A Pilot Clinical Trial of Oral Ketamine for Acute Pain Management After Amputation Surgery

A prospective open-label clinical trial to decrease the incidence of expected side effects of
oral ketamine dose administered presurgery and postsurgery, in 10 subjects undergoing
elective amputation of the lower extremity. The primary outcome measure is the incidence of
adverse events. Secondary outcome measures are decreased acute pain levels and decreased
incidence of stump and phantom limb pain at 6 months. Enrollment of participants will occur
at Rush University Medical Center (Rush), Chicago, IL. Consented participants will be
included in the study undergoing elective amputation of the lower extremity from all causes.

Rationale for using oral ketamine for acute pain after amputation surgery:

The common analgesic, morphine, has a narrow therapeutic window and numerous side effects.1
Ketamine, is a chemically stable compound, non-opioid with analgesic properties at low doses.
In addition, ketamine stimulates the cardio-respiratory system which is of great benefit in
injured patients.2-4 Ketamine is generally administered by the intravenous (IV) route and
provides analgesia via antagonism of the N-Methyl-D-Asparate (NMDA) receptor. Ketamine has
the added benefit of a wide therapeutic safety index. IV ketamine has been shown to provide
postoperative analgesia in many clinical trials; in particular to reduce opioid consumption.5
Severe acute pain has been shown to progress to chronic pain due to central sensitization.6
Perioperative IV ketamine has been shown in limited studies to decrease the incidence of
chronic pain after surgery. However, the IV route of administration of ketamine has
limitations due to difficulties with IV placement in certain tactical situations. Therefore,
the use of oral ketamine (non-opioid) for the purpose of acute pain management after trauma
or surgery is highly desirable.

Pharmacokinetic studies: Oral ketamine may seem disadvantageous because of 17%
bioavailability, mainly due to first-pass drug metabolism in the liver. However, there is not
a wide variability in bioavailability from patient-to-patient (mean 16.6%, SE = 2.8%) and
hence a predictable oral dosing can be achieved. Although investigators have tested
formulations with sublingual or buccal transmucosal administration of ketamine, in practice
they fail to increase the ketamine bioavailability versus oral ketamine. Ketamine as nasal
spray is problematic for acute use, since the amount of drug is difficult to control using an
atomizer.

Day 1 (day of surgery) Before Surgery: An analgesic dose of the oral ketamine (1.0 mg/kg)
will be administered one hour before surgery in the preoperative holding area.

If the subject is experiencing any adverse events (e.g. hallucinations) from the 1.0 mg/kg
pre-surgery dose of ketamine, then any further ketamine dosing will be delayed until the
following day (Day 2). In addition, subsequent subjects will receive a 33% reduction of the
pre-surgery dose (i.e. 0.67 mg/kg).

After Surgery: In the recovery room, when subjects are able to swallow, and if there were no
adverse events from the pre-surgery ketamine dose, oral ketamine (1.0 mg/kg) will be
administered (but no earlier than 8 hours after the pre-surgery dose). No doses will be
administered after midnight.

If adverse events have not resolved by the next morning (Day 2), then oral ketamine will be
discontinued. In addition, subsequent subjects will receive a 33% reduction in the recovery
room dose and/or the last dose of Day 1.

Day 2 (first post-op day) Subjects will receive oral ketamine (1.0 mg/kg) 3 times/day. The
first dose will be administered at 6 AM .If a subject experiences any adverse events after
the first dose, but one that resolves within 8 hours after that dose, the second dose will be
reduced by 33% (1.0 mg/mg to 0.67 mg/kg). If a subject experiences any adverse events after
the second dose, but one that resolves within 8 hours, the dose will be reduced again by 33%
(0.67 mg/kg to 0.45 mg/kg). If this dose reduction protocol does not eliminate adverse
events, then oral ketamine will be discontinued. In addition, subsequent subjects will
receive a 33% reduction in the Day 2 oral ketamine doses

Day 3 (second post-op day) (Tapering Down Period) Subjects will receive oral ketamine at half
of the previous day final dose (0.5 mg/kg if no dose reductions have occurred), 3 times a
day. For example, if the subjects' dose is already at 0.45 mg/kg from the previous day
reductions, then the third day dose will be 0.23 mg/kg. The first dose will be administered
at 6 AM. Even on the third day if there are adverse events after any dose, but one that
resolves within 8 hours after that dose, we will continue to reduce the dose by 33%. If this
dose reduction protocol does not eliminate adverse events, then the subject will not receive
any more ketamine. In addition, subsequent subjects will receive a 33% reduction in the Day 3
oral ketamine doses.

While in the hospital for 3 days, should breakthrough pain occur, all subjects will receive
standard of care pain control medication. All subjects will be discharged according to
standard discharge protocol.

Anticipated Adverse Events If a subject experiences adverse events, subjects will be closely
monitored every hour until the event resolves. Adverse event duration and resolution time
will be recorded. If the adverse event resolves, the next scheduled dose will be reduced by
33%. Each adverse event will be assessed by the Principal Investigator and a clinical
relevance determination will be made.

Inclusion Criteria:

1. Adults of at least 18 years of age, but not older than 80 years

2. Due to undergo elective major amputation of the lower extremity (above the knee
amputation (AKA), below the knee amputation (BKA), total knee amputation (TKA),
transmetatarsal amputation (TMA), toe amputation) from all causes.

Exclusion Criteria:

1. Pregnancy

2. Increased intracranial pressure or intraocular pressure

3. Allergy to ketamine

4. Morbid obesity (BMI > 40 kg/m2)

5. Significant comorbidity (ASA physical status classification > 3)

6. Inability to communicate with the investigators

7. Any history of known or suspected drug or alcohol abuse

8. History of impaired liver function

9. Significant history of hallucinations, delusions or other psychiatric medical
condition the investigator feels will prevent assessment of adverse events of study
drug.

10. Significant psychiatric history; a diagnosis of schizophrenia, bipolar disorder, or
severe depression.

11. Exposure to cytochrome P450 3A4 inhibitors or inducers (including grapefruit products)
within 2 weeks before enrollment; the inability to avoid these products during
ketamine administration.

12. Poorly-controlled hypertension