Doxepin Rinse Reduces Radiotherapy-Associated Oral Mucositis Pain in Patients With Head and Neck Cancer
In a phase III double-blind crossover trial (North Central Cancer Treatment Group [NCCTG] N09C6, Alliance for Clinical Trials in Oncology cooperative group) reported in the Journal of Clinical Oncology, Leenstra et al found that oral doxepin hydrochloride rinse significantly reduced radiotherapy-associated acute oral mucositis pain compared with placebo in patients receiving radiation therapy for head and neck malignancies. More patients also preferred to continue doxepin rinse treatment.
Study Details
In the study, 155 patients with oral mucositis pain who were undergoing radiotherapy with or without chemotherapy to a minimum planned dose of 50 Gy including one-third of the oral cavity mucosa using 1.6 to 2.2 Gy per fraction were randomly assigned to receive doxepin oral rinse (n = 77) or placebo (n= 78). Both three-dimensional conformal and intensity-modulated radiotherapy techniques were permitted.
Patients received a single dose of doxepin or placebo on day 1 (phase 1) and then crossed over to receive the other agent on a subsequent day (phase 2). Ora-Sweet SF, an alcohol-free flavored sugar-free syrup vehicle, was the placebo base solution. Patients swished the solution in their mouth for 1 minute and gargled before spitting out the solution. Patients were asked whether they wanted to continue their current treatment at the end of each phase.
Pain questionnaires based on the Oral Mucositis Daily Questionnaire and the Oral Mucositis Weekly Questionnaire–Head and Neck Cancer used 0 to 10 point numerical analog scales to measure pain, unpleasant taste, stinging or burning, and drowsiness (a known effect of doxepin) at 5, 15, 30, 60, 120, and 240 minutes after administration. The primary endpoint was pain reduction as measured by the area under the curve (AUC) of the pain scale using data from day 1.
Greater Pain Reduction
Among the randomly assigned doxepin and placebo groups, 69 and 71 patients had data available for primary endpoint analysis and 62 and 67 had data available for the crossover endpoint analysis. The mean time between treatment in the first period and the crossover period was 2.1 days and did not differ between groups.
In the primary endpoint analysis, the AUC for mouth and throat pain reduction was significantly greater with doxepin vs placebo (−9.1 vs −4.7, P < .001). Crossover analysis among patients completing both phases also showed greater pain reduction with doxepin (intrapatient changes of +4.1 for the doxepin-placebo arm and −2.8 for the placebo-doxepin arm, P < .001). During the second phase, doxepin was also associated with significant pain reduction (−7.9 vs −5.6, P < .001).
More Stinging/Burning and Drowsiness
During the first phase, the AUC for stinging or burning was significantly greater for doxepin (9.6 vs 4.0, P < .001), and the AUC for taste also favored placebo (7.7 vs 2.6, P = .0018). Doxepin was also associated with significantly greater drowsiness (AUC = −2.4 vs −0.7, P = .0297). There was no significant difference in additional analgesic use at 2 hours (8.8% vs 2.9%, P = .1392) or 4 hours (16.9% vs 14.5%, P = .6989) after doxepin vs placebo in the first phase.
Patients Preferred Doxepin
Significantly more patients reported interest in continuing doxepin vs placebo in both the first phase (77.3% vs 51.5%, P = .0018) and the second phase (69.8% vs 43.9%, P =.004). After completion of both phases and unblinding of treatment, 63% of eligible patients chose to continue with doxepin rinses.
The investigators concluded, “A doxepin rinse diminishes [oral mucositis] pain. Further studies are warranted to determine its role in the management of [oral mucositis].”
Robert C. Miller, MD, of the Mayo Clinic, is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by the Alliance for Clinical Trials in Oncology and grants from the National Cancer Institute. Dr. Miller receives research funding from Pfizer.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
