Results of Research

NMDA Receptor Antagonist Studies with Ketamine:

The results of these experiments have shown that low dose intravenous ketamine can prevent the acid induced visceral hypersensitivity in the oesophagus of healthy volunteers and more importantly reverse established visceral hypersensitivity. These studies have shown that the receptor mechanisms of visceral hypersensitivity are the same as those of somatic hypersensitivity i.e. skin. The experiments have also shown that this drug was acting at the spinal cord level and not at the brain or peripheral nerve level. Most subjects experienced mild side effects during the ketamine infusion in keeping with previous published studies of ketamine in somatic pain but no subject ceased the study due to side effects. These experiments have obvious clinical implications, since ketamine can reverse established hypersensitivity in healthy volunteers then ketamine-like drugs may have a role in reversing symptoms of visceral hypersensitivity in patients with FGD’s and such drugs are now in development by pharmaceutical companies.

Current & Future Studies and their Implications

Having shown that ketamine can both prevent and reverse the development of visceral hypersensitivity in healthy volunteers, I will be conducting experiments to assess if ketamine can reverse the hypersensitivity in the oesophagus of patients with non-cardiac chest pain. This is a condition in which patients have recurrent chest pain and have been shown to have no cardiac cause, but using our oesophageal model it has been shown that these patients have visceral hypersensitivity. Since the mechanism for visceral hypersensitivity will be the same throughout the digestive tract then this will also have implications for the potential treatment of patients with other forms of visceral hypersensitivity such as irritable bowel syndrome and functional dyspepsia.

Given the side effects of ketamine (due to its widespread effects on the brain as well as spinal cord), and given its intravenous mode of administration (oral ketamine absorption is notoriously unreliable), it would not be a clinically viable drug. However, the experiments I undertook were designed as mechanistic studies to determine “proof of principle” as to what receptors were involved in the development and maintenance of visceral hypersensitivity in our oesophageal model. The development of more specific ketamine-like compounds which act on the same receptor, but at the same time do not act on the brain, are currently in development by several pharmaceutical companies. These drugs hold significant promise for reversing established visceral hypersensitivity in patients with FGD’s and are an important avenue for future research which I will be exploring using human models of visceral pain.