Treatment of gastro‐esophageal reflux disease: the new kids to block

Refractory gastro‐esophageal reflux disease (GERD), defined as persistent symptoms despite proton pump inhibitor (PPI) therapy, is an increasingly prevalent condition and is becoming a major challenge for the clinician. Since non‐acidic reflux may be associated with symptoms persisting during PPI treatment, the lower esophageal sphincter (LES), the most important barrier protecting against reflux, has become an important target for the treatment of (refractory) GERD. Preclinical research has identified several receptors that are involved in the control of transient lower esophageal sphincter relaxations (TLESRs), the predominant mechanism of both acid and non‐acidic reflux events, and several drugs have now been tested in humans. The GABA_B agonist baclofen has demonstrated to effectively reduce the rate of TLESRs and the amount of reflux in both GERD patients and healthy volunteers. Nevertheless, the occurrence of central side effects limits its clinical use for the treatment of GERD. Several analogues are being developed to overcome this limitation and have shown promising results. Additionally, metabotropic glutamate receptor 5 (mGluR5) receptor antagonists have shown to reduce both acid and non‐acidic reflux in GERD patients and several molecules are currently being evaluated. Although CB₁ antagonists have been shown to reduce TLESRs, they are also associated with central side effects, limiting their clinical applicability. Despite the identification of several potentially interesting drugs, the main challenge for the future remains the reduction of central side effects. Moreover, future studies will need to demonstrate the efficacy of these treatments in patients with refractory GERD.