Excitability in pain research

'The excitability of peripheral nerves is often abnormal in pain patients and some agents such as local aesthetics reduce the excitability of pain nerves,' says Dr Jules Heuberger, head of the Experimental Medicine group. ‘That’s why we think it makes sense to study peripheral nerve excitability in the context of pain research and the clinical development of analgesics.'

Excitability research involves administering a series of stimuli and then measuring the effects. The analysis reveals how excitable the nerve is and its behaviour over time, including the refractory period and other relevant variables. The Experimental Medicine group which was established this year builds on CHDR’s existing experience in excitability research. In the context of pain research, these measurements can be used to profile patients with chronic pain syndromes and measure the effects of different compounds on peripheral pain nerves.

'It has been established that there are differences in the excitability of pain nerves between diabetic patients with and without pain due to diabetic neuropathy,' explains Heuberger. 'For example, a common phenomenon in many patients with neuropathic pain is an increased persistent sodium channel conductance. Some sodium channels that are constantly open cause something similar to leakage current in an electrical system. It is possible that drugs that reduce persistent sodium channel conductance may also help reduce neuropathic pain.'To get a better picture of nerve conduction and excitability in pain patients, Heuberger and his colleagues plan to screen patients with chronic pain. For instance, they will measure excitability in pain nerves in patients who are being studied in an ongoing CHDR research project on the effectiveness of medicinal cannabis in pain. They will then see if these measurements can demonstrate patient characteristics that can be used to optimise their therapy. They may even predict the effectiveness of cannabis, even though the peripheral nervous system does not have receptors for cannabinoids. 

A promising group of new analgesics target the voltage-gated sodium channels (NaV) in pain nerves. Heuberger's team investigated the effects of two orally administered non-selective sodium channel blockers, mexiletine and lacosamide, on the excitability of peripheral pain nerves. They demonstrated that these agents did have a detectable effect. However, these non-selective agents are of limited use for pain management. 'At doses where you expect significant effects on pain, serious side effects occur,' says Heuberger. In recent years, CHDR’s Pain Group has already shown that the effect of selective NaV 1.8 inhibitors can be measured with the PainCart®. A phase III study has already started for one of these agents. Heuberger: 'The PainCart already gives us a good biomarker. But we think our excitability measurements can have added value because they show what happens in the nerve. By comparing them with substances such as mexiletine and lacosamide, we hope to generate a fingerprint for future NaV 1.8 inhibitors and similar selective ion channel drugs.'