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

• Published in: Scientific reports Vol. 12; no. 1; pp. 17246 - 10
• Main Authors: Tanaka, Satoshi, Ishida, Takashi, Ishida, Kumiko, Fuseya, Satoshi, Ito, Mariko, Sakamoto, Akiyuki, Kawamata, Mikito
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.10.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 692/1807/410/2610; 692/700/565/411; Adult; Analgesics; Analgesics - therapeutic use; Animal models; Calcium Channel Blockers - therapeutic use; Capsaicin; Cross-Over Studies; Female; Healthy Volunteers; Humanities and Social Sciences; Humans; Hyperalgesia; Hyperalgesia - chemically induced; Hyperalgesia - drug therapy; Hyperpolarization; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Inflammation; Ion channels (cyclic nucleotide-gated); Ivabradine - pharmacology; Ivabradine - therapeutic use; Male; multidisciplinary; Neuralgia; Neuralgia - chemically induced; Neuralgia - drug therapy; Nucleotides, Cyclic; Pain; Pain perception; Placebos; Science; Science (multidisciplinary); Therapeutic targets
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-22309-7

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.