IIVoP

Patients with chronic neuropathic pain complain of pain in the absence of a painful stimulus. These spontaneous sensations can be constant and burning or intermittent and sharp or stabbing in quality. Pain can also be brought on by normally innocuous stimuli, such as the light touch of clothing, or gentle breeze against the skin, this is known as allodynia. Another feature is hyperalgesia, an increased sensitivity to mechanical pressure and thermal stimuli. We can mimic these symptoms and their underlying mechanisms in healthy volunteers using experimental models such as the capsaicin model, and investigate the effectiveness of analgesic drugs. These spontaneous sensations are likely to arise from ongoing neural activity, an explanation being that sensory pathways are hypersensitive and action potentials are generated too frequently. These frequent discharges are thought to play a fundamental role in initiating and maintaining the symptoms of hyperalgesia and allodynia in neuropathic pain.

Hyperpolarization-activated cyclic nucleotide gated (HCN) ion channels are important modulators of action potential frequency. They drive repetitive electrical activity in heart pacemaker tissue and in some neurons by generating an inward current, Ih, following hyperpolarisation of the membrane, and so play a key role in neuronal rhythmicity. The HCN ion channel family comprises four isoforms, HCN1-4, which carry an inward current called I_h (also I_q or I_f). I_h is activated by hyperpolarization in the range of membrane potentials between -60 and -90mV, and the activation of this inward current is a major driver of the pacemaker potential in cardiac muscle. The dependence of the activation of HCN2 and 4 on membrane potential is shifted in the positive direction when cyclic AMP (cAMP) binds to a domain in the C-terminal tail, a shift which increases the inward current carried by I_h in the pacemaker region of membrane potentials and thereby mediates the chronotropic action of adrenergic agonists on the heart. HCN1 and 3, on the other hand, are relatively insensitive to cAMP. I_h is important in driving repetitive firing in some CNS neurons and also in primary nociceptive neurons.

Our hypothesis is that blocking HCN channels reduces hyperalgesia and allodynia in humans, in a healthy volunteer model that mimics the symptoms seen in chronic pain patients. The concept that HCN channels are involved in the establishment and perpetuation of neuropathic pain is novel and has been demonstrated in experimental animals. This study is very important because neuropathic pain is difficult to treat and places a great burden on individuals who suffer from it, their families and carers, and society as a whole. There has not been a new anti-neuropathic drug for more than 5 years. If ivabradine is helpful in reducing hyperalgesia in healthy volunteers (in an enriched population trial in which all the volunteers display a hyperalgesia in response to capsaicin), it strongly suggests that HCN channels are potential molecular targets for novel pain treatments. Not only could ivabradine be used to treat neuropathic pain, but more selective HCN blockers, without cardiac effects, could be developed.

This is a randomised, double-blind, placebo-controlled, 2-period cross-over trial in an enriched population of healthy volunteers who display a defined degree of hyperalgesia in response to capsaicin cream. The choice of a cross-over is justified by the fact that each volunteer will be its own control. A wash-out period of 3 weeks between Visit 1 (screening) and Visit 2 ensures a minimum 4 week wash-out period between Visit 1 and Visit 3 and therefore on the forearm used twice. This design ensures there is no residual sensitisation towards the capsaicin cream. We intend to recruit up to 42 healthy volunteers into the treatment phase of the trial (visits 2 and 3). We will only enrol those participants who are defined as capsaicinresponders (someone who has an area of punctate hyperalgesia on the forearm equal to or greater than 20cm2) as determined at the screening visit (visit 1). We anticipate approximately 40% of participants undergoing screening to be capsaicin-responders and continue into the treatment phase of the trial, and therefore anticipate screening approximately 150 healthy volunteers, assuming a capsaicin responder drop-out rate of no more than 30% during the trial. Screening will continue until up to 42 responders have fully completed all trial visits. We will allow the screening of any volunteer who previously participated in the IISNeP trial who we anticipate will be a capsaicin-responder from their previous results.

The brevity of the trial (approximately 4-8 weeks) will mitigate against volunteers dropping out, and therefore the cross-over design will allow subjects to provide their own control observations, thus increasing the accuracy of the treatment effect estimate, in comparison to a parallel-arms trial. The choice of an enriched population trial is justified by the preliminary evidence from the previous trial (IISNeP) that some volunteers do not respond to capsaicin cream application and therefore there was no window to see an effect of ivabradine. This method of screening for capsaicinresponders
and non-responders prior to the trial treatment phase of the trial has been reported previously. We expect around 40% of participants to respond to capsaicin as defined by the degree of sensitisation they display.

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