Tags

Type your tag names separated by a space and hit enter

Effect of Doxepin Mouthwash or Diphenhydramine-Lidocaine-Antacid Mouthwash vs Placebo on Radiotherapy-Related Oral Mucositis Pain: The Alliance A221304 Randomized Clinical Trial.
JAMA. 2019 04 16; 321(15):1481-1490.JAMA

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 mouthwash or diphenhydramine-lidocaine-antacid mouthwash for the treatment of oral mucositis-related pain.

Design, Setting, and Participants

A phase 3 randomized trial was conducted from November 1, 2014, to May 16, 2016, at 30 US institutions and included 275 patients who underwent 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.

Interventions

Ninety-two patients were randomized to doxepin mouthwash (25 mg/5 mL water); 91 patients to diphenhydramine-lidocaine-antacid; and 92 patients to placebo.

Main Outcome and Measures

The primary end point was total oral mucositis pain reduction (defined by the area under the curve and adjusted for baseline pain score) during the 4 hours after a single dose of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash compared with a single dose of placebo. The minimal clinically important difference was a 3.5-point change. The secondary end points included drowsiness, unpleasant taste, and stinging or 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 during the first 4 hours decreased by 11.6 points in the doxepin mouthwash group, by 11.7 points in the diphenhydramine-lidocaine-antacid mouthwash group, and by 8.7 points in the placebo group. The between-group difference was 2.9 points (95% 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. More drowsiness was reported with doxepin mouthwash vs placebo (by 1.5 points [95% CI, 0-4.0]; P = .03), unpleasant taste (by 1.5 points [95% CI, 0-3.0]; P = .002), and stinging or burning (by 4.0 points [95% CI, 2.5-5.0]; P < .001). Maximum grade 3 adverse events for the doxepin mouthwash occurred in 3 patients (4%); diphenhydramine-lidocaine-antacid mouthwash, 3 (4%); and placebo, 2 (2%). Fatigue was reported by 5 patients (6%) in the doxepin mouthwash group and no patients in the diphenhydramine-lidocaine-antacid mouthwash group.

Conclusions and Relevance

Among patients undergoing head and neck radiotherapy, the use of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash vs placebo significantly reduced oral mucositis pain during 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 Identifier: NCT02229539.

Authors+Show Affiliations

Department of Radiation Oncology, Mayo Clinic Hospital, Phoenix, Arizona.Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota.Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota.Wichita National Cancer Institute Community Oncology Research Program, Wichita, Kansas.Southeast Clinical Oncology Research Consortium National Cancer Institute Community Oncology Research Program, Spartanburg, South Carolina.Roswell Park Cancer Institute, Buffalo, New York.Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota.Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota.Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota.Department of Radiation Oncology, Mayo Clinic, Jacksonville, Florida.Ohio State University Medical Center, Columbus.Department of Radiation Oncology, Mayo Clinic, Jacksonville, Florida. Now with the University of Maryland School of Medicine, Baltimore.

Pub Type(s)

Clinical Trial, Phase III
Comparative Study
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

30990550

Citation

Sio, Terence T., et al. "Effect of Doxepin Mouthwash or Diphenhydramine-Lidocaine-Antacid Mouthwash Vs Placebo On Radiotherapy-Related Oral Mucositis Pain: the Alliance A221304 Randomized Clinical Trial." JAMA, vol. 321, no. 15, 2019, pp. 1481-1490.
Sio TT, Le-Rademacher JG, Leenstra JL, et al. Effect of Doxepin Mouthwash or Diphenhydramine-Lidocaine-Antacid Mouthwash vs Placebo on Radiotherapy-Related Oral Mucositis Pain: The Alliance A221304 Randomized Clinical Trial. JAMA. 2019;321(15):1481-1490.
Sio, T. T., Le-Rademacher, J. G., Leenstra, J. L., Loprinzi, C. L., Rine, G., Curtis, A., Singh, A. K., Martenson, J. A., Novotny, P. J., Tan, A. D., Qin, R., Ko, S. J., Reiter, P. L., & Miller, R. C. (2019). Effect of Doxepin Mouthwash or Diphenhydramine-Lidocaine-Antacid Mouthwash vs Placebo on Radiotherapy-Related Oral Mucositis Pain: The Alliance A221304 Randomized Clinical Trial. JAMA, 321(15), 1481-1490. https://doi.org/10.1001/jama.2019.3504
Sio TT, et al. Effect of Doxepin Mouthwash or Diphenhydramine-Lidocaine-Antacid Mouthwash Vs Placebo On Radiotherapy-Related Oral Mucositis Pain: the Alliance A221304 Randomized Clinical Trial. JAMA. 2019 04 16;321(15):1481-1490. PubMed PMID: 30990550.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of Doxepin Mouthwash or Diphenhydramine-Lidocaine-Antacid Mouthwash vs Placebo on Radiotherapy-Related Oral Mucositis Pain: The Alliance A221304 Randomized Clinical Trial. AU - Sio,Terence T, AU - Le-Rademacher,Jennifer G, AU - Leenstra,James L, AU - Loprinzi,Charles L, AU - Rine,Grant, AU - Curtis,Amarinthia, AU - Singh,Anurag K, AU - Martenson,James A,Jr AU - Novotny,Paul J, AU - Tan,Angelina D, AU - Qin,Rui, AU - Ko,Stephen J, AU - Reiter,Paul L, AU - Miller,Robert C, PY - 2019/4/17/entrez PY - 2019/4/17/pubmed PY - 2019/4/25/medline SP - 1481 EP - 1490 JF - JAMA JO - JAMA VL - 321 IS - 15 N2 - 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 mouthwash or diphenhydramine-lidocaine-antacid mouthwash for the treatment of oral mucositis-related pain. Design, Setting, and Participants: A phase 3 randomized trial was conducted from November 1, 2014, to May 16, 2016, at 30 US institutions and included 275 patients who underwent 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. Interventions: Ninety-two patients were randomized to doxepin mouthwash (25 mg/5 mL water); 91 patients to diphenhydramine-lidocaine-antacid; and 92 patients to placebo. Main Outcome and Measures: The primary end point was total oral mucositis pain reduction (defined by the area under the curve and adjusted for baseline pain score) during the 4 hours after a single dose of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash compared with a single dose of placebo. The minimal clinically important difference was a 3.5-point change. The secondary end points included drowsiness, unpleasant taste, and stinging or 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 during the first 4 hours decreased by 11.6 points in the doxepin mouthwash group, by 11.7 points in the diphenhydramine-lidocaine-antacid mouthwash group, and by 8.7 points in the placebo group. The between-group difference was 2.9 points (95% 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. More drowsiness was reported with doxepin mouthwash vs placebo (by 1.5 points [95% CI, 0-4.0]; P = .03), unpleasant taste (by 1.5 points [95% CI, 0-3.0]; P = .002), and stinging or burning (by 4.0 points [95% CI, 2.5-5.0]; P < .001). Maximum grade 3 adverse events for the doxepin mouthwash occurred in 3 patients (4%); diphenhydramine-lidocaine-antacid mouthwash, 3 (4%); and placebo, 2 (2%). Fatigue was reported by 5 patients (6%) in the doxepin mouthwash group and no patients in the diphenhydramine-lidocaine-antacid mouthwash group. Conclusions and Relevance: Among patients undergoing head and neck radiotherapy, the use of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash vs placebo significantly reduced oral mucositis pain during 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 Identifier: NCT02229539. SN - 1538-3598 UR - https://www.unboundmedicine.com/medline/citation/30990550/Effect_of_Doxepin_Mouthwash_or_Diphenhydramine_Lidocaine_Antacid_Mouthwash_vs_Placebo_on_Radiotherapy_Related_Oral_Mucositis_Pain:_The_Alliance_A221304_Randomized_Clinical_Trial_ L2 - https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2019.3504 DB - PRIME DP - Unbound Medicine ER -