Pharmacological treatment of GERD – a look beyond PPIs?

Abstract

BACKGROUND: Approximately 20–30% of patients with gastro-esophageal reflux symptoms report inadequate symptom relief while on PPI therapy. Persisting acid or nonacid reflux can be demonstrated in 40–50% of them suggesting that there is room for anti-reflux therapy in these patients. Transient lower esophageal sphincter relaxations (TLESRs) are the main mechanism of all type of reflux, i.e. both acid and weakly acidic reflux episodes. Therefore, controlling the occurrence of TLESRs appears to be a relevant therapeutic objective in GERD. METHODS: Review on the pharmacological therapy of TLESRs for GERD management. RESULTS: Many compounds have been shown to decrease the number of TLESRs, but the most promising classes are GABAB agonists and mGluR5 antagonists both of which have orally formulations available for human use. The GABAB agonist baclofen, prescribed for the treatment of spasticity for many years, has been shown to decrease the number of TLESRs, esophageal acid exposure, and reflux symptoms. Considering the poor tolerability of this compound, more selective GABAB agonists are currently in development. ADX10059, a mGluR5 negative allosteric modulator, has been shown to decrease GER in both healthy subjects and GERD patients and has entered in phase IIb studies. CONCLUSIONS: Compounds that target TLESR activity represent a promising new therapeutic option for patients who suffer from GERD symptoms. These drugs will probably be developed as add-on therapy in combination with PPIs provided the tolerability and safety issues are resolved.