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The overall objective is to develop a patient oriented research program to efficiently evaluate the effects of pharmacogenetic variants on the dose-response relationships and safety of opioids and non-opioid analgesics. If an opioid regimen can be created that produces excellent opioid analgesia with minimal toxicity related to supratherapeutic opioid concentrations (i.e., ventilatory depression), other non-opioid analgesics (i.e., gabapentin/pregabalin, ketamine, lidocaine, cyclooxygenase inhibitors, etc.) that may decrease preoperative opioid requirements can be more efficiently and safely evaluated. These interventions may limit the opioid related toxicities related to effect site concentrations that are below those required when opioids are the predominant analgesic, such as opioid related ileus. Methadone's slow elimination clearance and limited pharmacokinetic drug-drug interactions make it an attractive perioperative opioid. The first step towards personalized opioid analgesia is to determine the effect of common pharmacogenetic variants that affect either methadone metabolism (CYP2B6) or opioid elimination.
This study is being done to find the optimal dose of methadone (a long acting pain medication) that decreases the amount of pain that people have after spine surgery. Five different doses of methadone will be compared to each other, while keeping the remainder of the anesthetic routine for surgery. The investigators will determine the analgesic dose-response of methadone. The investigators will also determine the effect of methadone on the incidence of opioid related side effects, the quality of outcome of recovery, and the change in the 3-month opioid use.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Methadone 0.5 mg/kg | Active Comparator | Methadone 0.5 mg/kg |
|
| Methadone 0.4 mg/kg | Experimental | Methadone 0.4 mg/kg |
|
| Methadone 0.3 mg/kg | Active Comparator | Methadone 0.3 mg/kg |
|
| Methadone 0.2 mg/kg | Active Comparator | Methadone 0.2 mg/kg |
|
| Methadone 0.15 mg/kg | Active Comparator | Methadone 0.15 mg/kg |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Methadone | Drug | Methadone IV Pre-Induction of Anesthesia 0.15 to 0.5 mg/kg |
|
| Measure | Description | Time Frame |
|---|---|---|
| Time until initial request for postoperative analgesic. | 60 minutes after extubation, 24, 48, and 72 hours after methadone administration |
| Measure | Description | Time Frame |
|---|---|---|
| The determination of minimum effective analgesic concentration of methadone. | 60 minutes after extubation, 24, 48, and 72 hours after methadone administration | |
| Postoperative pain at rest and with movement (numerical rating scale, NRS) | 60 minutes after extubation, 24, 48, and 72 hours after methadone administration |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Dhanesh K. Gupta, M.D. | Northwestern University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Northwestern Memorial Hospital | Chicago | Illinois | 60611 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 21311399 | Background | Rajaee SS, Bae HW, Kanim LE, Delamarter RB. Spinal fusion in the United States: analysis of trends from 1998 to 2008. Spine (Phila Pa 1976). 2012 Jan 1;37(1):67-76. doi: 10.1097/BRS.0b013e31820cccfb. | |
| 7500538 | Background | Jadad AR, Browman GP. The WHO analgesic ladder for cancer pain management. Stepping up the quality of its evaluation. JAMA. 1995 Dec 20;274(23):1870-3. |
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| ID | Term |
|---|---|
| D012600 | Scoliosis |
| D007738 | Kyphosis |
| ID | Term |
|---|---|
| D013121 | Spinal Curvatures |
| D013122 | Spinal Diseases |
| D001847 | Bone Diseases |
| D009140 | Musculoskeletal Diseases |
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| ID | Term |
|---|---|
| D008691 | Methadone |
| ID | Term |
|---|---|
| D007659 | Ketones |
| D009930 | Organic Chemicals |
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|
| The number of occurrences of ventilatory depression during each evaluation interval | 60 minutes after extubation, 24, 48, and 72 hours after methadone administration |
| Nausea and vomiting: number of rescue antiemetic doses and episodes of emesis | 60 minutes after extubation, 24, 48, and 72 hours after methadone administration |
| Level of sedation (modified Observer's Assessment of Alertness and Sedation Scale, modified OAA/S scale) | 60 minutes after extubation, 24, 48, and 72 hours after methadone administration |
| Occurence of pruritis | 60 minutes after extubation, 24, 48, and 72 hours after methadone administration |
| Algometry to assess pain tolerance | Pre-operatively, 60 minutes after extubation, 24, 48, and 72 hours after methadone administration |
| Degree of bother associated with opioid-related adverse effects: Opioid-related Symptom Distress Scale (OR-SDS) | 24, 48, and 72 hours after methadone administration |
| Quality of Recovery: Quality of Recovery-40 score | 24, 48, and 72 hours after methadone administration |
| Patient analgesic satisfaction | 24, 48, and 72 hours after methadone administration |
| Assessment of back condition pre and post-operatively | Pre-operatively, 6 weeks and 3 months post-operatively |
| Effects of common opioid related metabolic pathway polymorphisms on methadone's dose response relationships for analgesia and side effects | CYP2B6 Polymorphism effect on
| Preoperatively |
| Pupillometry for assessment of sedation | Pre-operatively, 60 minutes after extubation, 24, 48, and 72 hours after methadone administration |
| 20418538 | Background | Gottschalk A, Durieux ME, Nemergut EC. Intraoperative methadone improves postoperative pain control in patients undergoing complex spine surgery. Anesth Analg. 2011 Jan;112(1):218-23. doi: 10.1213/ANE.0b013e3181d8a095. Epub 2010 Apr 24. |
| 9314613 | Background | Upton RN, Semple TJ, Macintyre PE. Pharmacokinetic optimisation of opioid treatment in acute pain therapy. Clin Pharmacokinet. 1997 Sep;33(3):225-44. doi: 10.2165/00003088-199733030-00005. |
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| 2286697 | Background | Chernik DA, Gillings D, Laine H, Hendler J, Silver JM, Davidson AB, Schwam EM, Siegel JL. Validity and reliability of the Observer's Assessment of Alertness/Sedation Scale: study with intravenous midazolam. J Clin Psychopharmacol. 1990 Aug;10(4):244-51. |
| 15333398 | Background | Apfelbaum JL, Gan TJ, Zhao S, Hanna DB, Chen C. Reliability and validity of the perioperative opioid-related symptom distress scale. Anesth Analg. 2004 Sep;99(3):699-709. doi: 10.1213/01.ANE.0000133143.60584.38. |
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