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Original Investigation
April 16, 2019

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

Author Affiliations
  • 1Department of Radiation Oncology, Mayo Clinic Hospital, Phoenix, Arizona
  • 2Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota
  • 3Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota
  • 4Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota
  • 5Wichita National Cancer Institute Community Oncology Research Program, Wichita, Kansas
  • 6Southeast Clinical Oncology Research Consortium National Cancer Institute Community Oncology Research Program, Spartanburg, South Carolina
  • 7Roswell Park Cancer Institute, Buffalo, New York
  • 8Department of Radiation Oncology, Mayo Clinic, Jacksonville, Florida
  • 9Ohio State University Medical Center, Columbus
  • 10Now with the University of Maryland School of Medicine, Baltimore
JAMA. 2019;321(15):1481-1490. doi:10.1001/jama.2019.3504
Key Points

Question  Does doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash compared with placebo reduce oral mucositis–related pain in patients undergoing radiotherapy for head and neck cancer?

Findings  In this randomized clinical trial that included 275 patients undergoing radiotherapy, the use of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash reduced mucositis pain (defined by the area under the curve and adjusted for baseline pain score) during the first 4 hours after administration by 11.6 and 11.7 points, respectively, compared with 8.7 points for placebo mouthwash; both comparisons with placebo were statistically significant.

Meaning  Doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash may be effective in reducing radiotherapy-related mucositis pain, but further research is needed to assess longer-term efficacy and safety.

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

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