Importance:
Oral mucositis causes substantial morbidity during head-and-neck radiotherapy. In a randomized study, doxepin mouthwash was shown to reduce oral mucositis–related pain. A common mouthwash comprising diphenhydramine-lidocaine-antacid is also widely used.
Objective:
To evaluate the effect of doxepin or diphenhydramine-lidocaine-antacid mouthwash for the treatment of oral mucositis–related pain.
Design, Settings, and Participants:
A multi-institutional, 3-group, randomized, double-blind, placebo-controlled phase III trial was conducted from November 1, 2014, to May 16, 2016, in 30 institutions in the United States; 275 patients undergoing definitive head-and-neck radiotherapy with oral mucositis pain rated ≥4 (scale, 0-10) were eligible and randomized. Patients were followed up for a maximum of 28 days after randomization. The last follow-up occurred in June 2016.
Interventions:
Patients were randomized to doxepin (25 mg/5 mL water), 92 patients; diphenhydramine-lidocaine-antacid mouthwash, 91 patients; and placebo, 92 patients.
Main Outcome and Measures:
Primary end point was total oral mucositis pain reduction (area under the curve, adjusting for baseline pain scale) over 4 hours after a single dose of doxepin or diphenhydramine-lidocaine-antacid, compared with a single dose of placebo. Minimal clinically important difference was 3.5-point change. Secondary end points included drowsiness, unpleasant taste, and stinging/burning. All scales ranged from 0 (best) to 10 (worst).
Results:
Among the 275 patients randomized (median age, 61 years; 58 [21%] women), 227 (83%) completed treatment per protocol. Mucositis pain over the first 4 hours decreased by 11.6 points in the doxepin group, by 11.7 points in the diphenhydramine-lidocaine-antacid group, and by 8.7 points in the placebo group, with between-group differences of 2.9 points (95% CI [0.2 to 6.0]; P=.021) for doxepin vs placebo and 3.0 points (95% CI [0.1 to 5.9]; P=.004) for diphenhydramine-lidocaine-antacid vs placebo. More drowsiness (2.6 points; 95% CI [−0.7 to 5.9]; P=.03), unpleasant taste (2.8 points; 95% CI [0.8 to 4.8]; P=.002), and stinging/burning (4.9 points; 95% CI [2.9 to 6.9]; P<.001) were reported with doxepin mouthwash vs placebo. Maximum grade 3 adverse events for the doxepin mouthwash, diphenhydramine-lidocaine-antacid mouthwash, and placebo groups occurred in 3 (4%), 3 (4%), and 2 (2%) patients, respectively. Fatigue was reported by 5 patients (6%) in the doxepin mouthwash group and no patients in the diphenhydramine-lidocaine-antacid group.
Conclusions and Relevance:
Among patients undergoing head-and-neck radiotherapy, the use of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash compared with placebo significantly reduced oral mucositis pain for the first 4 hours after administration; however, the effect size was less than the minimal clinically important difference. Further research is needed to assess longer-term efficacy and safety for both mouthwashes.
Trial Registration:
clinicaltrials.gov Ident...
