Effect of Doxepin Mouthwash or Diphenhydramine-Lidocaine-Antacid Mouthwash vs Placebo on Radiotherapy-Related Oral Mucositis Pain

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 or diphenhydramine-lidocaine-antacid mouthwash for the treatment of oral mucositis–related pain. Design, Settings, and Participants: A multi-institutional, 3-group, randomized, double-blind, placebo-controlled phase III trial was conducted from November 1, 2014, to May 16, 2016, in 30 institutions in the United States; 275 patients undergoing definitive head-and-neck radiotherapy with oral mucositis pain rated ≥4 (scale, 0-10) were eligible and randomized. Patients were followed up for a maximum of 28 days after randomization. The last follow-up occurred in June 2016. Interventions: Patients were randomized to doxepin (25 mg/5 mL water), 92 patients; diphenhydramine-lidocaine-antacid mouthwash, 91 patients; and placebo, 92 patients. Main Outcome and Measures: Primary end point was total oral mucositis pain reduction (area under the curve, adjusting for baseline pain scale) over 4 hours after a single dose of doxepin or diphenhydramine-lidocaine-antacid, compared with a single dose of placebo. Minimal clinically important difference was 3.5-point change. Secondary end points included drowsiness, unpleasant taste, and stinging/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 over the first 4 hours decreased by 11.6 points in the doxepin group, by 11.7 points in the diphenhydramine-lidocaine-antacid group, and by 8.7 points in the placebo group, with between-group differences of 2.9 points (95% CI [0.2 to 6.0]; P=.021) for doxepin vs placebo and 3.0 points (95% CI [0.1 to 5.9]; P=.004) for diphenhydramine-lidocaine-antacid vs placebo. More drowsiness (2.6 points; 95% CI [−0.7 to 5.9]; P=.03), unpleasant taste (2.8 points; 95% CI [0.8 to 4.8]; P=.002), and stinging/burning (4.9 points; 95% CI [2.9 to 6.9]; P<.001) were reported with doxepin mouthwash vs placebo. Maximum grade 3 adverse events for the doxepin mouthwash, diphenhydramine-lidocaine-antacid mouthwash, and placebo groups occurred in 3 (4%), 3 (4%), and 2 (2%) patients, respectively. Fatigue was reported by 5 patients (6%) in the doxepin mouthwash group and no patients in the diphenhydramine-lidocaine-antacid group. Conclusions and Relevance: Among patients undergoing head-and-neck radiotherapy, the use of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash compared with placebo significantly reduced oral mucositis pain for 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 Ident...

Phase IIb, Randomized, Double-Blind Trial of GC4419 Versus Placebo to Reduce Severe Oral Mucositis Due to Concurrent Radiotherapy and Cisplatin For Head and Neck Cancer

“…Treatment options for SOM are limited to symptom management with topical agents and systemic analgesics. 11-19 No drugs are approved to reduce SOM duration, incidence, or severity for patients with solid tumors; palifermin is approved in the United States for patients with hematologic malignancies only. 20,21 Consequently, SOM management constitutes an unmet clinical need.…”

Opioid therapy vs. multimodal analgesia in head and neck Cancer (OPTIMAL-HN): study protocol for a randomized clinical trial

“… If more than 4–5 breakthrough doses are required daily for adequate pain relief, the baseline regular short-acting or long-acting opioid dose should be adjusted accordingly. The prescription of local analgesia in the form of creams or mouthwashes is left to the discretion of the treating physician since no clinically significant difference in pain relief has been observed between Doxepin Mouthwash or Diphenhydramine-Lidocaine-Antacid Mouthwash compared with placebo [ 31 ]. Extended release opioid tablets may not be prescribed to feeding-tube dependent patients as crushing impedes their slow-release mechanism, thereby altering opioid absorption and efficacy.…”

“…The prescription of local analgesia in the form of creams or mouthwashes is left to the discretion of the treating physician since no clinically significant difference in pain relief has been observed between Doxepin Mouthwash or Diphenhydramine-Lidocaine-Antacid Mouthwash compared with placebo [ 31 ].…”

Dermatologic conditions in women receiving systemic cancer therapy

“…According to clinical practice guidelines, the management of oral mucositis should be broadly approached in six categories: pain control, nutritional support, oral decontamination, xerostomia treatment, bleeding control, and therapeutic interventions for the mucositis itself (Lalla et al, 2008). Pain is the primary manifestation of oral mucositis and can be controlled via saline rinses, ice chips, and other rinses that contain topical anesthetics, diphenhydramine, doxepin, sucralfate, and/or aluminum hydroxide/magnesium hydroxide/simethicone (Lalla et al, 2008, Sio et al, 2019). Topical dexamethasone suspension may be used for symptomatic and painful ulcers, whereas systemic opioids may be required for higher-grade mucositis (Lalla et al, 2008).…”