title: Doxepin rinse versus placebo in the treatment of acute oral mucositis pain in patients receiving head and neck radiotherapy with or without chemotherapy: a phase III, randomized, double-blind trial (NCCTG-N09C6 [Alliance]).
abstract: OBJECTIVE
  Painful oral mucositis (OM) is a significant toxicity during radiotherapy for head and neck cancers. The aim of this randomized, double-blind, placebo-controlled trial was to test the efficacy of doxepin hydrochloride in the reduction of radiotherapy-induced OM pain.
  
  
  METHODS
  In all, 155 patients were randomly allocated to a doxepin oral rinse or a placebo for the treatment of radiotherapy-related OM pain. Patients received a single dose of doxepin or placebo on day 1 and then crossed over to receive the opposite agent on a subsequent day. Pain questionnaires were administered at baseline and at 5, 15, 30, 60, 120, and 240 minutes. Patients were then given the option to continue doxepin. The primary end point was pain reduction as measured by the area under the curve (AUC) of the pain scale using data from day 1.
  
  
  RESULTS
  Primary end point analysis revealed that the AUC for mouth and throat pain reduction was greater for doxepin (-9.1) than for placebo (-4.7; P < .001). Crossover analysis of patients completing both phases confirmed that patients experienced greater mouth and throat pain reduction with doxepin (intrapatient changes of 4.1 for doxepin-placebo arm and -2.8 for placebo-doxepin arm; P < .001). Doxepin was associated with more stinging or burning, unpleasant taste, and greater drowsiness than the placebo rinse. More patients receiving doxepin expressed a desire to continue treatment than did patients with placebo after completion of each of the randomized phases of the study.
  
  
  CONCLUSIONS
  A doxepin rinse diminishes OM pain. Further studies are warranted to determine its role in the management of OM.
authors.affiliation: James L. Leenstra, St Vincent Regional Cancer Center, Green Bay, WI; Robert C. Miller, Rui Qin, James A. Martenson, Paul J. Novotny, Robert L. Foote, and Charles L. Loprinzi, Mayo Clinic, Rochester; Kenneth J. Dornfeld, Essentia Health Cancer Center, Duluth, MN; James D. Bearden, Palmetto Hematology Oncology, Spartanburg, SC; Dev R. Puri, Mercy Cancer Center, Des Moines, IA; Philip J. Stella, St Joseph Mercy Cancer Care Center, Ann Arbor, MI; Miroslaw A. Mazurczak, Sandford Health Cancer Center, Sioux Falls, SD; and Marie D. Klish, Hope Cancer Center, Longmont, CO.
authors.forename: James L
authors.initials: JL
authors.lastname: Leenstra
authors.affiliation: James L. Leenstra, St Vincent Regional Cancer Center, Green Bay, WI; Robert C. Miller, Rui Qin, James A. Martenson, Paul J. Novotny, Robert L. Foote, and Charles L. Loprinzi, Mayo Clinic, Rochester; Kenneth J. Dornfeld, Essentia Health Cancer Center, Duluth, MN; James D. Bearden, Palmetto Hematology Oncology, Spartanburg, SC; Dev R. Puri, Mercy Cancer Center, Des Moines, IA; Philip J. Stella, St Joseph Mercy Cancer Care Center, Ann Arbor, MI; Miroslaw A. Mazurczak, Sandford Health Cancer Center, Sioux Falls, SD; and Marie D. Klish, Hope Cancer Center, Longmont, CO. miller.robert@mayo.edu.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Miller
authors.affiliation: James L. Leenstra, St Vincent Regional Cancer Center, Green Bay, WI; Robert C. Miller, Rui Qin, James A. Martenson, Paul J. Novotny, Robert L. Foote, and Charles L. Loprinzi, Mayo Clinic, Rochester; Kenneth J. Dornfeld, Essentia Health Cancer Center, Duluth, MN; James D. Bearden, Palmetto Hematology Oncology, Spartanburg, SC; Dev R. Puri, Mercy Cancer Center, Des Moines, IA; Philip J. Stella, St Joseph Mercy Cancer Care Center, Ann Arbor, MI; Miroslaw A. Mazurczak, Sandford Health Cancer Center, Sioux Falls, SD; and Marie D. Klish, Hope Cancer Center, Longmont, CO.
authors.forename: Rui
authors.initials: R
authors.lastname: Qin
authors.affiliation: James L. Leenstra, St Vincent Regional Cancer Center, Green Bay, WI; Robert C. Miller, Rui Qin, James A. Martenson, Paul J. Novotny, Robert L. Foote, and Charles L. Loprinzi, Mayo Clinic, Rochester; Kenneth J. Dornfeld, Essentia Health Cancer Center, Duluth, MN; James D. Bearden, Palmetto Hematology Oncology, Spartanburg, SC; Dev R. Puri, Mercy Cancer Center, Des Moines, IA; Philip J. Stella, St Joseph Mercy Cancer Care Center, Ann Arbor, MI; Miroslaw A. Mazurczak, Sandford Health Cancer Center, Sioux Falls, SD; and Marie D. Klish, Hope Cancer Center, Longmont, CO.
authors.forename: James A
authors.initials: JA
authors.lastname: Martenson
authors.affiliation: James L. Leenstra, St Vincent Regional Cancer Center, Green Bay, WI; Robert C. Miller, Rui Qin, James A. Martenson, Paul J. Novotny, Robert L. Foote, and Charles L. Loprinzi, Mayo Clinic, Rochester; Kenneth J. Dornfeld, Essentia Health Cancer Center, Duluth, MN; James D. Bearden, Palmetto Hematology Oncology, Spartanburg, SC; Dev R. Puri, Mercy Cancer Center, Des Moines, IA; Philip J. Stella, St Joseph Mercy Cancer Care Center, Ann Arbor, MI; Miroslaw A. Mazurczak, Sandford Health Cancer Center, Sioux Falls, SD; and Marie D. Klish, Hope Cancer Center, Longmont, CO.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Dornfeld
authors.affiliation: James L. Leenstra, St Vincent Regional Cancer Center, Green Bay, WI; Robert C. Miller, Rui Qin, James A. Martenson, Paul J. Novotny, Robert L. Foote, and Charles L. Loprinzi, Mayo Clinic, Rochester; Kenneth J. Dornfeld, Essentia Health Cancer Center, Duluth, MN; James D. Bearden, Palmetto Hematology Oncology, Spartanburg, SC; Dev R. Puri, Mercy Cancer Center, Des Moines, IA; Philip J. Stella, St Joseph Mercy Cancer Care Center, Ann Arbor, MI; Miroslaw A. Mazurczak, Sandford Health Cancer Center, Sioux Falls, SD; and Marie D. Klish, Hope Cancer Center, Longmont, CO.
authors.forename: James D
authors.initials: JD
authors.lastname: Bearden
authors.affiliation: James L. Leenstra, St Vincent Regional Cancer Center, Green Bay, WI; Robert C. Miller, Rui Qin, James A. Martenson, Paul J. Novotny, Robert L. Foote, and Charles L. Loprinzi, Mayo Clinic, Rochester; Kenneth J. Dornfeld, Essentia Health Cancer Center, Duluth, MN; James D. Bearden, Palmetto Hematology Oncology, Spartanburg, SC; Dev R. Puri, Mercy Cancer Center, Des Moines, IA; Philip J. Stella, St Joseph Mercy Cancer Care Center, Ann Arbor, MI; Miroslaw A. Mazurczak, Sandford Health Cancer Center, Sioux Falls, SD; and Marie D. Klish, Hope Cancer Center, Longmont, CO.
authors.forename: Dev R
authors.initials: DR
authors.lastname: Puri
authors.affiliation: James L. Leenstra, St Vincent Regional Cancer Center, Green Bay, WI; Robert C. Miller, Rui Qin, James A. Martenson, Paul J. Novotny, Robert L. Foote, and Charles L. Loprinzi, Mayo Clinic, Rochester; Kenneth J. Dornfeld, Essentia Health Cancer Center, Duluth, MN; James D. Bearden, Palmetto Hematology Oncology, Spartanburg, SC; Dev R. Puri, Mercy Cancer Center, Des Moines, IA; Philip J. Stella, St Joseph Mercy Cancer Care Center, Ann Arbor, MI; Miroslaw A. Mazurczak, Sandford Health Cancer Center, Sioux Falls, SD; and Marie D. Klish, Hope Cancer Center, Longmont, CO.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stella
authors.affiliation: James L. Leenstra, St Vincent Regional Cancer Center, Green Bay, WI; Robert C. Miller, Rui Qin, James A. Martenson, Paul J. Novotny, Robert L. Foote, and Charles L. Loprinzi, Mayo Clinic, Rochester; Kenneth J. Dornfeld, Essentia Health Cancer Center, Duluth, MN; James D. Bearden, Palmetto Hematology Oncology, Spartanburg, SC; Dev R. Puri, Mercy Cancer Center, Des Moines, IA; Philip J. Stella, St Joseph Mercy Cancer Care Center, Ann Arbor, MI; Miroslaw A. Mazurczak, Sandford Health Cancer Center, Sioux Falls, SD; and Marie D. Klish, Hope Cancer Center, Longmont, CO.
authors.forename: Miroslaw A
authors.initials: MA
authors.lastname: Mazurczak
authors.affiliation: James L. Leenstra, St Vincent Regional Cancer Center, Green Bay, WI; Robert C. Miller, Rui Qin, James A. Martenson, Paul J. Novotny, Robert L. Foote, and Charles L. Loprinzi, Mayo Clinic, Rochester; Kenneth J. Dornfeld, Essentia Health Cancer Center, Duluth, MN; James D. Bearden, Palmetto Hematology Oncology, Spartanburg, SC; Dev R. Puri, Mercy Cancer Center, Des Moines, IA; Philip J. Stella, St Joseph Mercy Cancer Care Center, Ann Arbor, MI; Miroslaw A. Mazurczak, Sandford Health Cancer Center, Sioux Falls, SD; and Marie D. Klish, Hope Cancer Center, Longmont, CO.
authors.forename: Marie D
authors.initials: MD
authors.lastname: Klish
authors.affiliation: James L. Leenstra, St Vincent Regional Cancer Center, Green Bay, WI; Robert C. Miller, Rui Qin, James A. Martenson, Paul J. Novotny, Robert L. Foote, and Charles L. Loprinzi, Mayo Clinic, Rochester; Kenneth J. Dornfeld, Essentia Health Cancer Center, Duluth, MN; James D. Bearden, Palmetto Hematology Oncology, Spartanburg, SC; Dev R. Puri, Mercy Cancer Center, Des Moines, IA; Philip J. Stella, St Joseph Mercy Cancer Care Center, Ann Arbor, MI; Miroslaw A. Mazurczak, Sandford Health Cancer Center, Sioux Falls, SD; and Marie D. Klish, Hope Cancer Center, Longmont, CO.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Novotny
authors.affiliation: James L. Leenstra, St Vincent Regional Cancer Center, Green Bay, WI; Robert C. Miller, Rui Qin, James A. Martenson, Paul J. Novotny, Robert L. Foote, and Charles L. Loprinzi, Mayo Clinic, Rochester; Kenneth J. Dornfeld, Essentia Health Cancer Center, Duluth, MN; James D. Bearden, Palmetto Hematology Oncology, Spartanburg, SC; Dev R. Puri, Mercy Cancer Center, Des Moines, IA; Philip J. Stella, St Joseph Mercy Cancer Care Center, Ann Arbor, MI; Miroslaw A. Mazurczak, Sandford Health Cancer Center, Sioux Falls, SD; and Marie D. Klish, Hope Cancer Center, Longmont, CO.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Foote
authors.affiliation: James L. Leenstra, St Vincent Regional Cancer Center, Green Bay, WI; Robert C. Miller, Rui Qin, James A. Martenson, Paul J. Novotny, Robert L. Foote, and Charles L. Loprinzi, Mayo Clinic, Rochester; Kenneth J. Dornfeld, Essentia Health Cancer Center, Duluth, MN; James D. Bearden, Palmetto Hematology Oncology, Spartanburg, SC; Dev R. Puri, Mercy Cancer Center, Des Moines, IA; Philip J. Stella, St Joseph Mercy Cancer Care Center, Ann Arbor, MI; Miroslaw A. Mazurczak, Sandford Health Cancer Center, Sioux Falls, SD; and Marie D. Klish, Hope Cancer Center, Longmont, CO.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Loprinzi
mesh_terms: D059787:Acute Pain / Q000139:chemically induced / Q000175:diagnosis / Q000188:drug therapy*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000700:Analgesics / Q000008:administration & dosage* / Q000009:adverse effects; D019540:Area Under Curve; D059248:Chemoradiotherapy / Q000009:adverse effects*; D016371:Cranial Irradiation / Q000009:adverse effects*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004316:Doxepin / Q000008:administration & dosage* / Q000009:adverse effects; D005157:Facial Pain / Q000139:chemically induced / Q000175:diagnosis / Q000188:drug therapy*; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000532:radiotherapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009067:Mouthwashes; D010147:Pain Measurement; D011237:Predictive Value of Tests; D013280:Stomatitis / Q000139:chemically induced / Q000175:diagnosis / Q000188:drug therapy*; D011795:Surveys and Questionnaires; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States
chemical_list: D000700:Analgesics; D009067:Mouthwashes; D004316:Doxepin
references.citation: Pharmacotherapy. 2005 Apr;25(4):540-54
references.pmid: 15977916
references.citation: Stat Med. 1989 Dec;8(12):1421-32
references.pmid: 2616932
references.citation: Cancer. 2001 Aug 15;92(4):875-85
references.pmid: 11550161
references.citation: Oral Oncol. 2001 Dec;37(8):632-7
references.pmid: 11590072
references.citation: Pain. 2003 May;103(1-2):49-55
references.pmid: 12749958
references.citation: Int J Oral Maxillofac Surg. 2012 Feb;41(2):225-38
references.pmid: 22071451
references.citation: J Clin Oncol. 2006 Nov 20;24(33):5186-93
references.pmid: 16391299
references.citation: Daru. 2010;18(1):46-50
references.pmid: 22615593
references.citation: J Clin Oncol. 2011 Jul 10;29(20):2808-14
references.pmid: 21670453
references.citation: Anesth Analg. 2006 Aug;103(2):465-70, table of contents
references.pmid: 16861436
references.citation: Semin Radiat Oncol. 2009 Jan;19(1):29-34
references.pmid: 19028343
references.citation: Radiother Oncol. 2003 Mar;66(3):253-62
references.pmid: 12742264
references.citation: Bone Marrow Transplant. 2006 Feb;37(4):393-401
references.pmid: 16415901
references.citation: J Clin Oncol. 2011 Jul 10;29(20):2815-20
references.pmid: 21670447
references.citation: Anesth Prog. 1999 Spring;46(2):52-5
references.pmid: 10853565
references.citation: Cancer Invest. 2003;21(1):21-33
references.pmid: 12643006
references.citation: Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000 Jul;90(1):39-47
references.pmid: 10884634
references.citation: Support Care Cancer. 2006 Jun;14(6):528-32
references.pmid: 16775648
references.citation: Dent Clin North Am. 2008 Jan;52(1):61-77, viii
references.pmid: 18154865
references.citation: Cochrane Database Syst Rev. 2010 Aug 04;(8):CD001973
references.pmid: 20687070
references.citation: Spec Care Dentist. 2008 Mar-Apr;28(2):73-7
references.pmid: 18402621
references.citation: J Natl Compr Canc Netw. 2008 Jan;6 Suppl 1:S1-21; quiz S22-4
references.pmid: 18289497
references.citation: Oncologist. 2008 Aug;13(8):886-98
references.pmid: 18701763
references.citation: J Pain Symptom Manage. 2006 Jul;32(1):27-37
references.pmid: 16824982
references.citation: Cancer. 2008 Nov 15;113(10):2704-13
references.pmid: 18973181
references.citation: Biometrics. 1975 Mar;31(1):103-15
references.pmid: 1100130
references.citation: Cochrane Database Syst Rev. 2011 Apr 13;(4):CD000978
references.pmid: 21491378
references.citation: Int J Radiat Oncol Biol Phys. 2007 Jul 15;68(4):1110-20
references.pmid: 17398022
references.citation: Cancer. 1999 May 15;85(10):2103-13
references.pmid: 10326686
references.citation: J Pain Symptom Manage. 2007 Feb;33(2):111-4
references.pmid: 17280915