Gastroesophageal reflux: Not a time to “relax”
Article Outline
Abbreviations: FDA, Food and Drug Administration, GABA, γ-aminobutyric acid, GERD, Gastroesophageal reflux disease, LES, Lower esophageal sphincter
Gastroesophageal reflux disease (GERD) is primarily a motility disorder. Escape of gastric contents into the esophagus occurs as a consequence of an incompetent gastroesophageal barrier. This barrier is weakened in the presence of an abnormally functioning lower esophageal sphincter (LES) and when there are associated anatomical abnormalities, such as a hiatal hernia. Transient LES relaxation represents the primary motility dysfunction affecting the sphincter; it leads to acid and non-acid gastroesophageal reflux. The LES is supposed to relax only to allow the aboral passage of ingested material and the retrograde escape of excessive swallowed air. Instead, transient relaxations represent prolonged relaxations that occur without an associated swallow. Once the sphincter has suddenly opened, gastric contents easily move from an area of higher to one of lower pressure, shifting from the stomach to the esophagus. Transient LES relaxations have been found to be responsible for 50% to 80% of reflux episodes both in adults and in children.1 They are particularly prevalent in persons with non-erosive esophagitis, the phenotype of GERD most commonly found in children. Motility dysfunction associated with GERD also includes impaired esophageal peristalsis, delayed gastric emptying, and defective post-prandial gastric relaxation. Yet, despite the fact that GERD is a motility disorder, the standard of care is to treat it using drugs that have no prokinetic properties, aiming instead at decreasing gastric acid secretion. There are two major factors that justify such an apparently irrational choice: effective acid suppression leads in most cases to quick symptomatic relief, and there is a paucity of effective and safe medications that improve gastrointestinal motility.
See related article, p 468
Reduction of acid secretion is achieved by using histamine-2 receptors antagonists or proton pump inhibitors. These are medications that have been approved by the Food and Drug Administration (FDA) for use in adults and children and that have revolutionized the treatment of acid-related disorders. Their efficacy is such that nowadays it can be claimed that the problem of peptic esophagitis has been solved! When adequate-dose proton pump inhibitors fail to cure esophagitis, one should suspect that the symptoms or the mucosal inflammation are because of a cause different from acid reflux.
In contrast with the success experienced by the acid suppressant medications, prokinetic drugs seem to have fallen on hard times. There is no widely available FDA-approved motility agent for treatment of GERD. The only prokinetic drug that had shown efficacy in the treatment of GERD was cisapride. The risk for potentially fatal side effects associated with its use has made cisapride for all purposes unavailable for general use. Domperidone has shown minimal efficacy in the treatment of pediatric GERD and is not available in the US.2 Despite its widespread use in infants and children with GERD, there is no convincing evidence that metoclopramide is effective in treating childhood GERD.3 Similarly, erythromycin and bethanechol provide no demonstrated therapeutic benefit in GERD. The reason why these prokinetic agents have provided disappointing results in the treatment of GERD is that none has an effect on transient LES relaxations. Is the lack of targeted therapy a problem in view of the efficacy of acid suppression? Yes, it is. Using combined impedance and pH measurement, it has been shown that the number of postprandial reflux episodes remains unchanged after treatment with omeprazole.4 Regurgitation is minimally affected by changing the pH characteristics of the refluxate. There is also increasing evidence supporting the contributing role of non-acid reflux in several extra-esophageal symptoms and diseases. Our goal should be to decrease all reflux episodes, not just make them less bothersome by neutralizing their acid content. In view of recent evidence that pediatric GERD could be a lifelong disease,5 one should also be cautious in recommending lifelong treatment with agents that significantly affect the gastric environment. Although concerns related to the long-term use of proton pump inhibitors have not been substantiated by the majority of clinical and research observations, the effect of their prolonged use in infants and children has not been yet carefully evaluated.6 Thus, there seems to be a need to improve our treatment of GERD. This should be accomplished ideally by decreasing the rate of transient LES relaxation. It has been estimated that at least a 50% reduction is needed to obtain a clinically significant reduction in reflux symptoms.7 Fortunately, the mechanisms involved in the control of transient LES relaxations have now been elucidated. A vagovagal reflex, triggered by subcardiac gastric distension and to a lesser extent by pharyngeal stimulation, mediates LES relaxations. The signal is carried to the nucleus of the solitary tract to activate motor neurons in the dorsal motor nucleus of the vagus leading to a cascade of events that cause LES relaxation, inhibition of the crural diaphragm, and contraction of the esophageal body.7, 8 A wide variety of pharmacologic agents have targeted peripheral and central mechanisms of transient LES relaxation to attempt to treat GERD (Table). Unfortunately, unwanted side effects or lack of efficacy have precluded the further development or the use in clinical practice of most of these agents.
Table. Compounds that have an effect on transient LES relaxations
| Compound | Effect |
|---|---|
| Baclofen | Decrease |
| Cholecystokinin-A | Increase |
| Nitric oxide | Increase |
| Morphine | Decrease |
| Sumatriptan | Increase |
| Ondansetron | Decrease |
| Atropine | Decrease |
| Somatostatin | Decrease |
In this issue of The Journal, Omari et al publish a carefully designed study addressing the effect of baclofen, the most promising among agents targeting transient LES relaxations, on the esophagus and the stomach of children with GERD.9 Baclofen is a γ-aminobutyric acid (GABA) receptor agonist, clinically used for management of spasticity. GABA receptors, identified in both the central and peripheral nervous system, inhibit mechanosensitivity of vagal afferents peripherally and mechanosensory input to brain-stem neurons.10 In healthy adults and in adults with GERD, baclofen reduces both acid and non-acid reflux.11 Now we have evidence that the number of transient LES relaxations can be reduced in children with severe GERD as well. Even more impressive was the finding in this study that gastric emptying was accelerated without any deleterious effect on LES basal pressure or esophageal peristalsis. These are novel findings and suggest that baclofen may improve most of the pathophysiologic mechanisms associated with GERD. Is baclofen the “magic bullet”? Probably not. Although no side effects were noted in the children carefully monitored in the study by Omari et al, baclofen is known to cause dyspeptic symptoms, drowsiness, dizziness, fatigue, and to lower the threshold for seizures. Such side effects will likely preclude its widespread use. However, the recent cloning of GABA receptors and their isoforms is likely to lead to new analogues with more targeted actions and fewer central side effects.12 Until that time, reduction of reflux episodes will remain a formidable challenge.
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PII: S0022-3476(06)00688-3
doi:10.1016/j.jpeds.2006.07.028
© 2006 Mosby, Inc. All rights reserved.
Refers to article:
- Effect of baclofen on esophagogastric motility and gastroesophageal reflux in children with gastroesophageal reflux disease: A randomized controlled trial
