Doxepin mouthwash and diphenhydramine/lidocaine/antacid (DLA) mouthwash can offer 4 hours of pain relief for cancer patients with oral mucositis, according to investigators.
Although these agents led to statistical improvements in pain, neither met predetermined clinical efficacy thresholds, reported lead author Terence T. Sio, MD, of the Mayo Clinic Hospital in Phoenix and his colleagues, who suggested that more safety and efficacy research is needed.
“Few pharmacological agents or interventions have been shown to effectively reduce the severity of radiotherapy-related oral mucositis and its associated pain,” the investigators wrote in JAMA.
They noted that this knowledge gap affects everyday practice since “more than 80% of patients develop oral mucositis during radiotherapy, and mouthwashes and systemic analgesic agents are frequently used to treat the condition.”
Small studies have shown that doxepin, a tricyclic antidepressant, could be an effective agent for oral mucositis, while a variety of DLA mouthwashes are commonly prescribed, despite a dearth of relevant Cochrane reviews or randomized placebo-controlled trials.
This background led to the present study, which included 275 patients who had developed oral mucositis while undergoing head and neck radiotherapy for cancer. The patients were randomized evenly into three mouthwash groups: placebo (2.5 mL Ora-Sweet SF oral solution and 2.5 mL of water), doxepin (25 mg in 5 mL solution), or diphenhydramine (12.5 mg in 5 mL alcohol-free solution), lidocaine (2% viscous solution), and antacid (20 mg of simethicone, 200 mg of magnesium hydroxide, and 200 mg of aluminum hydroxide in 355 mL solution). The study was divided into two cycles; in the first, patients used their assigned mouthwash once, whereas in the second cycle, which was optional, patients used their assigned treatment every 4 hours for up to 7 days.
The primary endpoint was oral mucositis pain. Multiple secondary endpoints were assessed, including patient preference for continued therapy and various adverse effects, such as drowsiness and taste. Responses were assessed using a combination of the Oral Mucositis Daily Questionnaire and the Oral Mucositis Weekly Questionnaire–Head and Neck Cancer. This modified questionnaire was conducted prior to treatment, then after treatment at 5, 15, 30, 60, 120, and 240 minutes. Pain improvements were compared by area under the curve after adjustment for baseline score. Clinical improvement was defined as a 3.5 point difference in pain score, compared with placebo.
Data analysis showed that pain in the first 4 hours decreased the most in the DLA group (11.7 points), slightly less in the doxepin group (11.6 points), and least in the placebo group (8.7 points). Compared with placebo, both treatments offered statistical improvements. DLA patients responded the most (3.0 points; P = .004), while, again, the average doxepin response was similar, albeit with a slightly higher P value. (2.9 points; P = .02). The investigators discouraged direct comparisons between the two agents because the study was not designed for this purpose.
Neither intervention met the predetermined 3.5-point threshold for clinical improvement, although the investigators suggested that some patients may have had meaningful responses.
“There is some suggestion in post hoc analyses that the findings may have been clinically relevant for some patients,” the investigators wrote, noting that responder analysis favored treatment with DLA versus placebo, but not doxepin versus placebo. “However,” they noted, “the overall clinical importance of the statistically significant primary findings remains uncertain.”
Compared with placebo, doxepin mouthwash was associated with stinging or burning, unpleasant taste, drowsiness, and fatigue. Of note, fatigue only occurred in the doxepin group, at a rate of 6%. Both treatment groups had a maximum grade 3 adverse event rate of 4%, while the placebo arm had an adverse event rate of 2%.
“Further research is needed to assess longer-term efficacy and safety for both mouthwashes,” the investigators concluded.
The study was funded by the National Cancer Institute and the Mayo Clinic Symptom Intervention Program. One investigator reported a nonfinancial support from CutisPharma. The other investigators declared no conflicts of interest.
SOURCE: Sio TT et al. JAMA. 2019 Apr 16. doi: 10.1001/jama.2019.3504.
