Clinical trial NCT04526236: Influence of Aging on Perioperative Methadone Dosing
Official title: Influence of Aging on Perioperative Methadone Dosing
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Pain, Postoperative
Opioid Use
Methadone Overdose of Undetermined Intent
Keywords: Methadone
Elderly
Postoperative Pain
Lead sponsor: Pontificia Universidad Catolica de Chile
Sponsor class: OTHER
First posted: 2020-08-25
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 105
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Over 18 years.
2. ASA I, II or III.
3. Laparoscopic Abdominal Surgery.

Exclusion Criteria:

1. BMI\> 35
2. Use of opioids up to 5 days before surgery.
3. Acute Liver Failure or Chronic Liver Damage Child C.
4. Kidney damage with creatinine clearance estimated by Cockcroft-Gault formula \<60 ml/min.

Primary outcomes:
measure: Methadone plasmatic levels Measured by high pressure liquid chromatography
timeFrame: From the first dose up to 24 hours.
Secondary outcomes:
measure: Hemodynamics
timeFrame: 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.
measure: Heart Rate
timeFrame: 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.
measure: Pulse oximetry
timeFrame: 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.
measure: BIS
timeFrame: Every 5 min. Since entering operating room up to end of anesthesia and leaving to recovery room. In average 2 hrs.
measure: Respiratory rate
timeFrame: Every 30 minutes. Since entering the recovery room up to 180 mins.
measure: Numeric Pain Rating Scale
timeFrame: Every 30 minutes. Since entering the recovery room up to 180 mins.
measure: Nausea or vomiting
timeFrame: Every 30 minutes. Since entering the recovery room up to 180 mins.
measure: Sedation (Ramsay Scale)
timeFrame: Every 30 minutes. Since entering the recovery room up to 180 mins.
measure: Respiratory depression
timeFrame: Every 30 minutes. Since entering the recovery room up to 180 mins.
measure: Other opioids and pain management drugs used during recovery stay
timeFrame: Since the admission to the recovery room up to 2 hours.
measure: Intestinal transit recovery
timeFrame: Since the admission to the recovery room up to 2 hours.
Other outcomes:
measure: Body fat
timeFrame: Once, before the anesthetic induction in the operating toom.
measure: Level of satisfaction with pain management: 10-point scale
timeFrame: Since the admission to the recovery room up to 2 hours.
measure: Lean Mass
timeFrame: Once, before the anesthetic induction in the operating toom.
measure: Total water
timeFrame: Once, before the anesthetic induction in the operating toom.
Locations:
city: Santiago
country: Chile
facility: Pontificia Universidad Católica de Chile
state: Metropolitana
Study officials:
affiliation: Associate Professor
name: Maria F Elgueta, MD
role: PRINCIPAL_INVESTIGATOR
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