A randomised, double-blind, placebo-controlled crossover trial of the influence of the HCN channel blocker ivabradine in a healthy volunteer pain model: an enriched population trial.

Abstract

Preclinical studies suggest that type 2 hyperpolarization-activated cyclic nucleotide gated ion channels (HCN2) are necessary for neuropathic pain. This trial assessed the influence of ivabradine, a non-selective HCN channel blocker, on capsaicin-induced hyperalgesia and pain in healthy human subjects. An enriched population comprising subjects who developed >20cm2 of punctate hyperalgesia from topical capsaicin (0.5% cream applied onto 9cm2 area) was identified. These subjects then received ivabradine (15mg) or placebo one hour prior to capsaicin application in randomly allocated order in a crossover study. The forearm site for capsaicin alternated with each application of the cream. The interval of time from screening to the 1st and to the 2nd treatment visits were at least 3 and 5 weeks respectively to minimize carry-over effects. 55 participants were screened, of which 25 completed at least one treatment visit. Intention-to-treat hierarchical analysis revealed no significant effects of the drug on primary trial outcome, defined as a difference in effects of placebo and ivabradine on the area of punctate hyperalgesia (ivabradine ⎼ placebo: mean=3.22 cm2, 95% CI: = -4.04, 10.48, p=0.37). However, ivabradine caused a slowing of heart rate (difference of 10.10 beats per min (95% CI ⎼ 6.48, ⎼ 13.73; p‐value <0.0001)). We conclude that ivabradine lacks analgesic effects in the capsaicin pain model at a dose that caused appreciable slowing of heart rate, and hence is unlikely to prove a useful analgesic in humans. More selective drugs are required to establish a role of HCN2 for pain in humans.