Recently, the Journal of Clinical Oncology (JCO) reported a phase 3 double-blind crossover trial (North Central Cancer Treatment Group [NCCTG] N09C6, in the Joint Clinical Trials in Oncology Collaborative Group), in which Leenstra et al. found that the use of doxorubicin hydrochloride oral rinses significantly reduced acute oral mucositis due to radiotherapy for head and neck cancer compared with the placebo group painful sensation. More patients also preferred to continue treatment with doxepin rinse. The trial showed that Doxepin rinses provided greater pain relief, accompanied by more tingling or burning sensations, unpleasant taste, and more drowsiness; more patients wanted to continue treatment with Doxepin. A total of 155 patients with painful oral mucositis were enrolled in this study, all of whom received radiotherapy (combined or not) for head and neck cancer with a planned minimum radiation dose of 50 Gy, of which one-third received oral mucosal radiotherapy at a dose of 1.6 to 2.2 Gy. The enrolled subjects were randomized to receive either a Doxepin oral rinse (n = 77) or a placebo (n = 78) oral rinse. Either three-dimensional conformal or intensity-modulated radiation treatment techniques were allowed. Patients received a single dose of either doxepin or placebo rinse on the first day (phase 1) and crossed over to the other drug rinse on the following day (phase 2). The placebo base solution was a sweet-tasting alcohol-free syrup-free liquid. Subjects rinsed their mouths for one minute using the rinse. The researchers asked patients at the endpoint of each phase whether they would like to receive continued treatment with the currently active rinse. Pain questionnaires were based on the Oral Mucositis Daily Questionnaire and the Oral Mucositis Weekly Questionnaire, and pain measures for head and neck cancer were on a scale from 0 to 10 for unpleasant taste, tingling or burning, and sleepiness (known Doxepin influencers) 5, 15, 30, 60, 120, and 240 minutes after administration. The primary endpoint was the degree of pain reduction, expressed as area under the curve (AUC). Data from 69 and 71 patients in the randomized Doxepin and placebo groups, respectively, were valid for analysis of the primary endpoint, and 62 and 67 patients, respectively, were valid for analysis of the crossover data. The mean duration of the first phase and crossover treatment period was 2.1 days and did not differ between groups. Analysis of the primary endpoint showed a significant increase in the AUC curve for reduction in oral and throat pain in the doxorubicin group compared to placebo. The doxepin group also demonstrated greater pain reduction in patients who completed both phases of the crossover treatment trial. In phase 2, doxepin was also associated with a significant reduction in pain. In the second phase of the trial, the Doxepin group showed more AUCs for more tingling or burning sensations, and patients in the placebo group also showed better taste performance. Doxepin treatment was significantly associated with drowsiness. In the first phase of the trial, there were no significant differences between the Doxepin and placebo groups in the use of other pain medications 2 or 4 hours after treatment. In the first and second phases of the trial, significantly more patients in the doxepin group expressed a desire to continue treatment compared to the placebo group. After completing both phases of unblinded treatment, 63% of eligible patients chose to continue Doxepin treatment. The researchers concluded that Doxepin lotion may reduce oral mucositis pain. Further studies are needed to determine its usefulness for the management of oral mucositis.