Introduction Levcromakalim opens ATP-sensitive potassium channels (KATP channel) and induces head pain in healthy volunteers and migraine headache in migraine patients, but no pain in other parts of the body. KATP channels are expressed in C- and Aδ-fibers, and these channels might directly activate nociceptors and thereby evoke pain in humans. Methods To assess the local effect of KATP channel opening in trigeminal and extra-trigeminal regions, we performed a crossover, double-blind, placebo-controlled study in healthy volunteers. Participants received intradermal and intramuscular injections of levcromakalim and placebo in the forehead and the forearms. Results Intradermal and intramuscular injections of levcromakalim did not evoke more pain compared to placebo in the forehead ( p > 0.05) and the forearms ( p > 0.05). Intradermal injection of levcromakalim caused more flare ( p < 0.001 ), skin temperature increase ( p < 0.001), and skin blood flow increase ( p < 0.001) compared to placebo in the forehead and the forearms. Conclusion These findings suggest that it is unlikely that levcromakalim induces head pain by direct activation of peripheral neurons.