Influence of Aging on Perioperative Methadone Dosing

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

Study Description

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.

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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.

Eligibility Criteria

• 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.

Contacts and Locations

Contacts

Contact: Victor Contreras, MSN; 2223439217; vecontre@uc.cl

Contact: Maria F Elgueta, MD; 222343270; panchielgueta@gmail.com

Locations

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

• Principal Investigator: Maria F Elgueta, MD; Associate Professor

  Study Documents (Full-Text)

Documents provided by Pontificia Universidad Catolica de Chile:

Study Protocol and Statistical Analysis Plan  [PDF] August 3, 2020

More Information

Publications:

Sadean MR, Glass PS. Pharmacokinetics in the elderly. Best Pract Res Clin Anaesthesiol. 2003 Jun;17(2):191-205. Review.

Shafer SL. The pharmacology of anesthetic drugs in elderly patients. Anesthesiol Clin North Am. 2000 Mar;18(1):1-29, v. Review.

Minto CF, Schnider TW, Egan TD, Youngs E, Lemmens HJ, Gambus PL, Billard V, Hoke JF, Moore KH, Hermann DJ, Muir KT, Mandema JW, Shafer SL. Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development. Anesthesiology. 1997 Jan;86(1):10-23.

Schnider TW, Minto CF, Shafer SL, Gambus PL, Andresen C, Goodale DB, Youngs EJ. The influence of age on propofol pharmacodynamics. Anesthesiology. 1999 Jun;90(6):1502-16.

Hilmer SN, McLachlan AJ, Le Couteur DG. Clinical pharmacology in the geriatric patient. Fundam Clin Pharmacol. 2007 Jun;21(3):217-30. Review.

Kaiko RF, Wallenstein SL, Rogers AG, Grabinski PY, Houde RW. Narcotics in the elderly. Med Clin North Am. 1982 Sep;66(5):1079-89.

Singleton MA, Rosen JI, Fisher DM. Pharmacokinetics of fentanyl in the elderly. Br J Anaesth. 1988 May;60(6):619-22.

Scott JC, Ponganis KV, Stanski DR. EEG quantitation of narcotic effect: the comparative pharmacodynamics of fentanyl and alfentanil. Anesthesiology. 1985 Mar;62(3):234-41.

Gallagher R. Methadone: an effective, safe drug of first choice for pain management in frail older adults. Pain Med. 2009 Mar;10(2):319-26. doi: 10.1111/j.1526-4637.2008.00551.x. Epub 2009 Jan 16.

Lugo RA, Satterfield KL, Kern SE. Pharmacokinetics of methadone. J Pain Palliat Care Pharmacother. 2005;19(4):13-24. Review.

Gagnon B, Almahrezi A, Schreier G. Methadone in the treatment of neuropathic pain. Pain Res Manag. 2003 Fall;8(3):149-54.

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

• 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:

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