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 nonselective HCN channel blocker, on
capsaicin-induced
hyperalgesia and
pain in healthy human subjects. An enriched population comprising subjects who developed >20 cm of punctate
hyperalgesia from topical
capsaicin (0.5% cream applied onto 9 cm area) was identified. These subjects then received
ivabradine (15 mg) or placebo 1 hour before
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 first and to the second treatment visits was at least 3 and 5 weeks, respectively, to minimize carryover effects. Fifty-five participants were screened, of which 25 completed at least 1 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 cm, 95% confidence interval: = -4.04 to 10.48, P = 0.37). However,
ivabradine caused a slowing of heart rate (difference of 10.10 beats per minute [95% confidence interval -6.48 to -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.