Oesophageal hypersensitivity in patients with gastro-oesophageal reflux symptoms: Prevalence and novel treatments

Background Gastro oesophageal reflux disease (GORD) is a leading cause of morbidity and economic importance worldwide. It is currently defined by the Montreal definition as a condition, which develops when the reflux of gastric content causes troublesome symptoms or complications. This definition based on symptoms is all encompassing, and further classification is made based on macroscopic mucosal injury as seen on gastroscopy, increased distal oesophageal acid and non acid exposure, based on 24 hour pH and impedance pH testing, and reflux symptom association. Thus, GORD may be sub classified into the following conditions – erosive reflux disease (ERD), non erosive reflux disease (NERD), reflux hypersensitivity (RH), functional heartburn (FH) and functional chest pain (FCP). Treatment of GORD is with acid suppression therapy, anti reflux therapy and pain modulation. The pathophysiology of GORD is thought to occur in a spectrum, with varying contributions from direct mucosal injury to peripheral sensitization and central sensitization. Further efforts to phenotype GORD populations, investigate mechanisms of symptom evolution and treatments are driven by a significant proportion of patients who are refractory to currently available therapies. Aims The aim of this body of work was to phenotype patients with RH, the least studied subtype of GORD, to investigate the effect of ONO 8539, a novel antagonist to the Prostaglandin E 1 receptor thought to be involved in pain perception on acid induced oesophageal pain hypersensitivity in patients with NERD, to investigate the effect of transcutaneous vagal nerve stimulation (tVNS) on an oesophageal pain model in healthy volunteers, and to investigate the effect of slow deep breathing on oesophageal pain hypersensitivity in patients with NERD. Methods I investigated the above aims in a retrospective cohort study on patients referred to the gastro intestinal physiology unit of the Royal London Hospital for investigation of typical GORD symptoms, a double blind placebo controlled two period cross over study in patients with NERD, a single blind sham controlled two period cross over study in healthy volunteers and single blind sham controlled parallel study in patients with NERD respectively. The first study was done as a service evaluation exercise and the latter three studies had ethical approval from the National Research and Ethics Service (NRES), QMUL Ethics and NRES respectively. Results I demonstrated that phenotypic characteristics in patients with RH were distinct from NERD and FH/FCP. This was the largest cohort of RH patients evaluated, and this body of work will contribute to further research on mechanisms, pathophysiology and treatments in RH. In my second study, I was not able to demonstrate an anti nociceptive effect of ONO 8539 versus placebo on oesophageal pain hypersensitivity in patients with NERD. In my third study, I was able to demonstrate an increase in anti nociceptive parasympathetic tone, and an increase in pain tolerance threshold with tVNS compared to sham stimulation in an oesophageal pain hypersensitivity model in healthy volunteers. In my final study, I was able to demonstrate an increase in parasympathetic tone, but no improvement in lag time to pain perception with a slow deep breathing protocol compared to a sham breathing protocol in a Modified Bernstein test model of distal oesophageal acid infusion in patients with NERD. Conclusions This body of work improves upon current knowledge of the phenotypic characteristics of RH, adding further weight to the definition of RH as a distinct condition. tVNS and deep slow breathing were shown to increase parasympathetic tone in healthy volunteers and patients with NERD respectively. The anti nociceptive effect of raising parasympathetic tone was only demonstrated in the healthy volunteer model of oesophageal pain hypersensitivity. The performance of the MBT model used in the two patient studies was not as reliable as the healthy volunteer model, and a new oesophageal pain hypersensitivity model for patients with NERD was propose