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

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ClinicalTrials.gov Identifier: NCT00899600
Recruitment Status : Completed
First Posted : May 12, 2009
Results First Posted : April 11, 2013
Last Update Posted : October 18, 2018
Sponsor:
Information provided by (Responsible Party):
Dartmouth-Hitchcock Medical Center

Tracking Information
First Submitted Date  ICMJE May 8, 2009
First Posted Date  ICMJE May 12, 2009
Results First Submitted Date  ICMJE November 27, 2012
Results First Posted Date  ICMJE April 11, 2013
Last Update Posted Date October 18, 2018
Study Start Date  ICMJE February 2007
Actual Primary Completion Date April 2009   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 5, 2013)
Morphine Consumption in the First 48 Hours After Surgery [ Time Frame: 48 hours ]
Total morphine(mg)consumed at 48 hours.
Original Primary Outcome Measures  ICMJE
 (submitted: May 11, 2009)
Morphine consumption and pain scores in the first 24 and 48 hours and at 6 weeks [ Time Frame: 24 and 48 hours, 6 weeks postoperatively ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 21, 2018)
  • Hospital Duration [ Time Frame: Discharge from hospital, approximately 2 days after surgery ]
  • Hemodynamic Changes - Heart Rate [ Time Frame: Baseline, Inoperative (approximately) 48 hours ]
    Hemodynamic change (Heart Rate) from baseline in the intraoperative and 48-h postoperative periods
  • Hemodynamic Changes - Blood Pressure [ Time Frame: Baseline, Inoperative (approximately) 48 hours ]
    Hemodynamic change (Blood Pressure) from baseline in the intraoperative and 48-h postoperative periods
  • Percentage of Participants With Complications/Adverse Events [ Time Frame: 48 hours and 6 weeks ]
    Adverse events
Original Secondary Outcome Measures  ICMJE
 (submitted: May 11, 2009)
  • Hospital Duration [ Time Frame: 24 and 48 hours ]
  • Mortality [ Time Frame: 1 year ]
  • Hemodynamic Changes [ Time Frame: 24 and 48 hours ]
  • Complications Related to Ketamine [ Time Frame: 24 and 48 hours ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Intra-operative Ketamine Infusions in Opioid-dependent Patients With Chronic Lower Back Pain
Official Title  ICMJE Intra-operative Ketamine Infusions in Patients With Chronic Lower Back Discomfort Undergoing Laminectomies.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Chronic Low Back Pain
Intervention  ICMJE
  • Drug: Ketamine
    Peripheral provision of 0.5mg/kg of ketamine on induction followed by a 10mcg/kg/min infusion until surgical wound closure
  • Other: Normal saline
    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).
Study Arms  ICMJE
  • Placebo Comparator: Normal saline
    Intervention: Other: Normal saline
  • Experimental: Ketamine
    Intervention: Drug: Ketamine
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 5, 2013)
102
Original Actual Enrollment  ICMJE
 (submitted: May 11, 2009)
100
Actual Study Completion Date  ICMJE April 2009
Actual Primary Completion Date April 2009   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 90 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00899600
Other Study ID Numbers  ICMJE 100674
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Dartmouth-Hitchcock Medical Center
Study Sponsor  ICMJE Dartmouth-Hitchcock Medical Center
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Jeffrey A Clark, MD DHMC
PRS Account Dartmouth-Hitchcock Medical Center
Verification Date September 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP