Effect of Capsaicinoids on Neurophysiological, Biochemical, and Mechanical Parameters of Swallowing Function.

Oropharyngeal dysphagia is prevalent in age-related neurological disorders presenting with impaired efficacy and safety of swallowing due to a loss of muscle force and sensory deficits. Stimulating the oropharynx with capsaicin that mediates Substance P release is an emerging pharmacological treatment option which needs further scientific evidence. Our aim was to comprehensively evaluate the effect of capsaicin on biochemical, neurophysiological, and biomechanical parameters of swallowing function. In a randomized study on healthy individuals, the impact of orally administered capsaicinoids at different dosages and application durations in comparison to non-carbonated water was evaluated. Time course and magnitude of salivary Substance P increase were monitored. Magnetoencephalography was used to detect cortical swallowing network alterations. Modifications in swallowing biomechanics were measured applying high-resolution pharyngeal manometry. Capsaicinoids at 10 µmol/L improved swallowing efficacy as seen by a significant increase of pharyngeal contractile integral and upper esophageal sphincter activation and relaxation times in manometry. Significant improvement of precision in a challenging swallow task accompanied by a reduction in swallowing-related submental electromyographic power was observed with capsaicinoids preconditioning at 10 µmol/L over 5 min, but not with continuous stimulation. The cortical activation pattern remained unchanged after any intervention. A significant increase of salivary Substance P was not detected with 10 µmol/L but with 50 µmol/L and lasted for 15 min after application. Capsaicinoids mediate dose-dependent Substance P release and positively alter swallowing biomechanics in healthy subjects. The results provide supportive evidence for the value of natural capsaicinoids to improve swallowing function.

Cricopharyngeal bar and dermatomyositis: A cause of rapidly progressive dysphagia.

BACKGROUND: Idiopathic inflammatory myopathies (IIM) are immune-mediated conditions that affect striated muscle, and are frequently associated with dysphagia. Dysphagia in these cases can be due to weakness of the muscles involved in swallowing or the presence of restrictive pharyngeal defects, such as cricopharyngeal bars. Treatment of dysphagia in IIM revolves around immunosuppressive therapies, and procedures to disrupt cricopharyngeus muscle when immunosuppressive therapies are unsuccessful. CASE REPORT: A 73-year-old female presented with rapidly progressive proximal muscle weakness and dysphagia to the point she could not swallow liquids or solids. She had a rash over the extensor surfaces of the limbs, and periorbital-edema. Her creatine kinase was elevated, and skin biopsy showed an interface inflammatory reaction; however, myositis line assay revealed no autoantibodies, and a muscle biopsy was unremarkable. She was diagnosed with dermatomyositis with life-threatening dysphagia, and was admitted to our institution and treated with corticosteroids, methotrexate and intravenous immunoglobulin. A videofluoroscopic swallowing study revealed a large esophageal protrusion at the level of C5-C6, which was thought to be consistent with a cricopharyngeal bar, with large boluses unable to pass, leading to aspiration. After 10 weeks of treatment, the cricopharyngeal bar remained present, but swallowing had improved to the point that she was successfully swallowing all consistencies. CONCLUSION: Dysphagia associated with IIM can be multifactorial, and can be due to the involvement of the muscles of swallowing in the inflammatory process, or due to restrictive pharyngeal defects, and determination of the cause of dysphagia can assist with management.

Codeine induces increased resistance at the esophagogastric junction but has no effect on motility and bolus flow in the pharynx and upper esophageal sphincter in healthy volunteers: A randomized, double-blind, placebo-controlled, cross-over trial.

BACKGROUND: Chronic opioid use can induce esophageal dysfunction with symptoms resembling achalasia and a manometric pattern of esophagogastric junction-outflow obstruction (EGJ-OO). However, the effect of opioids in acute setting on pharyngeal function and esophageal body contractility has not been investigated. METHODS: After positioning the high-resolution impedance manometry (HRiM) catheter, codeine (60 mg) or placebo (glucose syrup) was infused intragastrically. Forty-five minutes post-infusion, participants received liquid, semi-solid, and solid boluses to assess esophageal and pharyngeal function. HRiM analysis was performed adhering to the Chicago classification v3.0. (CC v3.0). Pressure flow analysis (PFA) for the esophageal body and the pharynx was performed using the SwallowGateway™ online platform. KEY RESULTS: Nineteen healthy volunteers (HV) [5 male; age 38.3] were included. After codeine administration, higher integrated relaxation pressure 4 s values resulted in significantly reduced deglutitive EGJ relaxation and distal latency was significantly shorter. Distal contractility was similar in both conditions. Bolus flow resistance at the EGJ and distention pressures increased significantly after codeine infusion. Based on CC v3.0, acute infusion of codeine induced EGJ-OO in six HV (p = 0.0003 vs. placebo). Codeine administration induced no significant alterations in any of the pharyngeal PFA metrics. CONCLUSIONS & INFERENCES: In HV, acute administration of codeine increased bolus resistance at the EGJ secondary to induced incomplete EGJ relaxation leading to major motility disorders in a subset of subjects including EGJ-OO. However, an acute single dose of codeine did not affect motility or bolus flow in pharynx and UES. ClinicalTrials.gov number, NCT03784105.

Effect of topical nasal anesthetic on swallowing in healthy adults: A double-blind, high-resolution manometry study.

OBJECTIVE: Topical nasal anesthetic (TNA) is used when evaluating pharyngeal swallowing with high-resolution manometry (HRM). It is unclear if desensitizing the nasal mucosa improves procedure tolerability or affects pharyngeal pressure. This study evaluated the effects of TNA on comfort and pharyngeal pressure using HRM. METHODS: A double-blinded study was conducted with 20 healthy participants ( x¯ = 27 years). Participants performed five saliva and five 10-mL swallows during two exams with ManoScan HRM ESO catheter (Medtronic, Minneapolis, MN) randomized under placebo (nonanesthetic lubricant) and anesthetized (0.4 mL of 2% viscous lidocaine hydrochloride) conditions. Comfort was rated using a 100-mm visual analog scale (VAS). Pharyngeal HRM amplitude and timing were analyzed. RESULTS: VAS ratings were similar under placebo (mean = 38.4, standard deviation [SD] = 19.92) and TNA conditions (mean = 33.78, SD = 18.9), with no significant differences between placebo and anesthetized conditions (t[19] = 1.23, P = 0.23) or tolerability at first and second procedure (t[19] = 1.38, P = 0.18). Lower maximum and mean pharyngeal pressure were found for the TNA condition when compared to placebo (dry: maximum [-15.45 mmHg, standard error (SE) = 5.06 mmHg, P = 0.021]; mean [-5.22 mmHg, SE = 1.58 mmHg, P = 0.005]), and (liquid: maximum [-14.79 mmHg, SE = 5.01 mmHg, P = 0.010]; mean [-2.79 mmHg, SE = 1.99 mmHg, P = 0.008]). CONCLUSION: This double-blind, randomized study is the first to investigate effects of TNA on tolerability and pharyngeal pressure using HRM. Results indicate TNA offered no significant difference in procedure comfort while affecting the magnitude of pharyngeal swallowing. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1335-1339, 2018.

The effects of paroxetine and amitriptyline on the upper esophageal sphincter (UES) pressure and its natural history in globus pharyngeus.

BACKGROUND: Antidepressant agents have been shown to be an effective and safe treatment method for patients with globus. However, there are few clinical trials dedicated to studying the effects of antidepressant agents on the natural history and upper oesophageal sphincter (UES) pressure of treated globus patients. AIMS: To evaluate the effect of paroxetine and amitriptyline to prevent relapses in patients with globus, the simultaneous relationship between changes in UES pressure and improvement of globus symptoms were measured. METHODS: Globus patients were randomised into amitriptyline, paroxetine and lansoprazole groups for a 6-week treatment period, and follow-up was extended to 12 additional months. Efficacy was evaluated in terms of the Glasgow-Edinburgh Throat Scale (GETS), and UES pressure was measured by standard oesophageal manometry. RESULTS: Paroxetine therapy resulted in a higher withdrawal rate due to symptom relapse (15.9% vs 44.1%, P=0.01; 15.9% vs 64.7, P=0.001) than amitriptyline and lansoprazole. Furthermore, globus symptoms were alleviated with the decrease of UES pressure after paroxetine and amitriptyline treatment (r=0.620, P=0.02; r=0.575, P=0.03) CONCLUSIONS: This follow-up study indicates that paroxetine may alter the natural history of globus and can effectively be used for the long-term management of patients with the disease. Apart from the clinical benefits, paroxetine and amitriptyline can potentially decrease UES pressure.

Normal and abnormal physiology, pharmacology, and anatomy of the gastroesophageal junction high-pressure zone.

The high-pressure zone of the gastroesophageal junction acts as a multifunctional valve that comprises different groups of smooth muscles located in the distal esophagus and the proximal stomach, in addition to the extrinsic crural diaphragm, composed of skeletal muscle. In this review article, we evaluate the current literature with respect to human subjects, discussing the anatomic locations and physiologic and pharmacologic processes controlling these muscles. These muscles work individually and as a group to prevent reflux of gastric contents while allowing anterograde passage of food and liquid and retrograde passage of gas. We also reviewed new findings with respect to abnormalities that are permissive of reflux of gastric contents into the esophagus, which may lead to gastroesophageal reflux disease.

Remifentanil alters sensory neuromodulation of swallowing in healthy volunteers: quantification by a novel pressure-impedance analysis.

Exposure to remifentanil contributes to an increased risk of pulmonary aspiration, likely through reduced pharyngeal contractile vigor and diminished bolus propulsion during swallowing. We employed a novel high-resolution pressure-flow analysis to quantify the biomechanical changes across the upper esophageal sphincter (UES). Eleven healthy young (23.3 ± 3.1 yr old) participants (7 men and 4 women) received remifentanil via intravenous target-controlled infusion with an effect-site concentration of 3 ng/ml. Before and 30 min following commencement of remifentanil administration, participants performed ten 10-ml saline swallows while pharyngoesophageal manometry and electrical impedance data were recorded using a 4.2-mm-diameter catheter housing 36 circumferential pressure sensors. Remifentanil significantly shortened the duration of UES opening (P < 0.001) and increased residual UES pressure (P = 0.003). At the level of the hypopharynx, remifentanil significantly shortened the latency from maximum bolus distension to peak contraction (P = 0.004) and significantly increased intrabolus distension pressure (P = 0.024). Novel mechanical states analysis revealed that the latencies between the different phases of the stereotypical UES relaxation sequence were shortened by remifentanil. Reduced duration of bolus flow during shortened UES opening, in concert with increased hypopharyngeal distension pressures, is mechanically consistent with increased flow resistance due to a more rapid bolus flow rate. These biomechanical changes are congruent with modification of the physiological neuroregulatory mechanism governing accommodation to bolus volume.

Cricopharyngeal achalasia in children: surgical and medical treatment.

BACKGROUND: Cricopharyngeal achalasia (CA) is a rare cause of dysphagia in children presenting with non-specific symptoms such as choking, food regurgitation, nasal reflux, coughing, recurrent pneumonia, cyanosis, and failure to thrive. It results from failure of relaxation of the upper esophageal sphincter (UES) and may appea reither as an isolated lesion or in conjunction with other pathologies. Recognition and early diagnosis of this condition may minimize morbidity in children. OBJECTIVES: To evaluate the clinical course of four children with cricopharyngeal achalasia presenting to our clinic. METHODS: We conducted a 5 year retrospective chart review in a tertiary referral center. RESULTS: Four children were diagnosed with primary cricopharyngeal achalasia between 2006 and 2010. Diagnosis was established by videofluoroscopy and all underwent uneventful cricopharyngeal myotomy. Three children recovered completely and one child showed partial improvement. For residual UES spasm in a partially improved patient, botulinum toxin was injected into the UES which led to further improvement. Dysphagia recurred in one child who was successfully treated with botulinum toxin injection. CONCLUSIONS: Cricopharyngeal myotomy is a safe procedure in infants and young children. Botulinum toxin injection of the UES was found to be effective in refractory cases.

Botulinum toxin injection for the treatment of upper esophageal sphincter dysfunction.

OBJECTIVES: We sought to review the dysphagia-related outcomes and quality of life in a series of patients with upper esophageal sphincter (UES) dysfunction treated with cricopharyngeal (CP) botulinum toxin (BTX) injection, and to identify patient characteristics or CP muscle histologic features that predict efficacy of BTX injection. METHODS: A retrospective chart review was performed on patients with UES dysfunction who underwent CP BTX injection. Dysphagia-related quality-of-life questionnaires based on the Eating Assessment Tool (EAT-10) were mailed to patients. RESULTS: Forty-nine patients (30 female, 19 male; average age, 59 +/- 16 years) with UES dysfunction have been treated at our institution with CP BTX injection since 2000. Seventeen of these patients also underwent CP myotomy. Injections of BTX were occasionally repeated after the treatment effect subsided, and the BTX dose varied widely (average, 39 +/- 19 units). Improvement in symptoms was noted by 65% of patients. The overall complication rate was minimal, although many patients complained of transient worsening of dysphagia after CP BTX injection. Biopsy specimens of the CP muscle were evaluated in the subset of patients with CP BTX injection who proceeded to myotomy, with results of neuropathic, myopathic, and mixed histologic subtypes. The EAT-10 scores demonstrated a general trend toward improved swallowing outcomes after CP BTX injection. CONCLUSIONS: This study reviewed findings from the largest published series of BTX treatment of UES dysfunction and evaluated the efficacy, patient satisfaction, and complications of this procedure. Dysphagia-related quality-of-life outcomes appear to be improved after CP BTX injection.

Modulation of esophageal afferent pathways by 5-HT3 receptor inhibition.

BACKGROUND: The study aims were to investigate whether neural pathways involving 5-HT3 receptors mediate: (i) distension-induced upper esophageal sphincter (UES) relaxation reflex, (ii) esophageal sensitivity to acid and electrical stimuli, and (iii) viserosomatic sensitization following acid exposure. METHODS: In Study I, in a double-blind crossover trial (n = 9) esophageal sensory and pain thresholds to electrical stimulation were measured in the esophagus, midsternum, and the foot, before subjects were randomized to receive either Ondansetron (8 mg i.v.) or NaCl (0.9% w/v). HCl (0.15 mol L(-1)) was then infused into distal esophagus and electrical thresholds were reassessed. Following electrical sensory threshold testing, subjects received a second esophageal infusion of HCl to evaluate esophageal sensitivity to acid. In Study II (N = 10), frequencies of distension-induced UES relaxation responses were scored before and after treatment with Ondansetron and NaCl in a double-blind crossover trial. KEY RESULTS: In Study I, ondansetron had no effect on esophageal sensitivity to HCl or acid-induced sensitization. However, blockade of 5-HT3 receptors did reduce midsternum somatic pain thresholds. Sixty minutes after esophageal acid exposure, pain thresholds were significantly lower in the ondansetron arm (mean Δ-1.36 ± 0.4 mA) when compared with NaCl (mean Δ-0.14 ± 0.58 mA) (P < 0.05). In Study II, 5-HT3 receptor blockade had no significant effect on UES relaxation reflex. CONCLUSIONS & INFERENCES: This study does not support the hypothesis that in health, 5-HT3 receptors play a significant role in esophago-UES distention-induced relaxation reflex and esophageal sensitivity to acid or electrical stimulation. It does provide new evidence for involvement of 5-HT3 receptors in viscerosomatic sensitization.

ALS dysphagia pathophysiology: differential botulinum toxin response.

OBJECTIVES: This study looked at the effect of botulinum toxin type A (BoTox-A) in patients with amyotrophic lateral sclerosis (ALS) with dysphagia due to isolated upper motor neuron (UMN) involvement or combined UMN/lower motor neuron (LMN) impairment associated with oral phase or oropharyngeal muscles involvement. Establishing whether different pathophysiologic mechanisms underlie different responses to BoTox-A treatment may have important implications for patient management. PATIENTS AND METHODS: We screened 35 patients with sporadic ALS with dysphagia and included in the study 20 out of 35 with upper esophageal sphincter (UES) hyperactivity. We divided these 20 patients into 2 groups, based on the presence or absence of LMN impairment. Irrespective of the groups, we treated all 20 patients with BoTox-A injected into the UES. The study outcome was dysphagia severity scored using the Penetration/Aspiration Scale (PAS), measured before and 2, 4, and 20 weeks after injection. RESULTS: Significant mean PAS reduction was noted at weeks 2 and 4. The botulinum-dependent PAS reduction was entirely associated with the variability shown by the group of patients with no sign of LMN impairment (group 2) and was not observed in group 1. CONCLUSIONS: The significant improvement observed in patients with isolated UES dysfunction suggests that a different pathophysiology of ALS dysphagia predisposes patients to a different response to treatment with BoTox-A. This treatment may represent an alternative treatment to percutaneous endoscopic gastrostomy (PEG) or prolong PEG-free time. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that botulinum is more effective at 2 and 4 weeks in improving dysphagia in patients with ALS with UES hyperactivity without LMN involvement (vs those with LMN involvement).

Endoscopic cricopharyngeal myotomy for management of cricopharyngeal achalasia (CA) in an 18-month-old child.

A 6-month-old patient presented with dysphagia and failure to thrive. Video fluoroscopic swallow study (VFSS), esophagogastroduodenoscopy, and manometry were diagnostic for CA. A gastrostomy tube was placed at 8 months. Botulinum toxin injection improved symptoms, but within 10 weeks symptoms returned. At 18 months, an uncomplicated endoscopic CPM was performed. A postoperative VFSS demonstrated cricopharyngeal bar resolution. Within 3 months, patient was feeding orally without a G tube. Pediatric CPA treatment options consist of dilation, botox, and transcervical CPM. To our knowledge, this is the youngest patient treated with endoscopic CPM. Intraoperative video and photographs are presented.

Influence of experimental esophageal acidification on sleep bruxism: a randomized trial.

UNLABELLED: The aim of this cross-over, randomized, single-blinded trial was to examine whether intra-esophageal acidification induces sleep bruxism (SB). Polysomnography with electromyogram (EMG) of masseter muscle, audio-video recording, and esophageal pH monitoring were performed in a sleep laboratory. Twelve healthy adult males without SB participated. Intra-esophageal infusions of 5-mL acidic solution (0.1 N HCl) or saline were administered. The frequencies of EMG bursts, rhythmic masticatory muscle activity (RMMA) episodes, grinding noise, and the RMMA/microarousal ratio were significantly higher in the 20-minute period after acidic infusion than after saline infusion. RMMA episodes including SB were induced by esophageal acidification. This trial is registered with the UMIN Clinical Trials Registry, UMIN000002923. ABBREVIATIONS: ASDA, American Sleep Disorders Association; EMG, electromyogram; GER, gastroesophageal reflux; LES, lower esophageal sphincter; NREM, non-rapid eye movement; REM, rapid eye movement; RMMA, rhythmic masticatory muscle activity; SB, sleep bruxism; SD, standard deviation; UES, upper esophageal sphincter.

Effects of cricoid pressure and remifentanil on the esophageal sphincters using high-resolution solid-state manometry.

BACKGROUND: Cricoid pressure has been shown to decrease the pressure in the lower esophageal sphincter (LES), increasing the risk of aspiration. Whether this reaction is due to pain associated with the application of cricoid pressure has not been studied. The aim of this study was to compare the effects of cricoid pressure with those of peripheral pain on pressures in the LES, and to study whether remifentanil influences these effects. Data from the upper esophageal sphincter (UES) are also described. METHODS: Continuous solid-state manometry was performed in 14 healthy volunteers. Initially, the effect of remifentanil (target-controlled infusion with a plasma target concentration of 5.0 ng/ml) was studied, and thereafter, the effects of cricoid pressure and peripheral pain stimulation (cold stimulation). Finally, these two interventions were repeated under ongoing remifentanil infusion. RESULTS: Remifentanil decreased the LES pressure significantly [ΔP-6.5 mmHg, 95% confidence interval (95% CI) -1.7 to -11.2]. Cricoid pressure application decreased the LES pressure significantly (ΔP-3.7 mmHg, 95% CI -1.4 to 6.1), whereas peripheral pain did not (ΔP 1.2 mmHg, 95% CI -3.5 to 1.1). Under ongoing remifentanil infusion, no cricoid pressure-induced LES relaxation was observed. Cricoid pressure induced high pressures in the area of the UES, 215.7 (±91.2) mmHg without remifentanil vs. 219.4 (±74.2) mmHg with remifentanil. CONCLUSIONS: Remifentanil as well as cricoid pressure per se induced decreases in LES pressure. However, cricoid pressure-induced changes of the barrier pressure were not significant whether induced with or without an infusion of remifentanil.

Effects of propofol on oesophageal sphincters: a study on young and elderly volunteers using high-resolution solid-state manometry.

BACKGROUND AND OBJECTIVE: The oesophageal sphincters play an important role in protecting the airway. During manometric studies, administration of an anxiolytic agent is often required to make insertion of the catheter acceptable for the patient. The anxiolytic should not affect the results of the measurements. This study evaluates the effects of two different doses of propofol on the pressures in the oesophageal sphincters. The effect of increased abdominal pressure was also studied. METHODS: Twenty healthy volunteers, 10 young (mean age 25 years) and 10 elderly (mean age 71 years), were recruited. The effects of a low dose of propofol [0.3 mg kg(-1) intravenously (i.v.)] and a high dose of propofol (young group 0.9 mg kg(-1) i.v. and elderly group 0.6 mg kg(-1) i.v.) were studied with and without external abdominal pressure. RESULTS: There were no statistically significant changes in lower oesophageal sphincter (LOS) pressure after the low dose of propofol. After the high dose, there was an increase in LOS pressure, which was statistically significant in the young group (P < 0.05). The upper oesophageal sphincter (UOS) pressure decreased after both doses of propofol (P < 0.01 for the higher dose and P < 0.05 for the lower dose). CONCLUSION: A low dose of propofol (0.3 mg kg(-1) i.v.) leaves the LOS unaffected in young and elderly volunteers and can be used safely as an anxiolytic agent during studies of the LOS without influencing the results. However, the UOS is more sensitive to the effects of propofol and we do not recommend the use of propofol as an anxiolytic agent during manometric studies of the UOS.

Effects of lesogaberan on reflux and lower esophageal sphincter function in patients with gastroesophageal reflux disease.

BACKGROUND & AIMS: Transient lower esophageal sphincter relaxations (TLESRs) are a major mechanism behind reflux. This study assessed the effects of lesogaberan (AZD3355), a novel gamma-aminobutyric acid type B receptor agonist, on reflux and lower esophageal sphincter (LES) function when used as add-on treatment in patients with reflux symptoms despite proton pump inhibitor (PPI) treatment. METHODS: In this randomized, double-blind, placebo-controlled, crossover study, patients received lesogaberan (65 mg) or placebo twice on day 1 (morning/evening) and once on day 2 (morning), in addition to existing PPI treatment. Patients consumed a standardized meal 45-60 minutes after morning doses. Ambulatory impedance-pH monitoring was conducted for 24 hours after the first dose on day 1. Stationary manometry and impedance-pH monitoring was conducted for 4 hours after the third dose on day 2. RESULTS: Of 27 randomized patients, 21 were included in the per-protocol efficacy analysis. During the 24 hours after treatment start, lesogaberan reduced the mean number of reflux events by approximately 35% compared with placebo. During the 3 postprandial hours on day 2, lesogaberan reduced the geometric mean number of TLESRs by 25% and increased geometric mean LES pressure by 28% compared with placebo. The most common adverse events were headache (placebo: 11/27 patients; lesogaberan: 8/25 patients) and paresthesia (transient; placebo: 3/27 patients; lesogaberan: 5/25 patients). CONCLUSIONS: In patients with reflux symptoms despite PPI treatment, lesogaberan decreased the number of TLESRs and reflux episodes, and increased LES pressure compared with placebo. These findings support further evaluation of lesogaberan as an add-on treatment in patients partially responding to PPIs.

Effect of systemic alcohol and nicotine on airway protective reflexes.

OBJECTIVES: Injection of water into the pharynx induces contraction of the upper esophageal sphincter (UES), triggers the pharyngo-UES contractile reflex (PUCR), and at a higher volume, triggers an irrepressible swallow, the reflexive pharyngeal swallow (RPS). These aerodigestive reflexes have been proposed to reduce the risks of aspiration. Alcohol ingestion can predispose to aspiration and previous studies have shown that cigarette smoking can adversely affect these reflexes. It is not known whether this is a local effect of smoking on the pharynx or a systemic effect of nicotine. The aim of this study was to elucidate the effect of systemic alcohol and nicotine on PUCR and RPS. METHODS: Ten healthy non-smoking subjects (8 men, 2 women; mean age: 32+/-3 s.d. years) and 10 healthy chronic smokers (7 men, 3 women; 34+/-8 years) with no history of alcohol abuse were studied. Using previously described techniques, the above reflexes were elicited by rapid and slow water injections into the pharynx, before and after an intravenous injection of 5% alcohol (breath alcohol level of 0.1%), before and after smoking, and before and after a nicotine patch was applied. Blood nicotine levels were measured. RESULTS: During rapid and slow water injections, alcohol significantly increased the threshold volume (ml) to trigger PUCR and RPS (rapid: PUCR: baseline 0.2+/-0.05, alcohol 0.4+/-0.09; P=0.022; RPS: baseline 0.5+/-0.17, alcohol 0.8+/-0.19; P=0.01, slow: PUCR: baseline 0.2+/-0.03, alcohol 0.4+/-0.08; P=0.012; RPS: baseline 3.0+/-0.3, alcohol 4.6+/-0.5; P=0.028). During rapid water injections, acute smoking increased the threshold volume to trigger PUCR and RPS (PUCR: baseline 0.4+/-0.06, smoking 0.67+/-0.09; P=0.03; RPS: baseline 0.7+/-0.03, smoking 1.1+/-0.1; P=0.001). No similar increases were noted after a nicotine patch was applied. CONCLUSIONS: Acute systemic alcohol exposure inhibits the elicitation PUCR and RPS. Unlike cigarette smoking, systemic nicotine does not alter the elicitation of these reflexes.

The effect of oral buspirone, pyridostigmine, and bethanechol on esophageal function evaluated with combined multichannel esophageal impedance-manometry in healthy volunteers.

BACKGROUND: There is limited information on medications with promotility effects on the esophagus. Studies in healthy volunteers have shown the potential role of the direct cholinergic agonist bethanechol and the serotonin receptor agonist buspirone in improving esophageal motility. It has been also shown that an acetylcholinesterase inhibitor, the short-acting drug edrophonium administered intravenously caused a greater increase in the esophageal contraction amplitude and duration than bethanechol. Edrophonium cannot be used as a promotility therapy owing to short duration of action and lack of oral administration. The use of another acetylcholinesterase inhibitor pyridostygmine with longer duration of action has not been studied. The aim of the study was to evaluate the effect of oral pyridostygmine (60 mg), buspirone (20 mg), and bethanechol (25 mg) on esophageal function assessed by combined multichannel intraluminal impedance-esophageal manometry. MATERIALS AND METHODS: Ten healthy volunteers were enrolled in a double blind randomized 3-period crossover study. Multichannel intraluminal impedance-esophageal manometry recorded esophageal pressures and bolus transit data during 6 liquid and 6 viscous swallows at baseline and 20, 40, and 60 minutes after the randomized oral administration of each drug. RESULTS: Blinded analysis found significant increases in mean distal esophageal amplitude for liquid swallows from baseline to 60 minutes postdosing after pyridostygmine (87.6 vs. 118.0 mm Hg, P<0.001), buspirone (85.1 vs. 101.9 mm Hg, P<0.05), and bethanechol (87.6 vs. 118.8 mm Hg, P<0.01). Only pyridostygmine showed a significant decrease in mean distal onset velocity for liquid swallows at 60 minutes postdosing (3.4 vs. 2.3 cm/s, P<0.01) and increase in total bolus transit time at 60 minutes postdosing (7.9 vs. 9.3 s, P<0.05). All 3 agents significantly increased mean lower esophageal sphincter residual pressure for liquid swallows at 20, 40, and 60 minutes postdosing. Increased lower esophageal sphincter resting pressure was not significant. Similar results were found with viscous swallows. CONCLUSIONS: Oral pyridostygmine, buspirone, and bethanechol enhance esophageal motility with pyridostygmine appearing to have the greatest effect. A potential effect on improving esophageal function and symptoms in patients requires further study.

Metoclopramide does not attenuate cricoid pressure-induced relaxation of the lower esophageal sphincter in awake volunteers.

BACKGROUND: The authors examined the influence of metoclopramide on cricoid pressure-induced relaxation of the lower esophageal sphincter (LES) in awake human volunteers. METHODS: With local institutional review board approval, measurements of LES and intragastric pressures were made in 10 consenting volunteers before cricoid pressure application, during 15 s of cricoid pressure application, and after release of cricoid pressure. The measurements were repeated after 0.15 mg/kg intravenous metoclopramide. Cricoid pressure was applied by one investigator trained to consistently apply a force of 44 N. RESULTS: Cricoid pressure resulted in immediate decrease in LES and barrier pressures from 14.1 +/- 2.9 mmHg to 3.2 +/- 3.7 mmHg and from 9.6 +/- 3.4 mmHg to -1.8 +/- 2.9 mmHg, respectively. These pressures promptly returned to baseline values after release of cricoid pressure. LES and barrier pressures increased after metoclopramide from 14.5 +/- 3.1 to 19.6 +/- 4.7 mmHg and from 10.2 +/- 3.6 to 14.1 +/- 5.5 mmHg, respectively. Cricoid pressure applied after metoclopramide resulted in immediate decreases in LES and barrier pressures to levels comparable to cricoid pressure before metoclopramide, but immediately returned to precricoid values after release of pressure. CONCLUSIONS: The current investigation demonstrates that cricoid pressure reflexly decreases LES tone and barrier pressure in awake subjects. Although metoclopramide increased LES and barrier pressures, it did not attenuate cricoid pressure-induced relaxation of the LES and barrier pressures and thus seems to have no value in preventing gastroesophageal reflux during cricoid pressure. Metoclopramide may be useful in preventing reflux when there is need to release or discontinue cricoid pressure.