Doxepin Hydrochloride

Doxepin cream, a tricyclic antidepressant with H1 receptor antagonistic properties, was tested for antipruritic effects on histaminergic (histamine) and nonhistaminergic (BAM8-22 and cowage) itch in 22 healthy subjects. Pretreatment with doxepin almost completely abolished histamine-induced itch, while modestly reducing BAM8-22 and cowage-induced itch.
Doxepin also reduced superficial blood perfusion (neurogenic inflammation) induced by all pruritogens, particularly the axon-reflex flare from histamine. Histamine caused greater mechanical sensitivity (mechanically evoked itch and mechanical pain sensitivity), which was reduced by doxepin. Thermal sensitivity was largely unaffected except for cold detection threshold. Doxepin’s antipruritic effect on histaminergic itch is attributed to peripheral H1 receptor blockade. The partial reduction of nonhistaminergic itch may involve sodium channel inhibition, reducing action potentials.

Fig. 1 Mechanism of action of Doxepin. (Aliotta G E.; et al. 2023)

A chitosan-based doxepin nanogel was developed to treat chemotherapy-induced oral mucositis. The nanogel was prepared by ionic gelation, yielding uniform spherical nanoparticles. In a randomized double-blinded placebo-controlled trial, 60 pediatric cancer patients were divided into four groups: control (diphenhydramine/aluminum-magnesium mouthwash), doxepin mouthwash (0.5% w/v), chitosan nanogel, and doxepin/chitosan nanogel. Treatments were applied four times daily for 14 days. At day 3, the doxepin/chitosan nanogel significantly reduced WHO, WCCNR, and VAS scores compared to control. At day 7, it reduced NCI and WCCNR scores more than control and outperformed chitosan nanogel alone on WCCNR. At day 14, it continued to show better NCI scores than control. The nanogel offers synergistic effects: chitosan provides antimicrobial and wound-healing properties, while doxepin offers analgesia and promotes healing.

Fig. 2 Average particle size of chitosan-based doxepin nanogel by DLS (A), Zeta potential of chitosan nanogel (B) and TEM image (C). (Samiraninezhad N.; et al. 2023)