{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T01:55:33Z","timestamp":1789523733673,"version":"build-2803163510"},"reference-count":33,"publisher":"BMJ","issue":"4","license":[{"start":{"date-parts":[[2023,4,11]],"date-time":"2023-04-11T00:00:00Z","timestamp":1681171200000},"content-version":"unspecified","delay-in-days":10,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2023,3,16]]},"published-print":{"date-parts":[[2023,4]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Curative intent treatment of head and neck cancer (HNC) is frequently radiation therapy over 7 weeks with concurrent chemotherapy. This regimen is effective but carries a burden of toxicity leading to severe pain and treatment breaks portending inferior outcomes. Conventional palliation methods include opioids, anticonvulsants and local anaesthetics. Breakthrough toxicities are nevertheless ubiquitous and present an urgent unmet need. Ketamine is an inexpensive drug with mechanisms of analgesia outside the opioid pathway including N-methyl-D-aspartate (NMDA) receptor antagonism and a pharmacologically unique property of opioid desensitisation. Systemic ketamine is validated in randomised controlled trials for efficacy in reducing pain and\/or opioid burden in the oncologic setting. Literature supports peripherally administered ketamine for pain control without systemic toxicity. These data support our rationale of using ketamine mouthwash to decrease acute toxicity of curative treatment of HNC, the efficacy of which is our aim to elucidate.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>This is a phase II, Simon\u2019s two-stage trial. Patients have pathologically confirmed HNC and an intended regimen of 70 Gy of radiation with concurrent cisplatin. The protocol is initiated on diagnosis of grade 3 mucositis and consists of 2 weeks of 4 times daily (QID) ketamine mouthwash use. The primary endpoint is pain response defined as a combination of pain score and opioid use. 23 subjects will be enrolled in stage 1. If statistical criteria are met, 33 subjects will be enrolled in stage 2. Secondary endpoints include daily pain, daily opioid use, dysphagia at baseline and completion, nightly sleep quality, feeding tube placement and any unscheduled treatment breaks.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>All trial data will be stored in an Institutional Review Board (IRB) approved database. The protocol is registered under Northwell IRB registration number #22-0292 and U.S. Food and Drug Administration (FDA) Investigational New Drug (IND) approval has been granted under IND number 161609. Results are intended to be published in an open-source journal and further data, statistics and source documents are available on request.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT05331131\">NCT05331131<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2022-064809","type":"journal-article","created":{"date-parts":[[2023,4,11]],"date-time":"2023-04-11T11:20:42Z","timestamp":1681212042000},"page":"e064809","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Efficacy of ketamine mouthwash in the management of oral and pharyngeal toxicity associated with head and neck chemoradiotherapy: protocol for a phase II, Simon\u2019s two-stage trial"],"prefix":"10.1136","volume":"13","clinical-trial-number":[{"clinical-trial-number":"nct05331131","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct01653327","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct01653327","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3878-3800","authenticated-orcid":false,"given":"Daniel","family":"Koffler","sequence":"first","affiliation":[{"name":"Department of Radiation Medicine, Donald and Barbara Zucker SOM at Hofstra\/Northwell and Northwell Health Cancer Institute, Lake Success, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Eckstein","sequence":"additional","affiliation":[{"name":"Department of Radiation Medicine, Donald and Barbara Zucker SOM at Hofstra\/Northwell and Northwell Health Cancer Institute, Lake Success, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Herman","sequence":"additional","affiliation":[{"name":"Department of Radiation Medicine, Donald and Barbara Zucker SOM at Hofstra\/Northwell and Northwell Health Cancer Institute, Lake Success, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Martins-Welch","sequence":"additional","affiliation":[{"name":"Department of Palliative Medicine, Donald and Barbara Zucker SOM at Hofstra\/Northwell and Northwell Health Cancer Institute, Lake Success, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3282-7622","authenticated-orcid":false,"given":"Nagashree","family":"Seetharamu","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Donald and Barbara Zucker SOM at Hofstra\/Northwell and Northwell Health Cancer Institute, Lake Success, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maged","family":"Ghaly","sequence":"additional","affiliation":[{"name":"Department of Radiation Medicine, Donald and Barbara Zucker SOM at Hofstra\/Northwell and Northwell Health Cancer Institute, Lake Success, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Kohn","sequence":"additional","affiliation":[{"name":"Division of Biostatistics, Feinstein Institute for Medical Research, Donald and Barbara Zucker SOM at Hofstra\/Northwell and Northwell Health Cancer Institute, Manhasset, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis","family":"Potters","sequence":"additional","affiliation":[{"name":"Department of Radiation Medicine, Donald and Barbara Zucker SOM at Hofstra\/Northwell and Northwell Health Cancer Institute, Lake Success, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas","family":"Frank","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Donald and Barbara Zucker SOM at Hofstra\/Northwell and Northwell Health Cancer Institute, Lake Success, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Donald and Barbara Zucker SOM at Hofstra\/Northwell and Northwell Health Cancer Institute, Lake Success, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhupesh","family":"Parashar","sequence":"additional","affiliation":[{"name":"Department of Radiation Medicine, Donald and Barbara Zucker SOM at Hofstra\/Northwell and Northwell Health Cancer Institute, Lake Success, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2023,4,11]]},"reference":[{"key":"2025121514285190000_13.4.e064809.1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21453"},{"key":"2025121514285190000_13.4.e064809.2","doi-asserted-by":"publisher","DOI":"10.1016\/S0360-3016(00)00663-5"},{"key":"2025121514285190000_13.4.e064809.3","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.55.3925"},{"key":"2025121514285190000_13.4.e064809.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2009.04.011"},{"key":"2025121514285190000_13.4.e064809.5","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(18)32779-x"},{"key":"2025121514285190000_13.4.e064809.6","doi-asserted-by":"crossref","DOI":"10.1016\/j.ijrobp.2020.07.1444","article-title":"Establishing a benchmark treatment termination rate in a multicenter radiation medicine department","volume":"108","author":"Ma","year":"2020","journal-title":"International Journal of Radiation Oncology*Biology*Physics"},{"key":"2025121514285190000_13.4.e064809.7","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1001\/jamaoto.2018.2838","article-title":"Defining optimal treatment times in head and neck cancer care: what are we waiting for?","volume":"145","author":"Houlton","year":"2019","journal-title":"JAMA Otolaryngol Head Neck Surg"},{"key":"2025121514285190000_13.4.e064809.8","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.oraloncology.2018.11.021","article-title":"The impact of treatment package time on survival in surgically managed head and neck cancer in the united states","volume":"88","author":"Goel","year":"2019","journal-title":"Oral Oncol"},{"key":"2025121514285190000_13.4.e064809.9","doi-asserted-by":"publisher","DOI":"10.1124\/pr.117.015198"},{"key":"2025121514285190000_13.4.e064809.10","doi-asserted-by":"crossref","DOI":"10.1038\/s41398-021-01588-0","article-title":"Mir-98-5P plays a critical role in depression and antidepressant effect of ketamine","volume":"11","author":"Huang","year":"2021","journal-title":"Transl Psychiatry"},{"key":"2025121514285190000_13.4.e064809.11","doi-asserted-by":"publisher","DOI":"10.1017\/S1461145713000448"},{"key":"2025121514285190000_13.4.e064809.12","doi-asserted-by":"crossref","first-page":"107079","DOI":"10.1016\/j.ntt.2022.107079","article-title":"Ketamine enhances dopamine D1 receptor expression by modulating micrornas in a ketamine-induced schizophrenia-like mouse model","volume":"91","author":"Li","year":"2022","journal-title":"Neurotoxicol Teratol"},{"key":"2025121514285190000_13.4.e064809.13","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1111\/odi.13960","article-title":"Analysis of the response to two pharmacological protocols in patients with oral lichen planus: a randomized clinical trial","volume":"29","author":"Polizzi","year":"2023","journal-title":"Oral Dis"},{"key":"2025121514285190000_13.4.e064809.14","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1111\/jre.13078","article-title":"Impact of periodontitis on gingival crevicular fluid miRNAs profiles associated with cardiovascular disease risk","volume":"58","author":"Isola","year":"2023","journal-title":"J Periodontal Res"},{"key":"2025121514285190000_13.4.e064809.15","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1111\/pme.12182","article-title":"Ketamine for pain in adults and children with cancer: a systematic review and synthesis of the literature","volume":"14","author":"Bredlau","year":"2013","journal-title":"Pain Med"},{"key":"2025121514285190000_13.4.e064809.16","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-200507000-00021"},{"key":"2025121514285190000_13.4.e064809.17","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1556\/ABiol.57.2006.3.12","article-title":"Evaluation of ketamine systemic absorption from topical preparations. short communication","volume":"57","author":"Zapantis","year":"2006","journal-title":"Acta Biol Hung"},{"key":"2025121514285190000_13.4.e064809.18","first-page":"440","article-title":"Analgesic effects of topical ketamine","volume":"81","author":"Kopsky","year":"2015","journal-title":"Minerva Anestesiol"},{"key":"2025121514285190000_13.4.e064809.19","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1111\/pan.12148","article-title":"Comparison of topical tramadol and ketamine in pain treatment after tonsillectomy","volume":"23","author":"Tekelioglu","year":"2013","journal-title":"Paediatr Anaesth"},{"key":"2025121514285190000_13.4.e064809.20","doi-asserted-by":"crossref","first-page":"17","DOI":"10.5812\/aapm.4092","article-title":"Comparison between effect of lidocaine, morphine and ketamine spray on post-tonsillectomy pain in children","volume":"2","author":"Hosseini Jahromi","year":"2012","journal-title":"Anesth Pain Med"},{"key":"2025121514285190000_13.4.e064809.21","doi-asserted-by":"publisher","DOI":"10.1007\/s00520-010-0911-0"},{"key":"2025121514285190000_13.4.e064809.22","first-page":"1515","article-title":"Topical amitriptyline, ketamine, and lidocaine in neuropathic pain caused by radiation skin reaction: a pilot study","volume":"20","author":"Uzaraga","year":"2012","journal-title":"Support Care Cancer"},{"key":"2025121514285190000_13.4.e064809.23","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1046\/j.1526-4637.2003.03032.x","article-title":"Topical ketamine in the treatment of mucositis pain","volume":"4","author":"Slatkin","year":"2003","journal-title":"Pain Med"},{"key":"2025121514285190000_13.4.e064809.24","first-page":"2215","article-title":"Treatment of severe mucositis pain with oral ketamine mouthwash","volume":"25","author":"Shillingburg","year":"2017","journal-title":"Support Care Cancer"},{"key":"2025121514285190000_13.4.e064809.25","unstructured":"Davis et al analgesic effects of topical ketamine mouthwash in patients receivingchemoradiation or radiotherapy for head & neck cancer. clinicaltrials.govidentifier: NCT01653327 . n.d. Available: https:\/\/clinicaltrials.gov\/ct2\/show\/study\/NCT01653327"},{"key":"2025121514285190000_13.4.e064809.26","doi-asserted-by":"crossref","DOI":"10.1002\/pbc.28573","article-title":"Ketamine mouthwash versus placebo in the treatment of severe oral mucositis pain in children with cancer: a randomized double-blind placebo-controlled trial","volume":"67","author":"Prakash","year":"2020","journal-title":"Pediatr Blood Cancer"},{"key":"2025121514285190000_13.4.e064809.27","doi-asserted-by":"publisher","DOI":"10.1016\/S0167-8140(02)00170-6"},{"key":"2025121514285190000_13.4.e064809.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2011.02.008"},{"key":"2025121514285190000_13.4.e064809.29","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1001\/jamaoncol.2019.0192","article-title":"Single-fraction stereotactic vs conventional multifraction radiotherapy for pain relief in patients with predominantly nonspine bone metastases: a randomized phase 2 trial","volume":"5","author":"Nguyen","year":"2019","journal-title":"JAMA Oncol"},{"key":"2025121514285190000_13.4.e064809.30","article-title":"Validation of digital visual analog scale pain scoring with a traditional paper-based visual analog scale in adults","volume":"2","author":"Delgado","year":"2018","journal-title":"J Am Acad Orthop Surg Glob Res Rev"},{"key":"2025121514285190000_13.4.e064809.31","unstructured":"Meijman et al . The evaluation of the groningen sleep quality scale. Groningen: Heymans Bulletin (HB 88-13-EX), 1988."},{"key":"2025121514285190000_13.4.e064809.32","first-page":"870","article-title":"The development and validation of a dysphagia-specific quality-of-life questionnaire for patients with head and neck cancer: the M. D. anderson dysphagia inventory","volume":"127","author":"Chen","year":"2001","journal-title":"Arch Otolaryngol Head Neck Surg"},{"key":"2025121514285190000_13.4.e064809.33","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1001\/jamaoncol.2015.2639","article-title":"Validity and reliability of the US National cancer Institute\u2019s patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE)","volume":"1","author":"Dueck","year":"2015","journal-title":"JAMA Oncol"}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2022-064809","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T22:29:01Z","timestamp":1765837741000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2022-064809"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4]]},"references-count":33,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,4,11]]},"published-print":{"date-parts":[[2023,4]]}},"alternative-id":["10.1136\/bmjopen-2022-064809"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2022-064809","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"value":"2044-6055","type":"print"},{"value":"2044-6055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4]]}}}