differential diagnosis and management of rumination syndrome. Aliment Pharmacol Ther 2011;33: Levine DF, Wingate DL, Pfeffer JM, et al. Habitual rumination: a benign disorder. Br Med J (Clin Res Ed) 1983;287: Malcolm A, Thumshirn MB, Camilleri M, et al. Rumination syndrome. Mayo Clin Proc 1997;72: Rommel N, Tack J, Arts J, et al. Rumination or belching-regurgitation? Differential diagnosis using oesophageal impedance-manometry. Neurogastroenterol Motil 2010;22:e97 e Tutuian R, Castell DO. Rumination documented by using combined multichannel intraluminal impedance and manometry. Clin Gastroenterol Hepatol 2004;2: Tack J, Talley NJ, Camilleri M, et al. Functional gastroduodenal disorders. Gastroenterology 2006;130: Blondeau K, Boecxstaens V, Rommel N, et al. Added value of combined high resolution manometry-impedance recordings in patients with belching and/or postprandial regurgitation. Dis Esophagus 2010;23(Suppl 1): Bredenoord AJ. Excessive belching and aerophagia: two different disorders. Dis Esophagus 2010;23: Bredenoord AJ, Smout AJ. Impaired health-related quality of life in patients with excessive supragastric belching. Eur J Gastroenterol Hepatol 2010;22: Hasler WL. Baclofen effects on esophageal function: a possible therapy for GERD? Gastroenterology 2002;123: Koek GH, Sifrim D, Lerut T, et al. Effect of the GABA(B) agonist baclofen in patients with symptoms and duodeno-gastro-oesophageal reflux refractory to proton pump inhibitors. Gut 2003;52: van Herwaarden MA, Samsom M, Rydholm H, et al. The effect of baclofen on gastro-oesophageal reflux, lower oesophageal sphincter function and reflux symptoms in patients with reflux disease. Aliment Pharmacol Ther 2002;16: Vela MF, Tutuian R, Katz PO, et al. Baclofen decreases acid and non-acid post-prandial gastro-oesophageal reflux measured by combined multichannel intraluminal impedance and ph. Aliment Pharmacol Ther 2003;17: Zhang Q, Lehmann A, Rigda R, et al. Control of transient lower oesophageal sphincter relaxations and reflux by the GABA(B) agonist baclofen in patients with gastro-oesophageal reflux disease. Gut 2002;50: Grossi L, Spezzaferro M, Sacco LF, et al. Effect of baclofen on oesophageal motility and transient lower oesophageal sphincter relaxations in GORD patients: a 48-h manometric study. Neurogastroenterol Motil 2008;20: Sifrim D, Castell D, Dent J, et al. Gastro-oesophageal reflux monitoring: review and consensus report on detection and definitions of acid, non-acid, and gas reflux. Gut 2004;53: Bredenoord AJ, Weusten BL, Sifrim D, et al. Aerophagia, gastric, and supragastric belching: a study using intraluminal electrical impedance monitoring. Gut 2004;53: Holloway RH, Penagini R, Ireland AC. Criteria for objective definition of transient lower esophageal sphincter relaxation. Am J Physiol 1995;268:G128 G Chial HJ, Camilleri M, Williams DE, et al. Rumination syndrome in children and adolescents: diagnosis, treatment, and prognosis. Pediatrics 2003;111: Rogers B, Stratton P, Victor J, et al. Chronic regurgitation among persons with mental retardation: a need for combined medical and interdisciplinary strategies. Am J Ment Retard 1992;96: Whitehead WE, Drescher VM, Morrill-Corbin E, et al. Rumination syndrome in children treated by increased holding. J Pediatr Gastroenterol Nutr 1985;4: Hornby PJ, Abrahams TP, Partosoedarso ER. Central mechanisms of lower esophageal sphincter control. Gastroenterol Clin North Am 2002;31(4 Suppl):S11 S20, v vi. 23. Page AJ, Blackshaw LA. GABA(B) receptors inhibit mechanosensitivity of primary afferent endings. J Neurosci 1999;19: Partosoedarso ER, Young RL, Blackshaw B. GABA (B) receptors on vagal afferent pathways: peripheral and central inhibition. Am J Physiol Gastrointest Liver Physiol 2001;280:G658 G668. Reprint requests Address requests for reprints to: Jan Tack, MD, PhD, Translational Research Center for Gastrointestinal Disorders (TARGID), Kuleuven, O&N1 Box 701, Herestraat 49, B-3000 Leuven, Vlaanderen, Belgium. Jan.Tack@med.kueleuven.be; fax: Conflicts of interest The authors disclose no conflicts. Funding Drs Blondeau and Farré receive funding from the FWO Flanders. This study was funded by a Methusalem grant from Leuven University to Prof Tack.

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