Clinical trial: a controlled trial of baclofen add-on therapy in PPI-refractory gastro-oesophageal reflux symptoms.

BACKGROUND: Proton pump inhibitors (PPI) have no effect on non-acid reflux events which can continue to provoke gastro-oesophageal reflux disease (GERD) symptoms. Baclofen, a γ-aminobutyric acid agonist, can decrease non-acid reflux but its symptomatic benefit in refractory GERD symptoms is understudied. AIMS: To assess the efficacy of baclofen 10 mg t.i.d. vs placebo as add-on therapy in PPI-refractory GERD symptoms, in a randomised, double-blind, placebo-controlled study. METHODS: Patients with persisting typical GERD symptoms on b.i.d. PPI therapy were randomised to 4 weeks of baclofen 10 mg or placebo t.i.d. Before and after treatment, patients underwent 24 h impedance-pH monitoring on-PPI. Throughout the study, patients filled out ReQuest diaries. Data were analysed using mixed models. RESULTS: About 60 patients were included (age 47.5 years [range 19-73], 41f/19 m), 31 patients were randomised to baclofen. One patient withdrew consent and five in the baclofen group stopped treatment due to side effects. There was a trend towards a better response for general wellbeing in the baclofen-treated group compared to placebo (p = 0.06). When subdividing patients according to symptom association probability (SAP), only the SAP+ (n = 25) group improved significantly with baclofen (pcorr  = 0.02), and worsened with placebo (pcorr  = 0.008). The total number of reflux events decreased over time (p = 0.01), mainly due to the baclofen condition (pcorr  = 0.1). The number of reflux events with a high proximal extent dropped significantly after baclofen (pcorr  = 0.009), but not placebo. CONCLUSION: Baclofen decreases several reflux parameters in PPI refractory GERD symptoms, but pH-impedance monitoring is necessary before treatment as only SAP+ patients experience clinical benefit after 4 weeks.

The role of serotonin in the control of esophageal sensitivity assessed by multimodal stimulation in health.

BACKGROUND: Esophageal hypersensitivity is considered an important pathophysiological mechanism in refractory gastroesophageal reflux disease (GERD) patients. Serotonin (5-HT) plays an important role in the regulation of GI (gastrointestinal) secretion, motility and sensitivity. Previous studies found that altered 5-HT availability has no clear effects on esophageal/GI sensations. Our aim was therefore to investigate the role of 5-HT in esophageal sensitivity in healthy volunteers (HV). METHODS: Esophageal sensitivity to thermal, mechanical, electrical, and chemical stimuli was assessed in 3 different placebo-controlled studies. In the first study, the effect of citalopram (40 mg; 5-HT reuptake inhibitor; intravenous) was investigated (n = 14). In the second study, the effect of buspirone (20 mg; 5HT1A agonist; oral) was investigated (n = 10). In the third study, acute tryptophan depletion (ATD) was used to decrease 5-HT levels to investigate the effect of reduced 5-HT availability on esophageal sensitivity (n = 15). KEY RESULTS: No difference was observed in esophageal sensitivity after the administration of citalopram or buspirone (all p > 0.06). In contrast, pain perception threshold to chemical stimulation was increased after ATD (p = 0.017, Cohen's d+ = 0.67). No effect was found on the first perception or pain tolerance threshold. ATD had no influence on esophageal sensitivity to thermal, mechanical, and electrical stimulation compared with placebo. CONCLUSIONS AND INFERENCES: ATD, which induces 5-HT depletion, significantly decreased pain perception threshold during chemical stimulation, without affecting sensitivity to mechanical, thermal, or electrical stimulation. These findings confirm the involvement of 5-HT in the control of esophageal acid sensitivity, but identifying the receptors involved requires more ligands and studies.

Effect of citalopram on esophageal motility in healthy subjects-Implications for reflux episodes, dysphagia, and globus.

BACKGROUND: Drugs such as citalopram, "targeting" the serotonin pathway, can alter esophageal mechano-chemical sensitivity and gastrointestinal motility. The aim of this study was to clarify the effect of citalopram on esophageal motility and sphincter function, transient lower esophageal sphincter relaxations (TLESRs), and reflux events. METHODS: Sixteen healthy volunteers (HV) receiving 20 mg citalopram or placebo intravenously, in a randomized cross-over fashion, underwent two high-resolution impedance manometry studies involving liquid swallows and a high-fat, high-caloric meal. Manometric, reflux, and symptom-related parameters were studied. KEY RESULTS: A lower distal contractile integral was recorded under citalopram, compared with placebo (P = 0.026). Upper esophageal sphincter (UES) resting pressure was significantly higher after citalopram administration throughout the study (P < 0.05, all periods). Similarly, the UES postswallow mean and maximum pressures were higher in the citalopram condition (P < 0.0001, in both cases) and this was also the case for the 0.2 s integrated relaxation pressure (P = 0.04). Esophagogastric junction resting pressures in the citalopram visit were significantly higher during swallow protocol, preprandial period, and the first postprandial hour (P < 0.05, in all cases). TLESRs and total reflux events were both reduced after citalopram infusion (P = 0.01, in both cases). During treatment with citalopram, five participants complained about globus sensation (P = 0.06). This citalopram-induced globus was associated with higher UES postswallow mean and maximum pressure values (P = 0.01 and P = 0.04, respectively). CONCLUSIONS AND INFERENCES: Administration of citalopram exerts a diversified response on esophageal motility and sphincter function, linked to clinically relevant phenomena: a reduction in postprandial TLESRs and the induction of drug-induced globus.

The optimal order of stimulation modalities and reproducibility of the multimodal esophageal stimulation paradigm.

BACKGROUND: Esophageal hypersensitivity can be triggered by different stimuli. We use a multimodal stimulation model to study esophageal sensitivity to four sensory modalities: thermal, mechanical, electrical, and chemical stimulation. The optimal order of these stimulations needs further validation. METHODS: Esophageal sensitivity to thermal (heated saline solution), mechanical (balloon distention), electrical (block pulses with electrodes), and chemical stimulation (acid solution, 0.1 N HCl) was assessed in 10 subjects. In one session, thermal stimulation was performed first, followed by mechanical stimulation ("original protocol"). In a second session, mechanical stimulation was performed first, followed by temperature stimulation ("reversed protocol"). Besides, the impact of balloon distention speed (25 mL/min vs 50 mL/min) during mechanical stimulation was evaluated. Secondly, in order to establish reproducibility, independent control sessions of multimodal stimulations in 15 healthy volunteers were used retrospectively. KEY RESULTS: A significant difference in pain perception threshold for thermal stimulation was found between the original and reversed protocol (P = 0.046), indicating that mechanical stimulation can sensitize the esophagus to thermal stimulation. Balloon distention rate had no impact on sensitivity thresholds for mechanical stimulation. Concerning the reproducibility, there were no differences for thermal, mechanical, electrical, and chemical stimulation in any of the control sessions. CONCLUSIONS: The optimal order of the multimodal stimulation protocol was to start with the thermal stimulation, followed by mechanical, electrical, and chemical stimulation. The optimal balloon distention rate was 25 mL/min. Multimodal esophageal stimulation generates reproducible perception scores in health and therefore provides a reliable method to assess esophageal sensitivity changes after interventions that may alter esophageal sensitivity.

A reduced esophageal epithelial integrity in a subgroup of healthy individuals increases with proton pump inhibitor therapy.

INTRODUCTION: Approximately 30% of healthy volunteers (HVs) show dilated intercellular spaces in the esophageal epithelium suggesting a functionally reduced epithelial integrity. We aimed to evaluate the presence of an altered epithelial integrity in HVs and whether physiological acid could explain such a difference. METHODS: Biopsies for Ussing chamber experiments were taken between 3 cm and 5 cm proximal to the gastroesophageal junction. Twenty-four-hour impedance-pH (MII-pH) monitoring was performed in the same 15 HVs. MII-pH tracings from 24 HVs before and after treatment with esomeprazole (40 mg b.i.d., two weeks), a proton pump inhibitor, were analyzed. Reflux parameters and impedance baseline (IB) at different levels of the esophagus were calculated. RESULTS: Epithelial integrity in the distal esophagus presents a large variability in vivo and in vitro (transepithelial electrical resistance 196.9 ± 16.27Ω. cm2; IB measurements 2022 ± 143.5Ω). Esomeprazole highly suppressed the total acid exposure time (AET) (1.9 (0.8-3.1) vs 0 (0-0)%, p < 0.0001). After splitting our participants into "high" and "low" IB, based on the median value, we observed only in the distal esophagus a higher total AET before (2.8 (1.6-4.8) vs 1.0 (0.5-2.2), p = 0.04) and increased IB values after esomeprazole (1620 (1347-1898) vs 2192 (1784-2503)Ω, p = 0.002) in the "low" IB group. CONCLUSION: A subgroup of HVs presents a low epithelial integrity in the distal esophagus probably due to the increased presence of physiological acid reflux. Whether these individuals have a higher chance to develop gastroesophageal reflux disease is unknown. The role of epithelial integrity in symptom perception needs to be further explored.

A Randomized Double-Blind, Placebo-Controlled, Cross-Over Study Using Baclofen in the Treatment of Rumination Syndrome.

OBJECTIVES: Both rumination syndrome and supra-gastric belching (SGB) have limited treatment options. We demonstrated (open-label) that baclofen reduces pressure flow events in these patients. We aimed to study the effect of baclofen in a placebo-controlled, double-blind, cross-over study in patients with clinically suspected rumination and/or SGB. METHODS: Twenty tertiary-care patients (mean age 42 years (range 18-61), 13f) with clinically suspected rumination and/or SGB were randomized to receive baclofen (10 mg, t.i.d) or placebo for 2 weeks with cross-over to the alternative intervention after a 1 week wash-out period. At the end of each treatment period, patients underwent a solid-state high-resolution impedance manometry measurement, during which they registered symptoms. Patients received a solid meal and recordings continued for 1 h. They scored overall treatment evaluation (OTE) on a -3 to +3 scale. RESULTS: Both the number of regurgitation event markers and rumination episodes were significantly decreased after baclofen (6 (0-19) vs. 4 (0-14), P=0.04; 13 (8-22) vs. 8 (3-11), P=0.004). The number of SGB episodes was similar in both groups. Lower esophageal sphincter (LES) pressure was significantly higher and the number of transient LES relaxations was significantly lower after baclofen (17.8 (12.7-22.7) vs. 13.1 (7.2-16.9) mm Hg, P=0.0002; 4(1-8) vs. 7(3-12), P=0.17). The number of reflux events decreased in the baclofen condition (4 (1-9) vs. 3 (0-6), P=0.03). Straining episodes were similar in both arms, but the rumination/straining ratio was significantly lower in the baclofen arm (0.06 (0-0.32) vs. 0.33 (0-0.51), P=0.0012). OTE was superior after baclofen compared to placebo (P=0.03). CONCLUSIONS: Baclofen is an effective treatment option for patients with rumination syndrome, probably through its effect on LES pressure.

The effect of intravenous corticotropin-releasing hormone administration on esophageal sensitivity and motility in health.

Esophageal hypersensitivity is important in gastroesophageal reflux disease (GERD) patients who are refractory to acid-suppressive therapy. Stress affects visceral sensitivity and exacerbates heartburn in GERD. Peripheral CRH is a key mediator of the gut stress response. We hypothesize that CRH increases esophageal sensitivity and alters esophageal motility in health. Esophageal sensitivity to thermal, mechanical, electrical, and chemical stimuli was assessed in 14 healthy subjects after administration of placebo or CRH (100 µg iv). Perception scores were assessed for first perception, pain perception threshold (PPT), and pain tolerance threshold (PTT). Esophageal motility was investigated by high-resolution impedance manometry, before and after CRH and evaluated by distal contractile integral (DCI) and intrabolus pressure (IBP). Pressure flow analysis assessed bolus clearance (impedance ratio), degree of pressurization needed to propel bolus onward (IBP slope), and pressure flow (pressure flow index, PFI). Stress and mood were assessed during the study. Sensitivity to mechanical distention was increased after CRH compared with placebo (PPT: P = 0.0023; PTT: P = 0.0253). CRH had no influence on the other stimulations. DCI was increased for all boluses (liquid, P = 0.0012; semisolid, P = 0.0017; solid, P = 0.0107). Impedance ratio for liquid (P < 0.0001) and semisolid swallows (P = 0.0327) decreased after CRH. IBP slope increased after CRH for semisolid (P = 0.0041) and solid (P = 0.0003) swallows. PFI increased for semisolid (P = 0.0017) and solid swallows (P = 0.0031). CRH increased esophageal sensitivity to mechanical distention, not to the other stimulation modalities. CRH increased esophageal contractility and tone, decreased LES relaxation, increased esophageal bolus pressurization, improved esophageal bolus clearance, and increased pressure flow.NEW & NOTEWORTHY This is the first study to address the effect of corticotropin-releasing hormone (CRH) on esophageal sensitivity and alterations in motility in health. CRH administration increased esophageal sensitivity to mechanical distention. This effect is accompanied by an increase in esophageal contractility and tone and a decrease in lower esophageal sphincter relaxation. CRH increased esophageal bolus pressurization, improved esophageal bolus clearance, and increased pressure flow. The changes in esophageal contractile properties may underlie the increased sensitivity to mechanical distention after CRH.

Shifting the circadian rhythm of feeding in mice induces gastrointestinal, metabolic and immune alterations which are influenced by ghrelin and the core clock gene Bmal1.

BACKGROUND: In our 24-hour society, an increasing number of people are required to be awake and active at night. As a result, the circadian rhythm of feeding is seriously compromised. To mimic this, we subjected mice to restricted feeding (RF), a paradigm in which food availability is limited to short and unusual times of day. RF induces a food-anticipatory increase in the levels of the hunger hormone ghrelin. We aimed to investigate whether ghrelin triggers the changes in body weight and gastric emptying that occur during RF. Moreover, the effect of genetic deletion of the core clock gene Bmal1 on these physiological adaptations was studied. METHODS: Wild-type, ghrelin receptor knockout and Bmal1 knockout mice were fed ad libitum or put on RF with a normal or high-fat diet (HFD). Plasma ghrelin levels were measured by radioimmunoassay. Gastric contractility was studied in vitro in muscle strips and in vivo (13C breath test). Cytokine mRNA expression was quantified and infiltration of immune cells was assessed histologically. RESULTS: The food-anticipatory increase in plasma ghrelin levels induced by RF with normal chow was abolished in HFD-fed mice. During RF, body weight restoration was facilitated by ghrelin and Bmal1. RF altered cytokine mRNA expression levels and triggered contractility changes resulting in an accelerated gastric emptying, independent from ghrelin signaling. During RF with a HFD, Bmal1 enhanced neutrophil recruitment to the stomach, increased gastric IL-1α expression and promoted gastric contractility changes. CONCLUSIONS: This is the first study demonstrating that ghrelin and Bmal1 regulate the extent of body weight restoration during RF, whereas Bmal1 controls the type of inflammatory infiltrate and contractility changes in the stomach. Disrupting the circadian rhythm of feeding induces a variety of diet-dependent metabolic, immune and gastrointestinal alterations, which may explain the higher prevalence of obesity and immune-related gastrointestinal disorders among shift workers.