Trial Information

Treatment of Severe Mucositis Pain With Oral Ketamine Mouthwash

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.