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Treatment of Severe Mucositis Pain With Oral Ketamine Mouthwash

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ClinicalTrials.gov Identifier: NCT01566448
Recruitment Status : Completed
First Posted : March 29, 2012
Results First Posted : January 11, 2021
Last Update Posted : January 11, 2021
Sponsor:
Information provided by (Responsible Party):
Aaron Cumpston, PharmD, BCOP, West Virginia University

Tracking Information
First Submitted Date  ICMJE March 27, 2012
First Posted Date  ICMJE March 29, 2012
Results First Submitted Date  ICMJE May 29, 2018
Results First Posted Date  ICMJE January 11, 2021
Last Update Posted Date January 11, 2021
Study Start Date  ICMJE February 2012
Actual Primary Completion Date July 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 15, 2020)
Change in Pain Scores [ Time Frame: 1 hour after baseline ]
Change in pain score as reported at baseline and after the use of ketamine mouthwash on a numeric scale from 0 to 10, with 0 representing no pain and 10 representing the worst pain.
Original Primary Outcome Measures  ICMJE
 (submitted: March 27, 2012)
Reduction in pain scores [ Time Frame: 1 hour, 1 day, 2 days and 3 days after start of ketamine mouthwashes ]
Reduction in pain score as reported after use of ketamine mouthwash on a numeric scale compared to a baseline assessment.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 15, 2020)
  • Time From Dose Administration to Change in Pain Intensity as Reported by Subject. [ Time Frame: 1 day after start of ketamine mouthwashes ]
    Patients will be questioned about time until maximal pain relief and given options of: no effect, 1-15 minutes, 15-30 minutes, 30-45 minutes, 45-60 minutes and greater than 1 hour.
  • Duration of Effect of Pain Reduction [ Time Frame: Day 1 after start of ketamine mouthwashes ]
    Patients will be question about the duration of pain relief and given the option of no effect, less than one hour, 1-2 hours, 2-3 hours, 3-4 hours, greater than 4 hours or N/A.
  • Change in Use of Narcotic Analgesics [ Time Frame: Days 1 after start of ketamine mouthwashes ]
    Change in IV morphine equivalents of opioid requirements
  • Change in Topical Lidocaine Usage [ Time Frame: Days 1 after start of ketamine mouthwashes ]
    Change of topical lidocaine uses in 24 hour period
  • Change in Sleep Quality [ Time Frame: Day 1 after start of ketamine mouthwashes ]
    Sleep quality, as reported by the subject on a numeric scale (1-10) will be used as a surrogate marker of quality of life with 0 indicating no sleep and 10 indicating the best sleep you have had.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 27, 2012)
  • Patient reported tolerability of mouthwashes due to taste and irritation [ Time Frame: 1 hour, 1 day, 2 days and 3 days after start of ketamine mouthwashes ]
    Patients will be questioned regarding tolerability of mouthwashes due to taste and irritation.
  • Assess the time from dose administration to reduction in pain intensity as reported by subject. [ Time Frame: 1 hour, 1 day, 2 days and 3 days after start of ketamine mouthwashes ]
    Patients will be questioned about time until maximal pain relief and given options of: no effect, 1-15 minutes, 15-30 minutes, 30-45 minutes, 45-60 minutes and greater than 1 hour.
  • Duration of Effect of Pain Reduction [ Time Frame: Days 1, 2, and 3 after start of ketamine mouthwashes ]
    Patients will be question about the duration of pain relief and given the option of no effect, less than one hour, 1-2 hours, 2-3 hours, 3-4 hours, greater than 4 hours or N/A.
  • Reduction in use of narcotic analgesics [ Time Frame: Days 1, 2 and 3 after start of ketamine mouthwashes ]
    Daily narcotic analgesic use will be recorded.
  • Reduction in topical lidocaine usage [ Time Frame: Days 1, 2 and 3 after start of ketamine mouthwashes ]
    Daily topical lidocaine usage will be recorded.
  • Quality of life [ Time Frame: Days 1, 2 and 3 after start of ketamine mouthwashes ]
    Sleep quality, as reported by the subject on a numeric scale, and food intake will be used as surrogate markers of quality of life.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Treatment of Severe Mucositis Pain With Oral Ketamine Mouthwash
Official Title  ICMJE Treatment of Severe Mucositis Pain With Oral Ketamine Mouthwash
Brief Summary

Oral mucositis (inflammation of the lining of the mouth) is a very common adverse effect when chemotherapy and radiation therapy are used to treat cancer. Mucositis occurs in about 40% of patients receiving standard dose chemotherapy, 80% of patients receiving radiation therapy of the head and neck, and up to 100% of patients undergoing a bone marrow transplant. Because the pain from mucositis can be so bad it can cause the inability to eat or drink, inability to talk, gagging and drooling. Many times mucositis can affect cancer treatment because patients may have to be given a lower dose of a drug or stop treatment completely. There are not many treatments today that can help relieve the severe pain caused from mucositis. This research study will help researchers determine if using an oral mouthwash called Ketamine will help lessen mucositis pain.

Ketamine is approved by the Food and Drug Administration (FDA) for use with general anesthesia, sedation and for severe pain. WVU Hospital is now using Ketamine mouthwash as a standard treatment option for mucositis pain.

During this study patients will be assessed to determine the level of pain caused by their mucositis. This will occur before the first dose, one hour after the first dose, and then daily until they are no longer on the study. Patients will use the mouthwash by swishing and spitting (20mg/5ml) four times each day, and also every four hours as needed. Patients will use the mouthwash on this study until their mucositis gets better or until the mucositis gets worse (or if the pain does not get better after three days of treatment).

Detailed Description

Mucositis

Mucositis is an adverse effect as a result of chemotherapy and radiation treatments and has significant quality of life and clinical consequences. Mucositis is a result of direct cytotoxic damage as well as a cytokine-mediated inflammatory response and can affect the epithelial mucosal surfaces along the entire gastrointestinal tract. Mucositis manifesting in the oral cavity can be especially distressing to patients and may involve erythema, cracking, inflammation, bleeding and ulceration and typically begins 5-10 days after starting chemotherapy. Mucositis occurs in about 40% of patients receiving standard dose chemotherapy, 80% of patients receiving radiation therapy to the head and neck, and up to 100% of patients undergoing a bone marrow transplant.(1)

Pain from oral mucositis has been reported as the single most debilitating side effect by patients receiving bone marrow transplants. Mucositis is also the most common condition requiring analgesics during cancer therapy. Complications of pain from mucositis include inability to tolerate food or fluid intake, difficulty or inability to talk, excess mucus, gagging, sleep disturbances, and drooling. Mucositis may also require hospital admission or extended admission for total parenteral nutrition, intravenous analgesia, and/or intravenous antibiotics. Seventy percent of patients with a grade 3 or 4 mucositis will require a feeding tube. Mucositis also has the potential to impact the effectiveness of cancer treatment as it is a dose-limiting toxicity and results in cessation or reduction of treatment in 35% of patients (2,3,4)

Current standard of care focuses on palliation and includes systemic opiate analgesics for moderate to severe mucositis pain, topical anesthetics and mucosal coating agents such as lidocaine, benzocaine, dyclonine, diphenhydramine, doxepin, and benzydamine for moderate pain, and bland rinses for mild pain. Data supporting these management options are limited. Other agents that have been investigated with variable responses are oral capsaicin, oral sulfasalazine, and growth factor mouthwashes. (5)

Ketamine

Ketamine is a sedative hypnotic with anesthetic and analgesic properties. Ketamine works by selectively depressing the thalamoneocortical system, non-competitively blocking N-methyl-D-aspartate (NMDA) receptors, and having intrinsic sympathomimetic activity. Ketamine also appears to selectively interrupt association pathways in the brain producing somatesthetic sensory blockade. Ketamine is FDA-approved for induction and maintenance of general anesthesia but has also been used for procedural sedation, refractory severe pain, and acute respiratory failure in children. (6)

Topical administration of ketamine was shown to cause a reduction in allodynia in a double-blind placebo controlled study and peripheral administration of ketamine has antinociceptive efficacy similar to that of systemic administration which is likely mediated by NMDA antagonism (7). Ketamine may also potentiate the effects of other systemic opioid analgesics and may reverse opiate tolerance to some degree. Also, given that topical administration of opiates has a local effect, topical ketamine may produce a local tolerance reversal. Ketamine also has modest anti-inflammatory properties which could provide beneficial effects in mucositis pain relief. (8)

Ketamine oral rinse use was described in a case report of a 32 year old female with radiation-induced mucositis pain refractory to Clark's solution, transdermal fentanyl, and intravenous hydromorphone. Ketamine oral rinse was given as 20mg of drug in a 5ml artificial saliva solution every 3 hours as needed with continued PCA use. She experienced decreased pain at rest and with eating and was able to decrease the dose of her opiate analgesics. Her overall pain was reported as decreased from 9/10 to 3/10 with oral ketamine use. No adverse effects were reported other than one episode of swallowing the solution which resulted in transient sedative and psychomotor effects. (8)

A retrospective chart review of ketamine mouthwash use in 8 patients over a period of 4 years was conducted to determine safety and efficacy. Patients in this review received ketamine 20mg/5ml mouthwashes every 4 hours as needed. Seven of the 8 patients were post-hematopoietic stem cell transplant (post-HSCT) patients. Five patients had a documented improvement in mucositis pain and 4 patients experienced an adverse event. Adverse events consisted of mild confusion, nausea, vertigo, and hallucinations; however 2 of the 4 patients had reports of these symptoms prior to beginning ketamine mouthwashes but were still included in the analysis. Patients received an average of 17 doses over an average of 6 days. Reporting of pain scores were variable and difficult to quantify but the authors concluded that ketamine may provide a viable treatment option for mucositis pain. (9)

Rationale for study

Evidence for the use of an oral ketamine rinse suggests that it could provide a distinct benefit for patients suffering from pain and other clinical consequences of mucositis as a result of cancer treatments. No treatment is currently available that provides a profound relief from this pain and available evidence suggests that ketamine could be a useful tool in the arsenal of agents available to patients. Ketamine mouthwash was approved by the WVUH Pharmacy Nutrition and Therapeutics (PNT) Committee as a treatment option for mucositis pain. It is commercially available and currently used at our hospital. No prospective data exists objectively evaluating the potential benefits and possible adverse effects of ketamine oral rinse. We postulate that using ketamine as an oral mouthwash will provide pain relief for patients with significant distress due to pain from oral mucositis.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Mucositis
Intervention  ICMJE Drug: Ketamine
20mg/5ml swish and spit four times daily
Study Arms  ICMJE Experimental: Ketamine
Ketamine oral mouthwash 20mg/5ml swish and spit four times daily
Intervention: Drug: Ketamine
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 27, 2012)
30
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE July 2015
Actual Primary Completion Date July 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patient has oral mucositis pain that is grade 3 or 4 according to the World Health Organization (WHO) Oral Mucositis Scale
  • Patient has received at least one prior chemotherapy or radiation treatment
  • Patient is at least 18 years old
  • Patient or their legally authorized representative understands and voluntarily signs the written informed consent prior to any study-specific procedures. A copy of the signed informed consent form will be retained by the treating institution.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01566448
Other Study ID Numbers  ICMJE WVU041011
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Aaron Cumpston, PharmD, BCOP, West Virginia University
Study Sponsor  ICMJE Aaron Cumpston, PharmD, BCOP
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Aaron Cumpston, PharmD West Virginia University
PRS Account West Virginia University
Verification Date December 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP