A randomized, double-blinded, placebo-controlled, crossover study of the HCN channel blocker ivabradine in a capsaicin-induced pain model in healthy volunteers

Abstract

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels have been focused on as a potential therapeutic target for inflammatory and neuropathic pain in rodent models. However, roles of HCN channels in human pain states have been scarcely investigated. We evaluated analgesic effects of 2-day administration of ivabradine, the only clinically available HCN channel blocker, on a capsaicin pain model in a randomized, double-blinded, placebo-controlled, crossover study. Twenty healthy adult subjects (18 males, 2 females) received ivabradine (5–7.5 mg) or a placebo 3 times in 2 days. Then capsaicin (0.5%) was topically applied on the volar forearm for 30 min. The primary outcome was capsaicin-induced spontaneous pain. The secondary outcomes included heat-pain threshold (HPT), flare size, and areas of secondary punctate mechanical hyperalgesia (PMH) and secondary dynamic mechanical allodynia (DMA). There was no significant difference in spontaneous pain (p = 0.7479), HPT (p = 0.7501), area of PMH (p = 0.1052) or flare size (p = 0.5650) at 30 min after capsaicin application between the groups. In contrast, the area of DMA in the ivabradine group was significantly smaller (p < 0.001) than that in the placebo group. HCN channels may be differentially involved in the various pain signal transmission pathways in humans.

Dexmedetomidine Prolongs Lidocaine Intravenous Regional Anesthesia in Rats by Blocking the Hyperpolarization-Activated Cation Current

“…23,24 Highly expressed in the nervous system, HCN channels govern action potential genesis thresholds in nociceptive neurons and contribute to rhythmic/spontaneous firing patterns underlying pain signaling. 25,26 Dexmedetomidine may dampen neuronal excitability by inhibiting HCN currents, raising firing thresholds and decreasing responsiveness to painful stimuli. This attenuates the propagation of pain signals along sensory neurons, enhancing lidocaine anesthesia and analgesia.…”

Ih current stabilizes excitability in rodent DRG neurons and reverses hyperexcitability in a nociceptive neuron model of inherited neuropathic pain

“…Notably, human clinical trials of the I h blocker ivabradine failed to demonstrate analgesic effects in capsaicin pain models (Lee et al., 2019; Tanaka et al., 2022). Additionally, clinical trials of ivabradine in patients with chronic peripheral neuropathic pain showed no significant treatment effect on the primary endpoint.…”