Clinical trial NCT00899600: Intra-operative Ketamine Infusions in Opioid-dependent Patients With Chronic Lower Back Pain
Official title: Intra-operative Ketamine Infusions in Patients With Chronic Lower Back Discomfort Undergoing Laminectomies.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Chronic Low Back Pain
Keywords: chronic pain
back surgery
opioid dependent
NMDA receptor antagonism
Ketamine
Central sensitization
Lead sponsor: Dartmouth-Hitchcock Medical Center
Sponsor class: OTHER
First posted: 2009-05-12
Enrollment: 102
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Noxious stimuli occurring intraoperatively and postoperatively generate central sensitization, decreasing pain thresholds and ultimately increasing analgesic requirements. The pathophysiology of central sensitization is thought to involve excitatory amino acid receptors such as N-methyl-d-aspartate (NMDA) (1, 2). 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 (3).

Spine surgery provides a unique opportunity to evaluate the preemptive and preventative impact of ketamine on the primary end points of postoperative 24 and 48 hour opioid consumption in patients with chronic pain. The goal of this double blinded, prospective, randomized placebo controlled trial is to 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 postoperative opioid use.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Morphine Consumption in the First 48 Hours After Surgery
timeFrame: 48 hours
Secondary outcomes:
measure: Hospital Duration
timeFrame: Discharge from hospital, approximately 2 days after surgery
measure: Hemodynamic Changes - Heart Rate
timeFrame: Baseline, Inoperative (approximately) 48 hours
measure: Hemodynamic Changes - Blood Pressure
timeFrame: Baseline, Inoperative (approximately) 48 hours
measure: Percentage of Participants With Complications/Adverse Events
timeFrame: 48 hours and 6 weeks
Other outcomes:
Locations:
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Medical Center
state: New Hampshire
Study officials:
affiliation: DHMC
name: Jeffrey A Clark, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 1. Wall PD. The prevention of postoperative pain. Pain 1988; 33: 289-90. 2. Katz J. George Washington Crile, anoci-association, and preemptive analgesia. Pain 1993;53: 243-5. 3. McQual HJ. Pre-emptive analgesia. Br J Anaesth 1992;69: 1-3. 4. Moiniche S, Kehlet H, Dahl JB. A qualitative and quantitative systematic review of preemptive analgesia for postoperative pain relief: the role of timing of analgesia. Anesthesiology 2002;96: 725-41. 5. Katz J. Pre-emptive analgesia: evidence, current status and future directions. Eur J Anaesthesiol Suppl 995;10:8-13. 6. Katz J, McCartney CJ. Update on pre-emptive analgesia. Curr Opin Anesthesiol 2002; 15: 435-41. 7. McCartney et al. A qualitative systematic review of the role of N-Methyl-D-Aspartate receptor antagonists in preventative analgesia. Anesth Analg 2004; 98: 1385-1400. 8. Wu CT, Yeh CC, Yu JC, et al. Pre-incisional epidural ketamine, morphine and bupivacaine combined with epidural and general anesthesia provides pre-emptive analgesia for upper abdominal surgery. Acta Anaesthesiol Scand 2000;44: 63-8.