Antipruritic Effects of Doxepin Cream on Experimentally Induced Histaminergic and Nonhistaminergic Itch

Abstract

Background. Itch can be transmitted by two parallel pathways, histaminergic and nonhistaminergic. Histaminergic itch is transmitted by a subgroup of mechano-insensitive C-fibers, while nonhistaminergic itch by a subgroup of polymodal C-fibers. Experimental models are used to study pruritus: histamine for the histaminergic itch by antagonizing the histamine H1-receptors, and BAM8-22 and cowhage for the nonhistaminergic by activating Mas-related G protein-coupled receptors and protease-activated receptors, respectively. This study aims to evaluate the antipruritic effects of topical doxepin (H1-receptor antagonistic effect) on histaminergic and nonhistaminergic itch induced by histamine, BAM8-22, and cowhage. Methods. This study was conducted on 22 healthy subjects. Histamine, BAM8-22, cowhage, and vehicle were applied to 4 areas on the forearms. After 7 days, the same substances were applied after $11/2$  hour-pretreatment with doxepin. After the application of pruritogens, itch and pain intensities were assessed for 9 minutes, followed by the measurement of superficial blood perfusion (SBP), mechanical and thermal sensitivities. Results. Application of histamine, BAM8-22, and cowhage all induced itch as compared to a vehicle. The pretreatment with doxepin almost abolished the histamine-induced itch and modestly reduced BAM8-22- and cowhage-induced itch. Histamine induced a higher SBP compared to the other conditions. Doxepin reduced SBP induced by each pruritogen, even though SBP of histamine remains the highest. Conclusion. Doxepin cream abolished histaminergic itch by antagonizing the peripheral H1-histamine receptors. Moreover, doxepin reduced nonhistaminergic itch and related neurogenic inflammation. Further studies are needed to elucidate the molecular mechanisms underlying this peripheral modulation of nonhistaminergic itch by a topically applied H1-antagonist. This trial is registered with NCT04588532.