Doxepin Rinse Eases Mucositis Pain in Cancer Patients

BOSTON – An oral rinse solution of the antidepressant doxepin provided modest relief of pain from cancer treatment–induced oral mucositis in a randomized phase III trial.

Patients with head and neck cancer had a mean reduction of about two points on a 0-10 pain scale 30 minutes after using a doxepin rinse, compared with an approximate one-point reduction for patients who rinsed with a placebo (P = .0003), investigators reported at the annual meeting of the American Society for Radiation Oncology (ASTRO).

All patients in the trial had been treated with radiation with or without chemotherapy.

"Doxepin was used solely for pain relief. We did not expect it to reduce or prevent mucositis, but merely [to] treat the patients’ pain symptoms," said Dr. Robert C. Miller, a radiation oncologist at the Mayo Clinic in Rochester, Minn.

He added that "the efficacy of doxepin in treating oral mucositis pain caused by chemotherapy alone, by stem cell transplantation, or benign conditions such as aphthous ulcers warrants further study."

Conclusion Called Premature

Dr. Paul M. Harari, professor and chairman of human oncology at the University of Wisconsin, Madison, the invited discussant, agreed that oral mucositis "is a very real entity, one that impacts both patients and health care providers."

He applauded the trial’s multicenter, randomized design but noted that the overall reduction in mucositis pain with doxepin was modest, only one point better than placebo, and that mucositis pain is only one element of a host of acute and late toxicities of radiation and chemotherapy for patients with head and neck cancer.

He also said that the authors’ conclusion that "this study provides a new standard of treatment of radiotherapy-induced oral mucositis" is premature and warrants closer scrutiny.

"I would just caution for careful thought and further study before we introduce a new class of agents into the context of agents that head and neck cancer patients receive," he said. "Is this the most effective way to lower the pain score by one point in a transient measure?"

Antidepressant and Antihistamine

Doxepin is a tricyclic antidepressant with antihistaminic properties, approved in the United States for treatment of depression and anxiety as well as moderate pruritus. Preliminary data from a 2007 study suggested that doxepin could reduce mucositis pain in cancer patients (J. Pain Symptom Manage. 2007;33:111-4).

In the current study, patients with radiation to the head and neck, with or without chemotherapy and oral mucositis pain of four or greater on a 10-point pain assessment scale were enrolled. Patients received definitive radiotherapy with doses of at least 50 Gy involving more than 30% of the oral cavity.

The patients were randomized on day 1 in a double-blinded fashion to use either a single dose of either placebo or doxepin 25 mg in a 5-mL rinse and gargle, which they spat out after 1 minute. The trial had a crossover phase on day 2, with optional continuation of the active agent at the end of the study.

Participants filled out pain assessment questionnaires at baseline, four times in the first hour after rinse (in clinic), and then at 2 and 4 hours at home. Those who opted to continue doxepin filled out weekly questionnaires. Patients also were allowed to take analgesics 1 hour before or after doxepin.

A total of 140 patients (69 in the doxepin group, 71 on placebo) were available for the primary end point, total pain reduction as calculated by average mouth and throat pain area-under-the-curve (AUC) reduction over time. The AUC reduction was –9.1 among patients on doxepin, compared with –4.7 for those on placebo (P = .0003), Dr. Miller reported.

However, in 129 patients available for secondary end point analysis, doxepin, which has a known sedative effect, was associated with significantly more mean drowsiness over time (P = .03). Patients on doxepin also reported temporary unpleasant taste in the mouth, burning, and stinging, he said.

Asked whether they would continue doxepin after the randomized phase, 64% said yes and 36% declined (P = .002).

In a crossover analysis comparing the effects of doxepin and placebo in each patient, doxepin was seen to generate a benefit whether it was given before or after placebo (P less than .0001), he noted.

The study was conducted through the Alliance for Clinical Trials in Oncology and supported by a grant from the North Central Cancer Treatment Group and Mayo Clinic. Dr. Miller disclosed serving on the scientific advisory board of Tekcapital Ltd. Dr. Harari disclosed receiving research grants from the National Cancer Institute, Genentech, and Symphogen.

BOSTON – An oral rinse solution of the antidepressant doxepin provided modest relief of pain from cancer treatment–induced oral mucositis in a randomized phase III trial.

Patients with head and neck cancer had a mean reduction of about two points on a 0-10 pain scale 30 minutes after using a doxepin rinse, compared with an approximate one-point reduction for patients who rinsed with a placebo (P = .0003), investigators reported at the annual meeting of the American Society for Radiation Oncology (ASTRO).

All patients in the trial had been treated with radiation with or without chemotherapy.

"Doxepin was used solely for pain relief. We did not expect it to reduce or prevent mucositis, but merely [to] treat the patients’ pain symptoms," said Dr. Robert C. Miller, a radiation oncologist at the Mayo Clinic in Rochester, Minn.

He added that "the efficacy of doxepin in treating oral mucositis pain caused by chemotherapy alone, by stem cell transplantation, or benign conditions such as aphthous ulcers warrants further study."

Conclusion Called Premature

Dr. Paul M. Harari, professor and chairman of human oncology at the University of Wisconsin, Madison, the invited discussant, agreed that oral mucositis "is a very real entity, one that impacts both patients and health care providers."

He applauded the trial’s multicenter, randomized design but noted that the overall reduction in mucositis pain with doxepin was modest, only one point better than placebo, and that mucositis pain is only one element of a host of acute and late toxicities of radiation and chemotherapy for patients with head and neck cancer.

He also said that the authors’ conclusion that "this study provides a new standard of treatment of radiotherapy-induced oral mucositis" is premature and warrants closer scrutiny.

"I would just caution for careful thought and further study before we introduce a new class of agents into the context of agents that head and neck cancer patients receive," he said. "Is this the most effective way to lower the pain score by one point in a transient measure?"

Antidepressant and Antihistamine

Doxepin is a tricyclic antidepressant with antihistaminic properties, approved in the United States for treatment of depression and anxiety as well as moderate pruritus. Preliminary data from a 2007 study suggested that doxepin could reduce mucositis pain in cancer patients (J. Pain Symptom Manage. 2007;33:111-4).

In the current study, patients with radiation to the head and neck, with or without chemotherapy and oral mucositis pain of four or greater on a 10-point pain assessment scale were enrolled. Patients received definitive radiotherapy with doses of at least 50 Gy involving more than 30% of the oral cavity.

The patients were randomized on day 1 in a double-blinded fashion to use either a single dose of either placebo or doxepin 25 mg in a 5-mL rinse and gargle, which they spat out after 1 minute. The trial had a crossover phase on day 2, with optional continuation of the active agent at the end of the study.

Participants filled out pain assessment questionnaires at baseline, four times in the first hour after rinse (in clinic), and then at 2 and 4 hours at home. Those who opted to continue doxepin filled out weekly questionnaires. Patients also were allowed to take analgesics 1 hour before or after doxepin.

A total of 140 patients (69 in the doxepin group, 71 on placebo) were available for the primary end point, total pain reduction as calculated by average mouth and throat pain area-under-the-curve (AUC) reduction over time. The AUC reduction was –9.1 among patients on doxepin, compared with –4.7 for those on placebo (P = .0003), Dr. Miller reported.

However, in 129 patients available for secondary end point analysis, doxepin, which has a known sedative effect, was associated with significantly more mean drowsiness over time (P = .03). Patients on doxepin also reported temporary unpleasant taste in the mouth, burning, and stinging, he said.

Asked whether they would continue doxepin after the randomized phase, 64% said yes and 36% declined (P = .002).

In a crossover analysis comparing the effects of doxepin and placebo in each patient, doxepin was seen to generate a benefit whether it was given before or after placebo (P less than .0001), he noted.

The study was conducted through the Alliance for Clinical Trials in Oncology and supported by a grant from the North Central Cancer Treatment Group and Mayo Clinic. Dr. Miller disclosed serving on the scientific advisory board of Tekcapital Ltd. Dr. Harari disclosed receiving research grants from the National Cancer Institute, Genentech, and Symphogen.

BOSTON – An oral rinse solution of the antidepressant doxepin provided modest relief of pain from cancer treatment–induced oral mucositis in a randomized phase III trial.

Patients with head and neck cancer had a mean reduction of about two points on a 0-10 pain scale 30 minutes after using a doxepin rinse, compared with an approximate one-point reduction for patients who rinsed with a placebo (P = .0003), investigators reported at the annual meeting of the American Society for Radiation Oncology (ASTRO).

All patients in the trial had been treated with radiation with or without chemotherapy.

"Doxepin was used solely for pain relief. We did not expect it to reduce or prevent mucositis, but merely [to] treat the patients’ pain symptoms," said Dr. Robert C. Miller, a radiation oncologist at the Mayo Clinic in Rochester, Minn.

He added that "the efficacy of doxepin in treating oral mucositis pain caused by chemotherapy alone, by stem cell transplantation, or benign conditions such as aphthous ulcers warrants further study."

Conclusion Called Premature

Dr. Paul M. Harari, professor and chairman of human oncology at the University of Wisconsin, Madison, the invited discussant, agreed that oral mucositis "is a very real entity, one that impacts both patients and health care providers."

He applauded the trial’s multicenter, randomized design but noted that the overall reduction in mucositis pain with doxepin was modest, only one point better than placebo, and that mucositis pain is only one element of a host of acute and late toxicities of radiation and chemotherapy for patients with head and neck cancer.

He also said that the authors’ conclusion that "this study provides a new standard of treatment of radiotherapy-induced oral mucositis" is premature and warrants closer scrutiny.

"I would just caution for careful thought and further study before we introduce a new class of agents into the context of agents that head and neck cancer patients receive," he said. "Is this the most effective way to lower the pain score by one point in a transient measure?"

Antidepressant and Antihistamine

Doxepin is a tricyclic antidepressant with antihistaminic properties, approved in the United States for treatment of depression and anxiety as well as moderate pruritus. Preliminary data from a 2007 study suggested that doxepin could reduce mucositis pain in cancer patients (J. Pain Symptom Manage. 2007;33:111-4).

In the current study, patients with radiation to the head and neck, with or without chemotherapy and oral mucositis pain of four or greater on a 10-point pain assessment scale were enrolled. Patients received definitive radiotherapy with doses of at least 50 Gy involving more than 30% of the oral cavity.

The patients were randomized on day 1 in a double-blinded fashion to use either a single dose of either placebo or doxepin 25 mg in a 5-mL rinse and gargle, which they spat out after 1 minute. The trial had a crossover phase on day 2, with optional continuation of the active agent at the end of the study.

Participants filled out pain assessment questionnaires at baseline, four times in the first hour after rinse (in clinic), and then at 2 and 4 hours at home. Those who opted to continue doxepin filled out weekly questionnaires. Patients also were allowed to take analgesics 1 hour before or after doxepin.

A total of 140 patients (69 in the doxepin group, 71 on placebo) were available for the primary end point, total pain reduction as calculated by average mouth and throat pain area-under-the-curve (AUC) reduction over time. The AUC reduction was –9.1 among patients on doxepin, compared with –4.7 for those on placebo (P = .0003), Dr. Miller reported.

However, in 129 patients available for secondary end point analysis, doxepin, which has a known sedative effect, was associated with significantly more mean drowsiness over time (P = .03). Patients on doxepin also reported temporary unpleasant taste in the mouth, burning, and stinging, he said.

Asked whether they would continue doxepin after the randomized phase, 64% said yes and 36% declined (P = .002).

In a crossover analysis comparing the effects of doxepin and placebo in each patient, doxepin was seen to generate a benefit whether it was given before or after placebo (P less than .0001), he noted.

The study was conducted through the Alliance for Clinical Trials in Oncology and supported by a grant from the North Central Cancer Treatment Group and Mayo Clinic. Dr. Miller disclosed serving on the scientific advisory board of Tekcapital Ltd. Dr. Harari disclosed receiving research grants from the National Cancer Institute, Genentech, and Symphogen.