Mouthwash containing diphenhydramine, lidocaine, and antacid (or doxepin) led to a statistically significant decrease in oral mucositis-related pain in patients undergoing radiotherapy for head and neck cancer in a large, federally funded randomized controlled trial.
However, the improvement fell shy of the minimally clinically important difference set by the investigators in the overall cohort, although there was a suggestion in post hoc analyses of clinically relevant benefits in some patients.
"Oral rinses such as those in the study provide a nonaddictive option for breakthrough pain with minimal side effects that can improve patients' quality of life during head and neck radiochemotherapy," first author Robert Miller, MD, of the Department of Radiation Oncology, University of Maryland School of Medicine in Baltimore, told Medscape Medical News.
The study was published online April 16 in JAMA.
More than 80% of patients develop oral mucositis during radiotherapy, and mouthwashes and systemic analgesic agents are often used to treat the condition. Despite a lack of high-quality evidence, diphenhydramine-lidocaine-antacid mouthwash (so-called magic mouthwash) is often recommended to patients.
The trial by Miller and colleagues included 275 patients (mean age, 61 years; 21% women) who had 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. Ninety-two patients were randomized to doxepinmouthwash, 91 to diphenhydramine-lidocaine-antacid mouthwash and 92 patients to placebo mouthwash.
Mucositis pain during the first 4 hours after a single dose (primary outcome) decreased by 11.6 points in the doxepin mouthwash group, by 11.7 points in the diphenhydramine-lidocaine-antacid group and by 8.7 points in the placebo group.
The between-group difference was 2.9 points (95% confidence interval [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, which is less than the 3.5-point change set as the minimal clinically important difference. However, the 95% CIs for the primary outcome included the minimal clinically important difference, the investigators note.
And in post hoc exploratory responder analyses, clinically important pain improvements occurred in 79.5% of patients in the doxepin group and 85.5% of patients in the diphenhydramine-lidocaine-antacid group compared with 68.4% of those in the placebo group (P = .14 for doxepin vs placebo and P = .02 for diphenhydramine-lidocaine-antacid vs placebo).
The current trial does not provide proof regarding relative efficacy of doxepin versus diphenhydramine-lidocaine-antacid mouthwash because it was not designed to directly compare the two, the investigators note.
Practice Changing?
Doxepin mouthwash was associated with drowsiness, fatigue, unpleasant taste, and stinging or burning. Sixty percent of patients in the doxepin mouthwash group and 63% in the mixed mouthwash group asked to continue with the treatment, as did 54% of patients using the placebo rinse.
Miller thinks the current results "will change practice guidelines for the management of oral mucositis during radiation and chemotherapy and allow patients more options for treatment of mucositis pain." The first clinical practice guidelines for management of oral and gastrointestinal mucositis were published 15 years ago and an update is expected sometime this year.
The authors of a linked editorial caution that "more high-quality prospective research is needed to refine the available treatments, to address all types of oral mucositis, to provide head-to-head comparisons of active treatments (in addition to comparisons with placebo), and, when applicable, to assess if the intervention carries a risk for severe, late adverse events."
Editorialists Sharon Elad, DMD, from the University of Rochester Medical Center, Rochester, New York, and Noam Yarom, DMD, from Sheba Medical Center, Tel HaShomer, Israel, are also hopeful that technological advances in the treatment of cancer, such as using proton-beam radiotherapy for head and neck cancers, "may substantially reduce the extent of oral mucositis."
However, the pair conclude that "until these advances are routinely used, the search for an effective, safe therapy for oral mucositis and its associated pain needs to continue."
Support for the study was provided by the National Cancer Institute and the Mayo Clinic Symptom Intervention Program. Miller reported receiving nonfinancial support from CutisPharma. Elad reported serving as a consultant to Falk Pharma as the medical expert for a clinical trial about oral chronic graft-vs-host disease and serving as the chair of the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer and the International Society of Oral Oncology. The remaining coauthors and editorialist have disclosed no relevant financial relationships.
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