Influence of Aging on Perioperative Methadone Dosing

Study Overview
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Brief Summary
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Increasingly, elderly patients undergo anesthesia and surgery. Methadone is a great opioid for perioperative pain management, however, to date there are no pharmacokinetic or pharmacodynamic studies that asses a methadone dose adjustment in the elderly patient. The present study is aimed to characterize the pharmacokinetic and pharmacodynamic age-related changes of methadone in the adult population and further to design reference dosing protocols for intraoperative methadone use according to patient age.

Detailed Description
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The subjects will be recruited from adult patients who undergo elective laparoscopic abdominal surgery at UC Christus Clinical Hospital (Santiago, de Chile). Patients will be randomly divided into four groups according to the dose of intravenous methadone to be administered during anaesthetic induction. BIS-guided and standard general anaesthesia will be administered with routine monitoring. Methadone will be administered once the patient is intubated and has hemodynamic stability. The only opioids that patients will receive will be remifentanil and methadone. Upon admission to the Post-anesthesia care unit, the patient is given a Patient-Control Analgesia pump for intravenous administration of morphine. Clinic evaluations will be carried out periodically and blood samples for measurement of plasma methadone will be taken at different times. Samples will be analyzed using high-performance liquid chromatography spectrofluorometric method. The data obtained will be collected in a form within the REDCAP application, to subsequently generate an encrypted database. Groups will be compared regarding pain score, drugs used, opioid consumption, side effects, time of recovery, and patient satisfaction. One, two and three-compartment linear models will be used to fit the plasma methadone concentration data over time. Models are parameterized in terms of elimination clearance, compartment distribution clearance, central volume and peripheral volume of distribution, as appropriate. The use of rescue morphine in the Post-anesthesia care unit will be used as a measure to relate the methadone dose (mg/kg) with the analgesic efficacy using an EMAX model. The data will be modelled using NONMEM VII. A proportional term will be used for variability between subjects. Additive and proportional terms will be used to characterize the unknown residual variability. Sample size calculations were estimated using a simulation-based approach and previous work with a similar methodology. To achieve an adequate representation of all age groups 60 patients will be required, distributed among 20 patients between 18 and 40 years, 20 patients between 41 and 65 years, and 20 patients> 65 years.

Official Title
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Influence of Aging on Perioperative Methadone Dosing

Conditions
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Methadone Overdose of Undetermined Intent, Pain, Postoperative, Opioid Use

Intervention / Treatment
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* Drug: Methadone Injectable Product


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Over 18 years. ASA I, II or III. Laparoscopic Abdominal Surgery. Exclusion Criteria: BMI> 35 Use of opioids up to 5 days before surgery. Acute Liver Failure or Chronic Liver Damage Child C. Kidney damage with creatinine clearance estimated by Cockcroft-Gault formula <60 ml/min.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 105 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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
Interventional Model Description: Patients will be randomly divided into four groups according to the dose of intravenous methadone to be administered during anesthetic induction, for a total number of 60 patients.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Methadone 0<br>Induction will be performed with a bolus of propofol, continuous infusion of remifentanil, and rocuronium. Once the patient is intubated and has hemodynamic stability will be administered the placebo drug. | Drug: Methadone Injectable Product<br>* Perioperative use of placebo for pain management and remifentanil during the surgery.<br>* Other names: Methadone 3 0,2 mg/kg;|
| Experimental: Methadone 1<br>Induction will be performed with a bolus of propofol, continuous infusion of remifentanil, and rocuronium. Once the patient is intubated and has hemodynamic stability will be administered an intravenous methadone dose of 0.05 mg/kg. | Drug: Methadone Injectable Product<br>* Perioperative use of placebo for pain management and remifentanil during the surgery.<br>* Other names: Methadone 3 0,2 mg/kg;|
| Experimental: Methadone 2<br>Induction will be performed with a bolus of propofol, continuous infusion of remifentanil, and rocuronium. Once the patient is intubated and has hemodynamic stability will be administered an intravenous methadone dose of 0.1 mg/kg. | Drug: Methadone Injectable Product<br>* Perioperative use of placebo for pain management and remifentanil during the surgery.<br>* Other names: Methadone 3 0,2 mg/kg;|
| Experimental: Methadone 3<br>Induction will be performed with a bolus of propofol, continuous infusion of remifentanil, and rocuronium. Once the patient is intubated and has hemodynamic stability will be administered an intravenous methadone dose of 0.2 mg/kg. | Drug: Methadone Injectable Product<br>* Perioperative use of placebo for pain management and remifentanil during the surgery.<br>* Other names: Methadone 3 0,2 mg/kg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Methadone plasmatic levels Measured by high pressure liquid chromatography | Five venous blood samples will be taken from each patient for methadone plasmatic level analysis. Patients will be randomly divided into two groups with different sample collection times. Group 1 at 0.05, 0.75, 1.5, 6, 18 hours post drug administration and Group 2 at 0.25, 1, 3, 12 and 24 hours. | From the first dose up to 24 hours. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemodynamics | Non invasive systolic and diastolic blood pressure monitoring (mmHg). | Every 5 min. Since entering operating room up to end of anesthesia and leaving to recovery room. In average 2 hrs. Then, from the entrance to the recovery room every 30 minutes up to 180 minutes. | 
| Heart Rate | Heart rate (bpm) | Every 5 min. Since entering operating room up to end of anesthesia and leaving to recovery room. In average 2 hrs. Then, from the entrance to the recovery room every 30 minutes up to 180 minutes. | 
| Pulse oximetry | % oximetry saturation | Every 5 min. Since entering operating room up to end of anesthesia and leaving to recovery room. In average 2 hrs. Then, from the entrance to the recovery room every 30 minutes up to 180 minutes. | 
| BIS | Depth of anesthesia will be recorded with BIS monitor. From 60 - 40 | Every 5 min. Since entering operating room up to end of anesthesia and leaving to recovery room. In average 2 hrs. | 
| Respiratory rate | bpm | Every 30 minutes. Since entering the recovery room up to 180 mins. | 
| Numeric Pain Rating Scale | Numeric Pain rating scale in rest and movement, from 0 (no pain) to 10 (maximum pain). | Every 30 minutes. Since entering the recovery room up to 180 mins. | 
| Nausea or vomiting | Presence of nausea or vomiting in the recovery room. | Every 30 minutes. Since entering the recovery room up to 180 mins. | 
| Sedation (Ramsay Scale) | Ramsay scale (1-6) | Every 30 minutes. Since entering the recovery room up to 180 mins. | 
| Respiratory depression | Presence of respiratory depression in the recovery room. (Respiratory rate less than 8 bpm requiring oxygen therapy). | Every 30 minutes. Since entering the recovery room up to 180 mins. | 
| Other opioids and pain management drugs used during recovery stay | Name and total doses, including Morphine PCA. | Since the admission to the recovery room up to 2 hours. | 
| Intestinal transit recovery | Time to first flatus, fist bowel movement and stool. Presence of abdominal bloating. | Since the admission to the recovery room up to 2 hours. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Elderly, Postoperative Pain, Methadone