Treatment of Severe Mucositis Pain With Oral Ketamine Mouthwash

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2014 by West Virginia University
Sponsor:
Information provided by (Responsible Party):
Aaron Cumpston, PharmD, West Virginia University
ClinicalTrials.gov Identifier:
NCT01566448
First received: March 27, 2012
Last updated: January 6, 2014
Last verified: January 2014
  Purpose

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).


Condition Intervention Phase
Mucositis
Drug: Ketamine
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Treatment of Severe Mucositis Pain With Oral Ketamine Mouthwash

Resource links provided by NLM:


Further study details as provided by West Virginia University:

Primary Outcome Measures:
  • Reduction in pain scores [ Time Frame: 1 hour, 1 day, 2 days and 3 days after start of ketamine mouthwashes ] [ Designated as safety issue: No ]
    Reduction in pain score as reported after use of ketamine mouthwash on a numeric scale compared to a baseline assessment.


Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    Daily narcotic analgesic use will be recorded.

  • Reduction in topical lidocaine usage [ Time Frame: Days 1, 2 and 3 after start of ketamine mouthwashes ] [ Designated as safety issue: No ]
    Daily topical lidocaine usage will be recorded.

  • Quality of life [ Time Frame: Days 1, 2 and 3 after start of ketamine mouthwashes ] [ Designated as safety issue: No ]
    Sleep quality, as reported by the subject on a numeric scale, and food intake will be used as surrogate markers of quality of life.


Estimated Enrollment: 30
Study Start Date: February 2012
Estimated Study Completion Date: September 2015
Estimated Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Ketamine
Ketamine oral mouthwash 20mg/5ml swish and spit four times daily
Drug: Ketamine
20mg/5ml swish and spit four times daily

  Hide Detailed Description

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01566448

Contacts
Contact: Pam Bunner, MT 304-598-4511 bunnerp@wvuhealthcare.com
Contact: Crystal Street, MT 304-598-4512 streetc@wvuhealthcare.com

Locations
United States, West Virginia
West Virginia University Hospitals Mary Babb Randolph Cancer Center Recruiting
Morgantown, West Virginia, United States, 26506
Contact: Pam Bunner, MT    304-598-4511    bunnerp@wvuhealthcare.com   
Contact: Crystal Street, MT    304-598-4512    streetc@wvuhealthcare.com   
Principal Investigator: Alex Shillingburg, PharmD         
Sub-Investigator: Michael Newtown, PharmD         
Sub-Investigator: Michael Craig, MD         
Sub-Investigator: William Tse, MD         
Sub-Investigator: Soumit Basu, MD, PhD         
Sub-Investigator: Abraham Kanate, MD         
Sponsors and Collaborators
Aaron Cumpston, PharmD
Investigators
Principal Investigator: Aaron Cumpston, PharmD West Virginia University
  More Information

Additional Information:
Publications:

Responsible Party: Aaron Cumpston, PharmD, Pharmacy Clinical Specialist (Principal Investigator), West Virginia University
ClinicalTrials.gov Identifier: NCT01566448     History of Changes
Other Study ID Numbers: WVU041011
Study First Received: March 27, 2012
Last Updated: January 6, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by West Virginia University:
Ketamine
Mucositis
Oral ketamine rinse

Additional relevant MeSH terms:
Mucositis
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Mouth Diseases
Stomatognathic Diseases
Ketamine
Anesthetics, Dissociative
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
Central Nervous System Depressants
Physiological Effects of Drugs
Pharmacologic Actions
Central Nervous System Agents
Therapeutic Uses
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Analgesics
Sensory System Agents
Peripheral Nervous System Agents

ClinicalTrials.gov processed this record on July 10, 2014