Pharmacogenomics of Methadone in Spine Fusion Surgery

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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The Influence of Pharmacogenetics on Methadone Dose, Safety, and Outcomes After Spine Fusion

Conditions
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Scoliosis, Kyphosis

Intervention / Treatment
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* Drug: Methadone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ASA physical status I, II, and III male and non-pregnant female English-speaking undergoing elective < 3 vertebral level lumbar spine fusion (with and without interbody fusion) Exclusion Criteria: Use of more than the equivalent of 20 mg of IV morphine/24 hr in the past 2 weeks history of substance abuse at any time in the past known QT prolongation Non-elective operations (i.e., cancer or trauma) severe hepatic impairment (serum albumin <3.0 g/dL, history of liver disease) pregnancy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Methadone 0.5 mg/kg<br>Methadone 0.5 mg/kg | Drug: Methadone<br>* Methadone IV Pre-Induction of Anesthesia 0.15 to 0.5 mg/kg<br>* Other names: Dolophine;|
| Experimental: Methadone 0.4 mg/kg<br>Methadone 0.4 mg/kg | Drug: Methadone<br>* Methadone IV Pre-Induction of Anesthesia 0.15 to 0.5 mg/kg<br>* Other names: Dolophine;|
| Active Comparator: Methadone 0.3 mg/kg<br>Methadone 0.3 mg/kg | Drug: Methadone<br>* Methadone IV Pre-Induction of Anesthesia 0.15 to 0.5 mg/kg<br>* Other names: Dolophine;|
| Active Comparator: Methadone 0.2 mg/kg<br>Methadone 0.2 mg/kg | Drug: Methadone<br>* Methadone IV Pre-Induction of Anesthesia 0.15 to 0.5 mg/kg<br>* Other names: Dolophine;|
| Active Comparator: Methadone 0.15 mg/kg<br>Methadone 0.15 mg/kg | Drug: Methadone<br>* Methadone IV Pre-Induction of Anesthesia 0.15 to 0.5 mg/kg<br>* Other names: Dolophine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time until initial request for postoperative analgesic. |  | 60 minutes after extubation, 24, 48, and 72 hours after methadone administration | 

Secondary Outcome Measures

| Outcome Measure | 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 | 
| 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 Time to first request for analgesia Secondary outcomes | Preoperatively | 
| Pupillometry for assessment of sedation |  | Pre-operatively, 60 minutes after extubation, 24, 48, and 72 hours after methadone administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Spinal Fusion, Opioid Analgesia