Late Breaking Abstract 1: N09C6 (Alliance) - A Phase III, Randomized Double-Blind Study of Doxepin Rinse versus Placebo in the Treatment of Acute Oral Mucositis Pain in Patients Receiving Head and Neck Radiotherapy with or without Chemotherapy

Reporter: Annemarie Fernandes, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 29, 2012

Presenter: Robert C. Miller
Presenter's Affiliation: Mayo Clinic, Minnesota


  • Radiation and chemotherapy induced oral mucositis pain is a significant clinical problem among patients receiving treatment for head and neck cancer
  • Doxepin is a tricyclic antidepressant approved in the US for depression/anxiety and moderate pruritis
    • Systemically, doxepin blocks the reuptake of serotonin and nor-epinephrine to improved mood and neuropathic pain. Topical application of doxepin has been prescribed for management of skin pruritis and neuropathic pain involving the skin
  • Preliminary data from Epstein et al. suggests that topical Doxepin as a mouth rinse reduces oral mucositis pain in cancer patients

Materials and Methods

  • This was a randomized Phase III double-blind placebo controlled trial with a cross over phase
  • Inclusion criteria: Head and neck cancer patients treated with radiation therapy to >50 Gy with or without chemotherapy. All patients had >30% of the oral cavity in the RT field and developed pain related to oral mucositis (severity of 4/10 or higher)
  • On day 1 of developing oral mucositis pain, patients were randomized to Doxepin rinse (25mg/5mL for 1 minute: swish and spit) vs. placebo
  • On day 2, patients then crossed over. Patients who received Doxepin on day 1 received the placebo on day 2 and vice versa
  • Patients were then given the option of using Doxepin for continued use (Q4 hours PRN)
  • Endpoints: pain from oral mucositis using a pain questionnaire (performed on day 1and day 2 at varying intervals over a period of 4 hours: 5, 10, 30, 60, 120, and 240 minutes) and CTCAEv4.0. A weekly questionnaire was used in patients who opted for continued use.
  • No other mouthwashes were allowed. Patients were allowed other analgesics as long as they were given at least 1 hour before or after study administration of mouthwash.


  • 155 patients enrolled from 26 institutions from December 2010-May 2012. 140 patients were analyzed (Doxepin: 69 patients, Placebo: 71 patients) for the primary analysis and 129 patients were analyzed for the secondary analysis. Patient characteristic were well balanced between the two groups. About 80% of patients in each group received concurrent chemotherapy.
  • Compared to placebo, Doxepin reduced pain (AUC reduction(determined from pain levels at various time intervals over 4 hours): -9.1 for Doxepin vs. -4.7 for placebo, p=0.0003)
  • Secondary endpoints:
    • Patients reported temporary burning/stinging and poor taste with Doxepin.
    • Doxepin was associated more drowsiness over the 4 hour period (p=0.03)
    • More patients wished to continue Doxepin than placebo (64% vs. 36%, p=0.002)
  • Crossover analysis was performed for each patient. Doxepin demonstrated an improvement in pain, regardless of administration on day 1 or day 2.

Authors Conclusions

  • Doxepin significantly reduced oral mucositis pain
  • Doxepin was well-tolerated, but caused more drowsiness than placebo
  • The majority of patients elected to continue doxepin when allowed to do so
  • This study provides a new standard for treatment of radiation-induced oral mucositis.

Clinical Implications

  • Patients who undergo radiation therapy, particularly concurrent chemoradiation therapy for head and neck cancer experience significant side effects. For many patients, oral mucositis is one of the most debilitating side effects that significantly impacts quality of life. Oral mucositis causing significant pain that prevents patients from eating, causing them to lose weight, nutrition and energy. Many patients require narcotic pain medication to control their mucositis.
  • Currently, the most common management regimens for oral mucositis involve pain management with narcotic pain medication, neuropathic pain medications such as gabapentin, topical magic mouth and topical lidocaine. Additionally, various radiation technique advancements have been able to spare unnecessary radiation dose to the oral cavity to limit the severity of oral mucositis
  • This study is a well-conducted study evaluating the impact of a new intervention to manage oral mucositis pain. The study was a multi-center, randomized, double-blinded study with cross-over to decrease the impact of unmeasurable confounders as the patients acted as their own controls. The study measured a subjective endpoint of pain as objectively as possible.
  • Patients were allowed to take systemic pain medication 1 hour before or after the administration of the mouth rinse. The authors do not address the impact of other pain medication on the outcome of the study, as this is a potential confounder
  • Additionally, location of primary tumor and volume of disease were not included in the patient characteristics. These variables impact the degree of oral mucositis that patients develop and should be controlled for in such a study
  • The secondary endpoint of the percent of patients wishing to continue Doxepin is not a robust endpoint. Many patients decide to continue with various therapeutic regimens even if they are not experiencing a significant improvement in their symptoms as their options for side effect management are often limited. This endpoint does, however, reflect the minimal adverse effects of Doxepin as patients would not continue the medication if it has intolerable side effects
  • Additionally, the cost of Doxepin compared to magic mouthwash is unclear.
  • Because magic mouthwash and topical lidocaine are common topical regimens of oral mucositis pain currently being used in radiation oncology clinics, this new regimen of topical Doxepin needs to be tested again the current regimen to fully assess its efficacy, ease of implementation and other benefits. Therefore, further randomized studies comparing topical Doxepin with the current standard of magic mouthwash need to be performed before Doxepin is considered a "new standard treatment," as the authors suggest.