1. In this randomized controlled trial, the use of doxepin or diphenhydramine-lidocaine-antacid mouthwash reduced mucositis pain four hours after treatment but below the threshold for minimal clinically important difference.
2. Doxepin but not diphenhydramine-lidocaine-antacid mouthwash was associated with drowsiness, unpleasant taste, and higher frequency of stinging or burning than placebo.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Pain from radiation-induced mucositis affects more than 80% of patients treated with radiation therapy for head and neck cancers. While a number of commercially available, combination mouthwash preparations have long existed for radiotherapy-related mucositis pain, it is unclear which ones work effectively. In this randomized controlled trial, doxepin or diphenhydramine-lidocaine-antacid mouthwash reduced radiotherapy-related mucositis pain after four hours but the difference did not meet a minimal clinically important difference threshold. Doxepin but not diphenhydramine-lidocaine-antacid mouthwash was associated with drowsiness, unpleasant taste, and higher frequency of stinging or burning than placebo.
While this study suggests that these mouthwashes may be of modest benefit, it is unclear if a certain subset of patients showed a large response while others derived no benefit. In addition, the long-term pain-relieving effects were difficult to estimate with this study.
In-Depth [randomized controlled trial]: The phase 3, Alliance A221304 Study recruited 275 patients randomized 1:1:1 to receive doxepin, diphenhydramine-lidocaine-antacid, or placebo mouthwash from November 1, 2014 to May 16, 2016. Included patients were >18 years old, had an Eastern Cooperative Oncology Group performance status of 0, 1, or 2, had head and neck cancer currently being treated with definitive radiotherapy of at least 45 Gy, and had oral mucositis pain rated as at least a 4 on a 0 to 10 scale. Patients were excluded if they had a known allergy to any of the treatments, used any antiarrhythmic medications, had a current diagnosis of untreated or unresolved oral candidiasis or oral herpes simplex virus infection, used glutamine or sucralfate powders during study registration, or used cryotherapy for prophylactic mucosal protection within 6 weeks of registration. The patients were recruited to two phases, one with single-dose treatment and 4 hour response and another phase with treatment every 4 hours for 7 days. Total pain during the first 4 hours after treatment decreased pain by 11.6 points in the doxepin group, 11.7 points in the diphenhydramine-lidocaine-antacid group, and 8.7 points in the placebo group (between-group difference for doxepin vs placebo 2.9 points; CI95, 0.2 to 6.0 points; diphenhydramine-lidocaine-antacid vs placebo 3.0 points; CI95, 0.1 to 5.9 points). Total pain reduction measured by the area under the curve during the first 4 hours after treatment was higher in the treatment groups. Doxepin but not diphenhydramine-lidocaine-antacid was associated with more drowsiness (difference 1.5 points; CI95, 0 to 4.0 points), higher frequencies of unpleasant taste than placebo (difference 1.5 points; CI95 0 to 3.0 points), and stinging or burning sensation (difference 4.0 points; CI95 2.5 to 5.0 points).
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