Effect of Doxepin Mouthwash or Diphenhydramine-Lidocaine-Antacid Mouthwash vs Placebo on Radiotherapy-Related Oral Mucositis Pain: The Alliance A221304 Randomized Clinical Trial

Abstract

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 mouthwash or diphenhydramine-lidocaine-antacid mouthwash for the treatment of oral mucositis-related pain.

Design, setting, and participants: A phase 3 randomized trial was conducted from November 1, 2014, to May 16, 2016, at 30 US institutions and included 275 patients who underwent definitive head and neck radiotherapy, had an oral mucositis pain score of 4 points or greater (scale, 0-10), and were followed up for a maximum of 28 days.

Interventions: Ninety-two patients were randomized to doxepin mouthwash (25 mg/5 mL water); 91 patients to diphenhydramine-lidocaine-antacid; and 92 patients to placebo.

Main outcome and measures: The primary end point was total oral mucositis pain reduction (defined by the area under the curve and adjusted for baseline pain score) during the 4 hours after a single dose of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash compared with a single dose of placebo. The minimal clinically important difference was a 3.5-point change. The secondary end points included drowsiness, unpleasant taste, and stinging or 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 during the first 4 hours decreased by 11.6 points in the doxepin mouthwash group, by 11.7 points in the diphenhydramine-lidocaine-antacid mouthwash group, and by 8.7 points in the placebo group. The between-group difference was 2.9 points (95% CI, 0.2-6.0; P = .02) for doxepin mouthwash vs placebo and 3.0 points (95% CI, 0.1-5.9; P = .004) for diphenhydramine-lidocaine-antacid mouthwash vs placebo. More drowsiness was reported with doxepin mouthwash vs placebo (by 1.5 points [95% CI, 0-4.0]; P = .03), unpleasant taste (by 1.5 points [95% CI, 0-3.0]; P = .002), and stinging or burning (by 4.0 points [95% CI, 2.5-5.0]; P < .001). Maximum grade 3 adverse events for the doxepin mouthwash occurred in 3 patients (4%); diphenhydramine-lidocaine-antacid mouthwash, 3 (4%); and placebo, 2 (2%). Fatigue was reported by 5 patients (6%) in the doxepin mouthwash group and no patients in the diphenhydramine-lidocaine-antacid mouthwash group.

Conclusions and relevance: Among patients undergoing head and neck radiotherapy, the use of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash vs placebo significantly reduced oral mucositis pain during 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 Identifier: NCT02229539.

Figure 1.. Recruitment, Randomization, and Patient Flow in a Study of Mouthwash to Treat Oral Mucositis Pain

^aThe number of patients approached and assessed for eligibility was not collected because it was not required per protocol.

Figure 2.. Pain Scores Over Time During Cycle 1 for Doxepin, Diphenhydramine-Lidocaine-Antacid, and Placebo Groups

Pain was measured on a scale from 0 (least burdensome) to 10 (most burdensome). Compared with placebo, both doxepin mouthwash and diphenhydramine-lidocaine-antacid mouthwash resulted in a statistically significant reduction in pain (P = .03 for doxepin mouthwash; P = .004 for diphenhydramine-lidocaine-antacid mouthwash). Boxplots of the pain scores for each group have been staggered at the time points so that they do not overlap. In the boxplots, the solid lines in the middle of the box are the median values, the top of the box is the 75th percentile, the bottom of the box is the 25th percentile, and the lines extending from the boxes extend out to the upper and lower adjacent values. Outliers are represented by the black dots.

Figure 3.. Mouth Pain Scores by Continuation Day During Cycle 2 for Doxepin, Diphenhydramine-Lidocaine-Antacid, and Placebo Groups

Pain was measured on a scale from 0 (least burdensome) to 10 (most burdensome). Boxplots of the pain scores for each group have been staggered at the time points so that they do not overlap. In the boxplots, the solid lines in the middle of the box are the median values, the top of the box is the 75th percentile, the bottom of the box is the 25th percentile, the black dots are mean values, and the lines extending from the boxes extend out to the upper and lower adjacent values. Outliers, which appear above and below doxepin mouthwash at continuation day 3, are represented by the black dots.