Intranasal (NAS) Ketamine for Cancer Pain

There are about 11.9 million Americans affected with cancer. 53% of patients with cancer
experience pain at all stages of cancer. These patients often require high doses of opioids
with uncontrolled pain that makes them too sedated to effectively participate in day-to-day
activities and have a good quality of life. Depression often co-exists with cancer pain due
to the nature of the disease. The researchers are searching for improved therapies for
chronic cancer pain and ketamine with its novel mechanism of action may be a promising
solution.

Ketamine is an FDA approved anesthetic with the ability to effect memory loss, pain relief
and sedation. Safety and efficacy of ketamine as an anesthetic and analgesic agent is well
documented. Low doses of ketamine have minimal adverse impact on circulatory or breathing
functions but can reduce pain. Research has shown that ketamine is effective in controlling
breakthrough pain and reducing depression in a randomized double blind controlled trial.
There is limited data regarding the use of ketamine for pain management in cancer.

One of the challenges with ketamine is the route of administration, most commonly given
intravenously (IV) or intramuscularly (IM). It has also been given by mouth and rectally, but
absorption is very poor. Intranasal (NAS) administration may be a promising method of
delivery and can be ordered by a physician from a compounding pharmacy. From other research
the investigators expect absorption to be higher than oral or rectal administration and this
method of delivery as needle-free is a patient-friendly route of administration.

The main purpose of this study is to determine the safety, feasibility, and utility of
intranasal (NAS) ketamine in persistent uncontrolled cancer related pain. In this prospective
clinical trial the researchers will investigate the use of NAS ketamine in patients with pain
related to cancer or cancer treatment. The researchers plan to enroll at least 15 patients
meeting inclusion/exclusion criteria, to achieve a minimum of 10 patients who complete the
study. Participants will be recruited from the oncology clinic, pain clinic and Acute Pain
Service at Emory. Participants will be asked to return to the Phase I unit of the Winship
Cancer Building C for a total of 5 study visits, each two to five days apart. During these
visits participants will complete questionnaires, have blood samples drawn and will have
study medication administered to them in escalating doses. For safety monitoring participants
will be contacted by telephone 14 days after the last dose of medication administered.

Data obtained from this study will help determine if ketamine provides a reduction of pain
using the Numeric Pain Rating Scale and a reduction in the use of opioid consumption and
other rescue medications. Additionally the researchers will study the bioavailability,
pharmacodynamics and pharmacokinetics of ketamine and the safety profile of NAS ketamine.

Inclusion Criteria:

- Patients with uncontrolled pain related to cancer or cancer treatment. Uncontrolled
pain will be defined as:

- Pain which persists for more than 7 days and is rated >/=4 on Numerical Pain
Rating Score (NPRS)

- Use of breakthrough medication more than 4 times in 24 hours or being treated
with oral morphine equivalent of 50 mg/d or more

- Patients who are able to follow-up in person during the trial

- Patient on stable analgesic regimen for >7 days without escalation during study period
with rescue or immediate release medication every 3 hours or longer

- Patients who are willing and able to maintain a daily pain diary

- Patients who are able to understand written and verbal English

- Patient weight >/= 50 kg

Exclusion Criteria:

- Transportation issues interfering with return study visits

- Patients with high disposition of laryngospasm or apnea

- Presence of severe cardiac disease

- Presence of conditions where significant elevations in blood pressure would be a
serious hazard.

- Stage 2 hypertension or greater (systolic blood pressure > 160 and/or diastolic blood
pressure >100)

- Baseline tachycardia, heart rate (HR) >100

- History of seizures, elevated intracranial pressure (ICP) or cerebrospinal fluid (CSF)
obstructive states (e.g. severe head injury, central congenital or mass lesions)

- Conditions that may increase intraocular pressure (e.g. glaucoma, acute globe injury)

- History of uncontrolled depression or other psychiatric comorbidity with psychosis

- History of liver disease

- History of interstitial cystitis

- History of nasal or sinus anomalies or dysfunction e.g. allergic or infectious
rhinitis.

- Patients with lesions to the nasal mucosa

- Pregnant women, nursing mothers and women of childbearing potential not using
contraception known to be highly effective. Highly effective contraception methods
include combination of any two of the following:

- Use of oral, injected or implanted hormonal methods of contraception or;

- Placement of an intrauterine device (IUD) or intrauterine system (IUS);

- Barrier methods of contraception: condom or occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository;

- Total abstinence or;

- Male/female sterilization.

- Illicit substance abuse within the past 6 months

- Documented history of medication abuse/misuse (e.g. Unsanctioned dose escalation,
broken opioid agreement etc.)

- Clinical requirement for medications that are concurrent inducers or inhibitors of
CYP3A4. CYP3A4 substrates are allowed.

- Porphyria (possibility of triggering a porphyric reaction)

- Severe active anemia ( a hemoglobin< 8 documented by labs drawn within 3 months of
first study treatment)

- History of difficult intravenous access

- Intractable vomiting