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A significant proportion of patients on proton pump inhibitors (PPI) reports insufficient control of symptoms, most probably resulting from ongoing reflux of non-acid and acid material. As reflux mainly occurs during transient lower esophageal sphincter relaxations (TLESRs), drugs targeting this motor pattern may be of great interest to further reduce symptoms. Baclofen, a GABAB receptor agonist, is the prototype of reflux inhibitors, reducing the number of TLESRs, reflux, and symptoms, but the central side effects are significant. Peripheral acting GABAB agonists hopefully devoid of these side effects are currently under study. Alternatively, antagonists to the metabotropic glutamate receptor 5 (mGluR5) reported to reduce TLESRs and reflux may be of interest. Upcoming clinical trials with these reflux inhibitors will hopefully answer the question whether reflux inhibitors are indeed a new approach to treat GERD.