Effect of pharmacological modulation of the autonomic nervous system on human oesophageal pain hypersensitivity

Abdominal pain is a very common and important symptom reported by patients with a variety of gastrointestinal diseases. Some of these have no evident underlying structural cause and are thus called ?functional?. Such increasingly recognized functional gastrointestinal disorders (FGID) are now known to at least in part occur because of increased gut sensitivity to stimuli such as chemicals and mechanical stretching (called visceral pain hypersensitivity: VPH). We have developed a well-validated human model of VPH by experimentally introducing acid into the oesophagus (gullet) of healthy volunteers. This model has allowed us to study why some people sensitize more to acid than others. We have recently shown that one important factor affecting this response is the activity of a part of the nervous system called the autonomic nervous system (ANS). The ANS controls many involuntary functions such as heart rate and blood pressure and has two main parts (called the sympathetic and parasympathetic). Depending on the relative activities of these parts different individuals show different responses to acid. We wish to further explore the exact mechanisms that lead to this observation and also prove the concept that altering these 2 ANS activities with drugs could affect the degree of VPH in the model. This has potential to lead to new uses of existing drugs particularly in patients with FGID, but also perhaps in the field of chronic pain management in general.

Background and aims
The factors that predict the development of pain hypersensitivity after gut injury are incompletely understood. In a human model of acid-induced esophageal pain hypersensitivity in healthy volunteers, we have previously shown that the autonomic nervous system (ANS) may have a modulatory role on visceral pain hypersensitivity with sympathetic and parasympathetic nervous systems being facilitatory and inhibitory respectively. We aim to prove the concepts that physiological and pharmacological modulation of ANS activities can affect degree of sensitization in this model and translate these findings to patients with established visceral pain hypersensitivity.
Methods
75 healthy volunteers will undergo a validated oesophageal acid sensitization protocol (distal 0.15M HCl infusion over 30mins with proximal oesophageal electrical stimulation thresholds determined at 4 subsequent time points over 2 hours). On this basis, n = 44 sensitizers (allowing for non-sensitisers and drop outs) will be selected to undergo a series of further infusions, 2 weeks apart in which sensitization is modulated by physiological paradigms (sympathetic and parasympathetic activation by isometric exercise and 0.1Hz deep breathing respectively) and pharmacological manipulations (sympathetic and parasympathetic block by atropine and clonidine respectively vs. placebo; 22 subjects in each arm based on sample size calculation). In all protocols, the selective activities of the ANS will be studied using novel real-time techniques (neuroscope). In a final study, 22 patients with non-erosive reflux disease (NERD) with prior proven chemosensitivity (modified Bernstein test) will undergo a trial of the drug showing best efficay in healthy subject studies with effects on baseline and post-infusion symptoms and sensory thresholds determined.
Expected outcomes
In healthy volunteers we expect to prove the concept that visceral pain hypersensitivity can be modulated by physiological and pharmacological effects on the ANS. The novel application of existing drugs may thus be possible in patients with functional conditions characterized by visceral hypersensitivity such as NERD and the irritable bowel syndrome. Given the well-recognised increasing burden of these disorders, this research is timely and important.