Anti-relaxation therapy in GORD

Gastro-oesophageal reflux disease (GORD), defined as the presence of symptoms or lesions that can be attributed to the reflux of gastric contents into the oesophagus, is one of the most common disorders affecting the gastrointestinal tract. Gastric acid is essential in the development of GORD and the duration of oesophageal acid exposure is a major determinant of the severity of reflux oesophagitis.¹ This is the reason why proton pump inhibitors, with their strong acid suppressing action, have brought relief to the majority of these patients, although most GORD patients do not have increased gastric acid secretion.²

The pathophysiology of GORD is multifactorial, including alterations in the volume, composition, or distribution of gastric contents, anatomical and/or motor dysfunction of the antireflux barrier at the gastro-oesophageal junction, impaired clearance mechanisms, and defective resistance to injury at the mucosal level. Acid suppressive therapy addresses one of the pathophysiological mechanisms—that is, gastric acid volume—without affecting others such as the non-acid component of the gastric contents or the function of the antireflux barrier. In spite of the efficacy of acid suppressive therapy, there have been many attempts to target other aspects of GORD pathophysiology, such as basal lower oesophageal sphincter (LOS) pressure, oesophageal body motility, or gastric emptying. Unfortunately, most of these approaches have been clinically disappointing.

The prerequisite for the development of acid reflux events is the occurrence of functional and/or anatomical failure of the antireflux barrier at the gastro-oesophageal junction. In healthy subjects and in patients with mild to moderate GORD, reflux occurs mainly during transient LOS relaxations (TLOSRs).^3–7 TLOSRs are LOS relaxations not induced by swallowing, which occur mainly during the first two postprandial hours. In patients with more severe GORD and in those with a hiatal hernia, although TLOSRs account for the majority of reflux episodes, a greater proportion occurs during absent basal LOS pressure and swallow induced LOS relaxations.⁸ Transient LOS relaxations are a neural reflex, triggered mainly by distention of the proximal stomach and organised in the brain stem, with efferent and afferent pathways travelling in the vagus nerve, activating an intramural inhibitory neurone which releases nitric oxide to relax the LOS.⁹ Pharmacological intervention to reduce TLOSRs has been proposed as a non-surgical strategy to improve the antireflux barrier in patients with GORD, and several agents that inhibit the occurrence of TLOSRs were identified, including atropine, cholecystokinin_A receptor antagonists, morphine, and nitric oxide synthase inhibitors.¹⁰ However, an unfavourable pharmacological profile precluded clinical application of these agents. More recently, the gamma aminobutyric acid (GABA) receptor type B agonist baclofen was shown to inhibit TLOSRs, thereby significantly decreasing acid reflux after a meal in healthy controls.¹¹ Inhibitory GABA_B receptors are present at many levels of the vago-vagal pathway that organises TLOSRs.

In this issue of Gut, Zhang and colleagues¹² demonstrated that acute administration of baclofen reduced the rate of TLOSRs and reflux events by approximately 40% in a group of patients with reflux oesophagitis (see 19). Based on these findings, the authors concluded that reduction in the rate of TLOSRs is an appropriate target in GORD. In addition, they suggest that GABA_B agonists may be useful as therapeutic agents for the management of reflux disease. As baclofen is already in use for the long term treatment of spasticity, in higher doses than used in the present study, there is a potential for clinical application in GORD in the not so distant future. However, in spite of the reduction in the number of reflux episodes, baclofen caused no significant decrease in postprandial oesophageal acid exposure in the present study. The lack of a significant effect on acid exposure is at least partly related to patient selection, as many patients had only minimal amounts of acid reflux during the placebo arm of the study. Confirmation of a clinically relevant effect of baclofen in GORD therefore awaits long term studies, with efficacy assessment on both reflux related symptoms and prolonged pH monitoring, in patients with a high rate of TLOSR related acid reflux events.

Although initial postprandial motility studies, performed in the right supine position, reported an increased rate of TLOSRs in patients with GORD,^3,4 recent postprandial studies in the more physiological upright position show a similar rate of TLOSRs in healthy controls and patients with GORD.^5–7 A more consistent finding among different studies is the higher prevalence of acid reflux during TLOSRs in patients with reflux disease. Because TLOSRs are the major mechanism of reflux, inhibition of TLOSRs has the potential to provide a substantial reduction in acid reflux events in GORD.

Acid suppressive therapy is most successful in patients with mild to moderate reflux disease with predominantly upright reflux, and less successful in patients with more severe reflux oesophagitis and patients with supine reflux.^13–16 As TLOSR related acid reflux is predominant in patients with mild to moderate GORD, treatment of these patients by inhibiting TLOSRs may provide an alternative to acid suppression. Furthermore, baclofen or related agents could be used as add-on therapy in GORD patients with incomplete relief by acid suppression and/or in patients with more severe GORD. In about half of patients with persisting reflux symptoms, in spite of standard proton pump inhibitor therapy, refractory acid reflux can be demonstrated which often responds to a further increase in proton pump inhibitor dose.^15,16 In the remaining patients, symptoms may be related to ongoing non-acid reflux, for which treatment options are limited.^17,18 As recent data suggest that TLOSRs are the principal mechanism underlying non-acidic reflux episodes as well,⁷ assessment of the therapeutic potential of baclofen or related compounds under these specific circumstances seems warranted.

The relevance of TLOSRs in the pathophysiology of GORD may be more related to what is present at the level of the cardia, at the moment of a TLOSR, than to their frequency. Postprandial gastric acid secretion and the composition and/or distribution of the fundic contents appear to be critical variables in the development of GORD. Therefore, the most pathophysiologically oriented strategy should aim to minimise the number of “harmful” TLOSRs associated with acid reflux by both reducing the triggering of TLOSRs and modifying the composition and/or distribution of gastric fundic contents.

The paper by Zhang et al demonstrates that inhibition of TLOSRs with baclofen reduces the frequency of acid reflux in GORD patients. Both acid suppressive therapy and reduction of TLOSRs address one important factor of the pathophysiology of GORD. Because the major functional abnormality in reflux disease appears to be the occurrence of acid reflux during TLOSRs, both strategies are not exclusive and may become complementary in the near future.