The Effect of Chlorpromazine (Largactil®), a Dopamine Receptor Antagonist, on Esophageal Sensitivity in Healthy Volunteers: a Randomized, Double-blind, Placebo-controlled Study.

INTRODUCTION Gastro-esophageal reflux disease (GERD), defined as the presence of symptoms or lesions that can be attributed to the reflux of gastric contents into the esophagus, is an increasingly prevalent condition in Western societies. The most typical symptoms are heartburn and regurgitation, however GERD can also manifest itself through a variety of esophageal and extra-esophageal symptoms (e.g. chronic cough).

In humans, pain is a multimodal experience composted of sensory, physiological and psychological aspects. In order to mimic the clinical situation, experimental models should be based on multimodal testing regimens in which different receptors and central nervous system mechanisms are activated.

Advances in esophageal sensory stimulation have established that both typical and atypical symptoms may not only arise from acid reflux, but also from reflux events with less acidic pH (pH 4-7). Literature review shows that in GERD patients with persisting symptoms in spite of PPI therapy, ongoing weakly acidic reflux can be considered as an important underlying factor. The basis for symptom generation during weakly-acidic reflux events remains to be determined, but acid sensitivity in the pH range 4-7, mechanical distention (enhanced by air in the refluxate), sensitivity to other chemical factors (e.g. bile salts) and esophageal hypersensitivity to physiological levels of reflux have all been proposed.

Kahrilas et al. described psychogenic factors as an alternative explanation for PPI-refractory symptoms: hyperalgesia, allodynia, hypervigilance, and increased anxiety. Anxiety and depression were found to increase GERD-related symptoms in a population-based study. Patients with a poor reflux-symptom correlation reportedly exhibit a high level of anxiety compared with patients exhibiting good reflux-symptom correlation. In addition, it has been shown that increased levels of anxiety were associated with more severe retrosternal pain and retrosternal burning in GERD patients along with increased levels of anxiety and depression.

The study of the interaction between psychological state and gastrointestinal function is complex. It is known that anxiety is one of the factors affecting visceral sensitivity in humans. The investigators speculate that visceral hypersensitivity plays an important role in symptom perception in refractory GERD. This is suggested by the reflux parameters that are usual within the physiological range during PPI therapy. The investigators previously demonstrated that refractory GERD patients have increased visceral sensitivity for thermal, chemical and mechanical esophageal stimulation compared to healthy subjects.