Doxepin is a tricyclic antidepressant and has anxiolytic properties. Doxepin also has been used to suppress itching and has antihistamine effects. Doxepin mouth rinse has been evaluated in patients with cancer for management of painful mucositis.
Epstein, J.B., Epstein, J.D., Epstein, M.S., Oien, H., & Truelove, E.L. (2008). Doxepin rinse for management of mucositis pain in patients with cancer: One week follow-up of topical therapy. Special Care in Dentistry, 28(2), 73–77.
To determine the impact of repeated dosing with doxepin rinse over the course of one week in patients with oral mucositis
Patients were instructed to rinse the oral cavity for 1 minute with 5 mL doxepin suspension (5 mg/mL) and then spit it out. Patients were to continue using the rinse as needed, 3–6 times per day, for the following week until their second visit and assessment. Standard of care for mucositis also was used during this time. Subjects used diaries to record analgesic use and mouth rinses.
The study was conducted at a single site, outpatient setting in Canada.
This was a nonrandomized, unblinded, uncontrolled, open-label study.
Statistically significant reductions in pain scores were reported for two hours following doxepin rinse during the initial visit (p < 0.05). Patients recalled that their pain significantly dropped within 5 minutes of rinsing over the week of repeated dosing (p < 0.05). At the follow-up visits, subjects reported statistically significant pain reduction 5 minutes after doxepin rinsing (p < 0.05). No changes were reported in systemic analgesics used during the study week despite the increasing severity of mucositis. No significant differences were found in mucositis scores over time.
Doxepin rinsing in addition to usual oral care produced reduced intensity of pain levels but no apparent difference in mucositis severity. No firm conclusions can be drawn from this extremely small sample.
The doxepin rinse was well tolerated, and the results warrant a larger, randomized, controlled clinical trial.
Leenstra, J.L., Miller, R.C., Qin, R., Martenson, J.A., Dornfeld, K.J., Bearden, J.D., ... Loprinzi, C.L. (2014). Doxepin rinse versus placebo in the treatment of acute oral mucositis pain in patients receiving head and neck radiotherapy with or without chemotherapy: A phase III, randomized, double-blind trial (NCCTG-N09C6 [Alliance]). Journal of Clinical Oncology, 32, 1571–1577.
To test the efficacy of doxepin hydrochloride in reducing radiotherapy-induced oral mucositis pain
Arm 1: Doxepin oral rinse 10 mg/ml x 2.5 ml = 25 mg diluted with sterile or distilled water for a total of 5 ml. Arm 2: Placebo rinse prepared in similar manner with flavored syrup added. Study dose was prepared by unblinded nurse or pharmacist. Blinded personnel administered the rinse. On day 1, the patients swished for one minute, gargled, and spit. On day 2, patients received the opposite rinse. Patients completed symptom questionnaires at set time intervals during the hour following administration and then again at home at two and four hours. No analgesics or oral rinses were allowed 60 minutes prior to and following the study doses. Patients returned the next time their oral pain was ≥ 4/10 and received their second study dose, after which they were unblinded and given the option to continue use of doxepin rinses prn. Patient-reported questionnaires with numerical pain analog scale (0–10) done at BL, 5, 15, 30, 60, 120, and 240 minutes after the rinse on days 1 and 2 to measure pain, taste, stinging or burning, and drowsiness.
Randomized, double-blind, placebo-controlled, phase III trial with crossover phase followed by continued use of active agent
Primary outcome: AUC for mean mouth and throat pain reduction was greater for doxepin compared with placebo (–4.4 difference p < .001). Crossover data revealed similar findings with –2.3 difference p < .001.
Largest placebo-controlled trial to date for oral mucositis pain with positive results
This is a promising option for mucositis pain although there are concerns about how the solution will be made, the cost, the ease of use, the side effects, and adherence to the rinse. Additional questions exist concerning whether or not this data can also be applied to patients receiving chemotherapy or those who have cancers other than head and neck cancer.