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Influence of Aging on Perioperative Methadone Dosing

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ClinicalTrials.gov Identifier: NCT04526236
Recruitment Status : Recruiting
First Posted : August 25, 2020
Last Update Posted : April 1, 2021
Sponsor:
Information provided by (Responsible Party):
Pontificia Universidad Catolica de Chile

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.

Condition or disease Intervention/treatment Phase
Pain, Postoperative Opioid Use Methadone Overdose of Undetermined Intent Drug: Methadone Injectable Product Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
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)
Masking Description: The masking will be generated on a research laboratory computer and will be stored in an encrypted file. This information will be known exclusively to a member of the research team present during the surgery, who will hand over preparing the corresponding medicine in a 20 cc syringe and hand it over to the treating anesthesiologist.
Primary Purpose: Treatment
Official Title: Influence of Aging on Perioperative Methadone Dosing
Actual Study Start Date : September 9, 2019
Estimated Primary Completion Date : August 1, 2021
Estimated Study Completion Date : September 1, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Placebo Comparator: Methadone 0
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
Perioperative use of placebo for pain management and remifentanil during the surgery.
Other Names:
  • Methadone 0
  • Methadone 1 0,05 mg/kg
  • Methadone 2 0,1 mg/kg
  • Methadone 3 0,2 mg/kg

Experimental: Methadone 1
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
Perioperative use of placebo for pain management and remifentanil during the surgery.
Other Names:
  • Methadone 0
  • Methadone 1 0,05 mg/kg
  • Methadone 2 0,1 mg/kg
  • Methadone 3 0,2 mg/kg

Experimental: Methadone 2
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
Perioperative use of placebo for pain management and remifentanil during the surgery.
Other Names:
  • Methadone 0
  • Methadone 1 0,05 mg/kg
  • Methadone 2 0,1 mg/kg
  • Methadone 3 0,2 mg/kg

Experimental: Methadone 3
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
Perioperative use of placebo for pain management and remifentanil during the surgery.
Other Names:
  • Methadone 0
  • Methadone 1 0,05 mg/kg
  • Methadone 2 0,1 mg/kg
  • Methadone 3 0,2 mg/kg




Primary Outcome Measures :
  1. Methadone plasmatic levels Measured by high pressure liquid chromatography [ Time Frame: From the first dose up to 24 hours. ]
    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.


Secondary Outcome Measures :
  1. Hemodynamics [ Time Frame: 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. ]
    Non invasive systolic and diastolic blood pressure monitoring (mmHg).

  2. Heart Rate [ Time Frame: 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 (bpm)

  3. Pulse oximetry [ Time Frame: 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. ]
    % oximetry saturation

  4. BIS [ Time Frame: Every 5 min. Since entering operating room up to end of anesthesia and leaving to recovery room. In average 2 hrs. ]
    Depth of anesthesia will be recorded with BIS monitor. From 60 - 40

  5. Respiratory rate [ Time Frame: Every 30 minutes. Since entering the recovery room up to 180 mins. ]
    bpm

  6. Numeric Pain Rating Scale [ Time Frame: Every 30 minutes. Since entering the recovery room up to 180 mins. ]
    Numeric Pain rating scale in rest and movement, from 0 (no pain) to 10 (maximum pain).

  7. Nausea or vomiting [ Time Frame: Every 30 minutes. Since entering the recovery room up to 180 mins. ]
    Presence of nausea or vomiting in the recovery room.

  8. Sedation (Ramsay Scale) [ Time Frame: Every 30 minutes. Since entering the recovery room up to 180 mins. ]
    Ramsay scale (1-6)

  9. Respiratory depression [ Time Frame: Every 30 minutes. Since entering the recovery room up to 180 mins. ]
    Presence of respiratory depression in the recovery room. (Respiratory rate less than 8 bpm requiring oxygen therapy).

  10. Other opioids and pain management drugs used during recovery stay [ Time Frame: Since the admission to the recovery room up to 2 hours. ]
    Name and total doses, including Morphine PCA.

  11. Intestinal transit recovery [ Time Frame: Since the admission to the recovery room up to 2 hours. ]
    Time to first flatus, fist bowel movement and stool. Presence of abdominal bloating.


Other Outcome Measures:
  1. Body fat [ Time Frame: Once, before the anesthetic induction in the operating toom. ]
    Body fat (kilograms) by body impedance analysis.

  2. Level of satisfaction with pain management: 10-point scale [ Time Frame: Since the admission to the recovery room up to 2 hours. ]
    10-point scale: very unsatisfied to very satisfied.

  3. Lean Mass [ Time Frame: Once, before the anesthetic induction in the operating toom. ]
    Lean mass (kilograms) by body impedance analysis.

  4. Total water [ Time Frame: Once, before the anesthetic induction in the operating toom. ]
    Total water (kilograms) by body impedance analysis.



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Ages Eligible for Study:   18 Years to 105 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04526236


Contacts
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Contact: Victor Contreras, MSN 2223439217 vecontre@uc.cl
Contact: Maria F Elgueta, MD 222343270 panchielgueta@gmail.com

Locations
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Chile
Pontificia Universidad Católica de Chile Recruiting
Santiago, Metropolitana, Chile, 8320000
Contact: Victor Contreras, MSN    +5698420525      
Contact: María F. Elgueta, MD    +56962187863    panchielgueta@gmail.com   
Sponsors and Collaborators
Pontificia Universidad Catolica de Chile
Investigators
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Principal Investigator: Maria F Elgueta, MD Associate Professor
  Study Documents (Full-Text)

Documents provided by Pontificia Universidad Catolica de Chile:
Publications:

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Responsible Party: Pontificia Universidad Catolica de Chile
ClinicalTrials.gov Identifier: NCT04526236    
Other Study ID Numbers: 190510001
First Posted: August 25, 2020    Key Record Dates
Last Update Posted: April 1, 2021
Last Verified: March 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Pontificia Universidad Catolica de Chile:
Methadone
Elderly
Postoperative Pain
Additional relevant MeSH terms:
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Pain, Postoperative
Postoperative Complications
Pathologic Processes
Pain
Neurologic Manifestations
Methadone
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Antitussive Agents
Respiratory System Agents