MICA: The Role of GABAB Receptor Mechanisms in Chronic Cough

Coughing is the most common reason for which people visit their GP, but currently we know very little about why people cough and the current medications for treating cough are not helpful. Some people suffer from severe coughing which can last from eight weeks to many years, and yet they seem to have no obvious cause for their cough. This is known as a Chronic Cough. One theory is that chronic cough might be a response to a condition known as gastro-oesophageal reflux, where food and acid in the stomach flow back into the oesophagus (food pipe). Gastro-oesophageal reflux usually causes heartburn and indigestion which can get better with acid blocking medicines, but in people who develop cough, rather than heartburn, acid does not seem to be the problem and these treatments do not work. Previous research has suggested that in up to 50% of patients with chronic cough, the coughing may be triggered by gastro-oesophageal reflux.
This project will study a new medicine, known as a GABA-B receptor agonist, developed to reduce the amount of gastro-oesophageal reflux. Although this medicine was not found to be helpful in patients with heartburn who were already taking acid blocking treatments, but we will test whether it improves chronic cough which has been triggered by reflux. This new medicine may also reduce the sensitivity of the nerves that make people cough and could also be helpful in chronic cough patients where reflux is not a problem for them.
We plan two studies using this medicine. Firstly we will test this treatment in healthy people to see whether it reduces the sensitivity of the nerves responsible for coughing. Secondly we will test the treatment in patients with chronic cough and measure any reduction in the number of times people cough compared to a placebo (dummy) treatment. In this study we will also measure gastro-oesophageal reflux and the sensitivity of the cough reflex to work out which patients might find this medication helpful in the future.
If these studies show this GABA-B receptor agonist improves chronic cough, then this could lead to the development of more effective treatments for coughing, which in turn may help more patients that just those with chronic cough.

Cough is the most common symptom for which patients seek medical care. Chronic cough (>8weeks) is reported by 14-23% of the population and has a substantial impact on quality of life. Remarkably little is understood about the mechanisms involved in the human cough reflex. Gastro-oesophageal reflux disease is thought to be a major cause of chronic cough but evidence suggests acid suppressing therapies such as proton pump inhibitors are ineffective. We have developed a validated, semi-automated ambulatory monitoring system, which objectively identifies the precise timing and frequency of coughing episodes. Combining this method with oesophageal pH/impedance monitoring, we have shown that in almost 50% of chronic cough patients, cough follows reflux events more often than expected by chance alone, and irrespective of the acidity of the refluxate.
The main mechanism underlying gastro-oesophageal reflux events is transient lower oesophageal sphincter relaxation (tLOSR). Gamma-aminobutyric acid type B (GABAB) receptor agonists such as Baclofen inhibit tLOSRs and consequently reflux events by up to 40%. Baclofen also inhibits cough responses to inhaled capsaicin in healthy controls and subjectively improves treatment resistant chronic cough, but longterm therapy is poorly tolerated due to CNS side effects and acute withdrawal can result in seizures.
We hypothesise that Lesogaberan, a novel mainly peripherally acting GABAB receptor agonist will inhibit human cough (without CNS side effects) via two mechanisms i) a direct inhibitory effect on afferent pathways responsible for evoking cough and ii) an indirect effect via reduction in tLOSRs and reflux events in patients where reflux is temporally linked to cough. We therefore propose two studies to investigate the effect of Lesogaberan i) on cough reflex sensitivity in healthy controls and ii) on objective cough frequency in chronic cough patients with and without cough triggered by reflux events.

The main beneficiaries of this proposal are patients suffering from chronic cough, as the medication to be investigated has the potential to be an effective anti-tussive treatment. This project may find that GABAB agonism has an inhibitory effect on the cough reflex in all patients with chronic cough, therefore all patients may benefit. It is also possible that GABAB agonsim will only be effective in patients in whom significant reflux-cough associations are present, which according to our previous data represents approximately 50% of those presenting to specialist cough clinics. Should this be the case, this study will identify those patients who will benefit the most. As there are currently no licensed treatments for chronic cough, and established anti-tussive agents seem to be ineffective in these patients, the identification of an effective novel therapy would be an important development. Furthermore as a peripherally acting therapy, this treatment has been found to be associated with few side effects, this is in contrast to many treatments used in chronic cough such as opioids and baclofen. Further clinical clinical trials will be required, following these proof of principle studies, to progress this treatment to be available to patients, however a substantial body of work on safety, tolerability and dosing has already been completed by Astrazeneca for the original indication of treatment of typical reflux symptoms, shortening the time to availability for patients.