HCN channels: novel therapeutic targets for peripheral neuropathic pain

Hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels control neuronal firing thresholds. Together with sodium channels, they accumulate at sites of nerve injury, creating ectopic foci of action potential generation (EFAPG) that result in neuropathic pain. Their presence may explain why EFAPG do not always respond to sodium channel blockers (eg, lacosamide). Further, several current analgesics (clonidine, dexmedetomidine, ketamine and systemic lidocaine) block HCN channels in addition to their better-known actions. Future research could explore the use of ivabradine (an HCN blocker) and multichannel blockade for refractory EFAPG and develop tools to distinguish EFAPG from secondary ‘upstream’ pain mechanisms (eg, central sensitisation).