Capsaicin, the compound that gives chili peppers their heat, soothes pain and itch by acting on an ion channel called TRPV1 in cells. But along with this relief, capsaicin and some of its derivatives can deliver troubling side effects, including a burning sensation and fever spikes. Now researchers have developed a modified capsaicin that skin enzymes inactivate within hours, averting some side effects while demonstrating pain and itch relief in mice (J. Med. Chem. 2018, DOI: 10.1021/acs.jmedchem.8b00109). Asia Fernández-Carvajal of Miguel Hernández University, Tracey Pirali of the University of Eastern Piedmont, and their colleagues made capsaicin derivatives (example shown) with a built-in self-destruct switch: an ester bond in the tail of the compounds. Esterase enzymes in skin hydrolyze this bond, producing two metabolites that the body easily eliminates. The researchers tested the compounds for activity on TRPV1 and then assayed the most potent candidates in human skin cells to find those that were significantly hydrolyzed. In mice, the best-performing molecule reduced sensitivity to heat, touch, and itch without producing body temperature spikes. The effects lasted up to 90 minutes.