Methadone and Ketamine for Spinal Surgery
Condition: Pain
Study type: Interventional
Phase: Phase 4

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.
    

Intervention name(s): Ketamine; Control
Intervention type(s): Drug; Drug
Other intervention name(s): dextrose infusion
Intervention MeSH terms: Ketamine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment