Pain mechanism of oral ulcerative mucositis and the therapeutic traditional herbal medicine hangeshashinto

Background: Oral ulcerative mucositis causes severe pain during eating and speaking, resulting in poor quality of life for patients with cancer undergoing chemoradiotherapy. Recently, some basic and clinical studies demonstrated that hangeshashinto, a traditional Japanese herbal medicine, alleviated oral ulcerative mucositis-induced pain. Here, we review a recently revealed pain mechanism underlying oral ulcerative mucositis in a preclinical rat model and the pharmacological analgesic effect of hangeshashinto. Highlight: In a rat model of experimentally induced oral ulcerative mucositis, the mucosal surface of the ulcerative region is damaged, which increases oral bacterial loading in the mucosa and prostanoid production. Chemotherapeutic drugs exaggerate the pathological condition and cause severe pain. The pain-related TRP channels, TRPV1, TRPA1, and/or TRPV4, mediate spontaneous and mechanical pain in oral ulcerative mucositis models. Swab application of hangeshashinto had a prolonged localized analgesic effect on oral ulcerative mucositis, even in a chemotherapy-treated oral ulcer model. Two ingredients of hangeshashinto, gingerol and shogaol, strongly inhibit voltage-activated sodium channels (though they have agonistic effects on TRPV1 and TRPA1), which confers hyposensitivity to the oral mucosa. Their analgesic effects on oral ulcerative mucositis are accompanied by accelerated delivery of drugs (other saponin-containing herbal extracts) into the ulcerative region. Conclusion: Elucidation of the pain mechanism of oral ulcerative mucositis and analgesic mechanism of hangeshashinto will allow identification of novel therapeutic approaches against oral ulcerative mucositis-induced pain in patients. The traditional Japanese herbal medicine hangeshashinto is a reliable drug with supporting scientific evidence.