Doxepin or Diphenhydramine/Lidocaine/Antacid Mouthwash for Radiotherapy-Related Oral Mucositis Pain


Key Points

  • Doxepin mouthwash and diphenhydramine-lidocaine-antacid mouthwash reduced pain compared with placebo.
  • The difference in pain did not reach the minimal clinically important difference.

In the phase III Alliance A221304 trial reported in JAMA, Sio et al found that doxepin mouthwash and diphenhydramine/lidocaine/antacid mouthwash reduced oral mucositis pain for the first 4 hours after administration in patients with oral mucositis pain from head and neck radiotherapy, but the reduction failed to meet the standard for minimal clinically important difference.

Study Details

In the trial, 275 patients at 30 U.S. sites who underwent definitive head and neck radiotherapy and had an oral mucositis pain score of 4 points or greater (0­–10 scale) were randomly assigned 1:1:1 between November 2014 and May 2016. Patients either received doxepin mouthwash (n = 92), diphenhydramine/lidocaine/antacid mouthwash (n = 91), or placebo mouthwash (n = 92). The primary endpoint was total oral mucositis pain reduction during the 4 hours after a single dose of mouthwash (using mean score measured by area under the curve and adjusted for baseline pain score). The minimal clinically important difference was a 3.5-point change relative to placebo.

Pain Reduction

Mucositis pain during the first 4 hours after dosing decreased by 11.6 points in the doxepin mouthwash group (2.9-point difference vs placebo, P = .02), 11.7 points in the diphenhydramine/lidocaine/antacid mouthwash group (3.0-point difference vs placebo, P = .004), and 8.7 points in the placebo group. The doxepin group reported greater drowsiness (1.5-point difference, P = .03), unpleasant taste (1.5-point difference, P = .002) and stinging and burning (4.0-point difference, P < .001) vs placebo. Grade 3 adverse events occurred in 4% of the doxepin group, 4% of the diphenhydramine/lidocaine/antacid group, and 2% of the placebo group. Fatigue was reported by 6% of the doxepin group, and by no patients in the diphenhydramine/lidocaine/antacid group. A preference for continued therapy was expressed by 60% of the doxepin group, 63% of the diphenhydramine/lidocaine/antacid group, and 54% of the placebo group (no significant differences).

The investigators concluded, “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.”

Robert C. Miller, MD, MBA, of the Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, is the corresponding author for the JAMA article.

Disclosure: The study was supported by grants from the National Cancer Institute and by the Mayo Clinic Symptom Intervention Program. For full disclosures of the study authors, visit

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