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.

• N = 129 
• MEAN AGE = Doxepin-Placebo, 62 years (range = 39–93 years), Placebo-Doxepin, 60 years (range 37–86 years)
• MALES: 80%, FEMALES: 20%
• KEY DISEASE CHARACTERISTICS: Patients 18 years or older with head and neck malignancy currently undergoing radiotherapy, with or without chemotherapy, with a minimum planned dose of 50 Gy, including one third of the oral cavity mucosa using 1.6–2.2 Gy per fraction currently experiencing oral mucositis without infection and mouth pain rated 4 or higher (0–10 scale) and ECOG 0-2.
• OTHER KEY SAMPLE CHARACTERISTICS: No known allergies to doxepin or TCAs, use of TCAs or MAO inhibitors two weeks prior, no active or untreated herpes simplex virus or oral candidiasis, and no untreated narrow angle glaucoma or urinary retention within six weeks of registration. Patients were stratified according to sex, concurrent sensitizing chemotherapy, and age (< vs ≥ 60 years of age). Patients had to receive an oral examination with confirmed oral mucositis and without oral infection to be enrolled. 

• SITE: Multi-site
• SETTING TYPE: Outpatient
• LOCATION: 26 radiation centers in the United States

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Elder care, palliative care

Randomized, double-blind, placebo-controlled, phase III trial with crossover phase followed by continued use of active agent

• Questionnaires were based on the Oral Mucositis Daily Questionnaire and the Oral Mucositis Weekly Questionnaire-Head.  
• CTCAEv.4.0 was used for toxicities.

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

• Doxepin can cause drowsiness, caused more stinging and burning, and had a worse taste than placebo. Patients may have suspected what arm they were receiving because of these side effects, and it may have affected their decision about continuing with the doxepin rinses rather than efficacy alone. 
• Lack of longitudinal comparison data beyond one or two doses.
• Minimal data was collected in the continuation phase.
• No comparison with magic mouthwash. 
• Further studies are needed to confirm results. Prevention of mucositis was not looked at in this study, which is a much needed indication that should be researched.   

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.