Intra-operative Ketamine Infusions in Opioid-dependent Patients With Chronic Lower Back Pain
Condition: Chronic Low Back Pain
MeSH terms: Back Pain; Low Back Pain
Study type: Interventional

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.
    

Intervention name(s): Ketamine; Normal saline
Intervention type(s): Drug; Other
Intervention description(s): Peripheral provision of 0.5mg/kg of ketamine on induction followed by a 10mcg/kg/min infusion until surgical wound closure; Normal saline at same rate as the previously described ketamine infusion (10mcg/kg/min), same amount of ketamine/placebo syringe on induction (0.5mg/kg).
Intervention MeSH terms: Ketamine
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: chronic pain; back surgery; opioid dependent; NMDA receptor antagonism; Ketamine; Central sensitization