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Methadone and Ketamine for Spinal Surgery

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ClinicalTrials.gov Identifier: NCT02827526
Recruitment Status : Active, not recruiting
First Posted : July 11, 2016
Last Update Posted : August 24, 2020
Sponsor:
Information provided by (Responsible Party):
Glenn Murphy, NorthShore University HealthSystem

Tracking Information
First Submitted Date  ICMJE July 6, 2016
First Posted Date  ICMJE July 11, 2016
Last Update Posted Date August 24, 2020
Actual Study Start Date  ICMJE July 2016
Actual Primary Completion Date December 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 6, 2016)
hydromorphone consumption [ Time Frame: first 24 hours ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 14, 2017)
  • hydromorphone consumption [ Time Frame: second 24 hours ]
  • hydromorphone consumption [ Time Frame: third 24 hours ]
  • postoperative pain [ Time Frame: morning of postoperative day 1 ]
    scale of 0 to 10 (0=no pain 10=worst pain imaginable))
  • postoperative pain [ Time Frame: morning of postoperative day 2 ]
    scale of 0 to 10, 0=no pain, 10=worst pain imaginable)
Original Secondary Outcome Measures  ICMJE
 (submitted: July 6, 2016)
  • hydromorphone consumption [ Time Frame: second 24 hours ]
  • hydromorphone consumption [ Time Frame: third 24 hours ]
  • postoperative pain [ Time Frame: morning of postoperative day 1 ]
  • postoperative pain [ Time Frame: morning of postoperative day 2 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Methadone and Ketamine for Spinal Surgery
Official Title  ICMJE Methadone and Ketamine for Spinal Surgery
Brief Summary Patients undergoing major spinal surgery continue to experience moderate-to-severe pain during the first 2-3 days following the operative procedure. Several factors contribute to postoperative pain in this patient population. Many patients present to surgery dependent on relatively high doses of oral opioids; this daily administration leads to tolerance to the effects of these drugs as well as hyperalgesia (exposure to opioids makes subsequent pain worse). In addition, surgical procedures on the spine are very painful. Furthermore, most of the opioids used after surgery only produce analgesia (pain relief) for 2-4 hours, which leads to fluctuations in levels of pain control (patients have to push a button to deliver pain medication when they begin to feel discomfort). Recent data suggest that the use of a long-acting opioid like methadone in the operating room, which provides analgesia for 24-36 hours, may improve pain control after spinal fusion surgery. However, other pain treatment modalities are required in this patient population. Studies have demonstrated that ketamine, a drug that prevents pain by a mechanism different from opioids, is effective in reducing pain medication requirements when given in the perioperative period. Small-dose infusions not only provide analgesia, but also prevent opioid tolerance and hyperalgesia. In particular, the combination of methadone and ketamine may be especially effective in controlling pain in patients following major operations. The aim of this randomized clinical trial is to examine the effect of a low-dose perioperative infusion of ketamine, when given with methadone in the operating room, on postoperative pain medication requirements, pain scores, and clinical recovery characteristics after spinal fusion surgery.
Detailed Description

Methadone is an opioid with the potential to provide prolonged and constant analgesia. It has a half-life that is significantly longer than other clinically-used opioids (25-52 hours). This unique property of methadone suggests that a single dose administered in the operating room can result in extended pain relief following surgery. When given intravenously to surgical patients, a half-life of 35 hours was observed, resulting in a median duration of analgesia of 26 hours. In patients undergoing abdominal, orthopedic, or gynecologic surgery, the use of a single dose of methadone (20 mg or 0.2-0.3 mg/kg) at induction of anesthesia resulted in reduced analgesic requirements and improved pain scores for the first 24-48 postoperative hours (when compared to patients given traditional intraoperative opioids). Only one retrospective study has examined the use of intraoperative methadone in adult patients undergoing spinal instrumentation. In this investigation, methadone use was associated with a 50% reduction in postoperative opioid requirements, compared to patients receiving shorter-acting opioids. Despite the use of methadone and postoperative PCA opioids, however, average pain scores were greater than 3 (on a 0 to 10 scale) in the methadone group. These findings suggest that methadone alone is insufficient in alleviating pain after major spine surgery.

A large number of clinical trials have examined the use of ketamine in the perioperative period. Several systematic reviews and meta-analyses have assessed the benefits and risks of ketamine in surgical patients. Bell et al. concluded that perioperative ketamine reduced analgesic requirements or pain intensity, or both. The incidence of nausea and vomiting was reduced, and adverse events were mild or absent. Himmelseher et al. noted that intravenous subanesthetic ketamine in general anesthesia provided pain prevention after surgery. Jouguelet-Lacoste et al. determined that low-dose ketamine reduced opioid consumption by 40%. Pain scores were also reduced, and no major complications were noted. Laskowski et al. concluded that ketamine resulted in a reduction in opioid consumption across all studies, and lower pain score were reported in most investigations. No significant differences in adverse events were noted in most meta-analyses, with the exception of a lower risk of nausea and vomiting in patients randomized to receive ketamine (a higher risk of hallucinations was reported in one meta-analysis). A large number of different dosing strategies have been used for ketamine. However, the greatest efficacy appears to result when a bolus dose is given (0.5 mg/kg) before incision, followed by an intraoperative (0.25-0.5 mg/kg/hr) infusion, and a postoperative (0.06-0.12 mg/kg/hr) infusion continued for at least 24-48 hours

Like methadone, ketamine is used most frequently in patients undergoing spinal fusion surgery due to the high incidence of pre-existing opioid tolerance and hyperalgesia (personal communication). Ketamine infusions have been investigated in 6 randomized studies in this patient population. In 5 of the trials, reduced postoperative opioid requirements, decreased pain scores, or both, were observed in patients randomized to receive ketamine. Shorter-acting opioids were used with ketamine in 5 of the investigations. Despite data suggesting a beneficial effect of ketamine in patients undergoing major spine surgery, a recent "best evidence" review stated that "there is insufficient and /or conflicting evidence that ketamine provides a significant reduction in postoperative pain or narcotic usage"

In theory, the use of a combination of a long-acting opioid and ketamine may be particularly efficacious in optimizing postoperative pain management. Recent evidence has demonstrated that methadone, like ketamine, has the ability to block NMDA receptors. In a neuropathic animal model, the combination of methadone and ketamine produced an analgesic synergy of a supra-additive nature. In the clinical setting, the administration of methadone and ketamine has only been examined in one small trial (20 patients). Patients randomized to receive methadone and ketamine required 70% less pain medication than those administered methadone alone. Although clinicians at NorthShore and other institutions are beginning to use methadone and ketamine in patients undergoing spinal surgery, there is limited evidence examining this approach in this patient population.

The primary aim of this randomized, double-blind study is to examine a perioperative analgesic strategy utilizing both ketamine and methadone in patients undergoing posterior spinal fusion. Patients randomized to the ketamine group will be given 0.2 mg/kg of methadone at anesthetic induction, and a ketamine infusion will be used intraoperatively and for 48 hours after surgery. Patients in the control group will receive 0.2 mg/kg of methadone at anesthetic induction, and then a D5W (sugar water) infusion intraoperatively and for 48 hours postoperatively. The total amount of PCA hydromorphone used postoperatively will be recorded, as well as postoperative pain scores. Recovery variables will be measured and patients will be assessed for adverse events potentially related to opioids and ketamine. NMDA receptor stimulation is also thought to play an important role in the development of chronic pain after surgery. Therefore, patients will be surveyed about chronic postsurgical pain 1, 3, 6, and 12 months after the operation to determine whether intraoperative management may influence the development of long-term adverse events.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Pain
Intervention  ICMJE
  • Drug: Ketamine
  • Drug: Control
    Other Name: dextrose infusion
Study Arms  ICMJE
  • Active Comparator: Ketamine
    Patients in the ketamine arm will receive an intraoperative and postoperative infusion of ketamine
    Intervention: Drug: Ketamine
  • Placebo Comparator: Control
    Patients in the control arm will receive an intraoperative and postoperative infusion of dextrose
    Intervention: Drug: Control
Publications * Not Provided

*   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 Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: March 2, 2020)
130
Original Estimated Enrollment  ICMJE
 (submitted: July 6, 2016)
140
Estimated Study Completion Date  ICMJE November 2020
Actual Primary Completion Date December 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients presenting for elective posterior spinal fusion surgery (lower thoracic, lumbar, sacral)
  • Ages 18-80

Exclusion Criteria:

  • Preoperative renal failure (defined as a serum creatinine > 2.0 mg/dL.)
  • American Society of Anesthesiologists Physical Status IV or V
  • Pulmonary disease necessitating home oxygen therapy
  • Allergy to methadone, hydromorphone, or ketamine
  • Preoperative recent history of opioid or alcohol abuse
  • Significant liver disease
  • Inability to use a PCA device or speak the English language
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 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 NCT02827526
Other Study ID Numbers  ICMJE EH15-268
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Glenn Murphy, NorthShore University HealthSystem
Study Sponsor  ICMJE NorthShore University HealthSystem
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Glenn S Murphy, MD NorthShore University HealthSystem
PRS Account NorthShore University HealthSystem
Verification Date August 2020

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