Treatment of Severe Mucositis Pain With Oral Ketamine Mouthwash
Treatment of Severe Mucositis Pain With Oral Ketamine Mouthwash
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).
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.
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.