Influence of Aging on Perioperative Methadone Dosing
Condition: Pain, Postoperative; Opioid Use; Methadone Overdose of Undetermined Intent
MeSH terms: Pain, Postoperative
Study type: Interventional
Phase: Phase 4

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.
    

Intervention name(s): Methadone Injectable Product
Intervention type(s): Drug
Intervention description(s): Perioperative use of placebo for pain management and remifentanil during the surgery.
Other intervention name(s): Methadone 0; Methadone 1 0,05 mg/kg; Methadone 2 0,1 mg/kg; Methadone 3 0,2 mg/kg
Intervention MeSH terms: Methadone
Allocation: Randomized
Intervention model: Parallel Assignment
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.
Masking: Double (Participant, Care Provider)
Primary purpose: Treatment
Keywords: Methadone; Elderly; Postoperative Pain