Intra-operative Ketamine Infusions in Opioid-dependent Patients With Chronic Lower Back Pain

Noxious stimuli occurring intra-operatively and post-operatively generate central
sensitization, decreasing pain thresholds and ultimately increasing analgesic requirements.
The pathophysiology of central sensitization is thought to involve excitatory amino acid
receptors that have been implicated in the prolongation of painful states in animal models.
The N-methyl-d-aspartate (NMDA) receptor is one such excitatory amino acid receptor (1, 2).

The underlying mechanism of central sensitization is thought to involve c-fiber associated
injury occurring with incision. Crile and Wall brought about the concept that attenuation of
central sensitization could be accomplished via the provision of analgesic interventions
(opioids, local anesthesia) prior to the noxious insult. They termed the central
sensitization attenuation preemptive analgesia. The concept of preemptive analgesia was later
expanded to implicate both pre and post-incisional noxious stimuli as part of this process,
resulting in studies designed to provide interventions throughout the surgical intervention
(peri-procedural) (3). Reduction in analgesic requirements or pain scores for more than five
half-lives (1st order kinetics) following the provision of the intervening analgesic agent
peri-procedurally is now known as preventative analgesia. The term preemptive analgesia is
now reserved for interventions that occur only before the noxious stimuli.

Multiple studies have investigated the concepts of preemptive analgesia and preventative
analgesia by providing a variety of analgesic interventions at various times throughout the
surgical insult in addition to more conventional means of anesthesia provision, including
opioids, Non-Steroidal Anti-Inflammatory Drugs (NSAID)s, Cyclooxygenase-II (COX-2)
inhibitors, alpha-2 agonists, and ketamine (4, 5, 6). Preemptive and preventative analgesia
using a variety of pharmacological agents with at least partially known mechanisms of actions
has provided some insight into potential mechanisms of central sensitization.

Ketamine is a N-methyl-d-aspartate (NMDA) receptor antagonist that has been shown to be
useful in the reduction of acute postoperative pain and analgesic consumption in a variety of
surgical interventions with variable routes of administration. It has also been shown to be
effective in the presence and absence of opioids, suggesting that it has more than one
mechanism of action in preemptive and preventative analgesia, including but not limited to
decreasing central excitability, decreasing acute post-operative opioid tolerance, and a
possible modulation of opioid receptors (7). Ketamine is a common anesthetic agent and has
been in use since the Vietnam War. Clinically, ketamine provides pain relief with minimal
respiratory depression, and at higher doses (1-2mg/kg) can induce general anesthesia while
maintaining blood pressure and cardiac output.

Recently, a qualitative systematic review of the role of NMDA receptor antagonists was
completed. Twenty-four studies investigating the role of ketamine met the inclusion criteria
of the study, 58% of which demonstrated a preemptive or preventative analgesic effect.
Patients underwent a variety of surgical procedures, both ambulatory and inpatient, and there
was no obvious effect of either surgical type or dose of ketamine (range 0.15 to 1mg/kg) on
the success of preventative intervention. However, the authors were unable to quantify the
degree of reduction in primary end-points (opioid consumption, pain scores, both) due to
variability in recording of such data. In addition, most inpatient studies were limited to
abdominal procedures while the outpatient studies investigated mainly knee arthroscopies,
providing no insight into the degree of impact of NMDA receptor antagonism in the setting of
high pre-operative opioid tolerance combined with surgical procedures known to be associated
with an invariably high degree of post-operative pain. Of note, only 1/24 studies documented
a significant difference in side effects related to ketamine provision in patients who had
received 20mg of epidural ketamine (7).

Laminectomy procedures provide a unique opportunity to evaluate the preemptive and
preventative impact of ketamine on the primary end points of acute post-operative pain scores
and opioid consumption in a patient population with opioid dependence and a high degree of
post-operative and intra-operative noxious stimuli. The goal of this double blinded,
randomized placebo controlled trial will be to test for the presence of, and quantify, the
preemptive and preventative analgesic effects of ketamine infusions in this patient
population. Such insight may lead to better pain control, improved satisfaction, and
ultimately a reduction in side-effects related to post-operative opioid use including but not
limited to respiratory depression, constipation, and delirium.

Inclusion Criteria:

- Laminectomy procedures.

- History of chronic back pain.

- Daily opioid use.

- Capable of providing informed consent.

Exclusion Criteria:

- Intolerance/allergy to ketamine.

- Intolerance/true allergy to morphine.

- Elevated intra-ocular pressure.

- Uncontrolled hypertension.

- Elevated intra-cranial pressure.

- Any history of a psychosis.

- Pregnancy.