Influence of Aging on Perioperative Methadone Dosing

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.

Study Overview

• Status: Completed
• Conditions: Pain, Postoperative; Opioid Use; Methadone Overdose of Undetermined Intent
• Intervention / Treatment: Drug: Methadone Injectable Product

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 Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Victor Contreras, MSN; Phone Number: 2223439217; Email: vecontre@uc.cl
• Study Contact Backup: Name: Maria F Elgueta, MD; Phone Number: 222343270; Email: panchielgueta@gmail.com

Study Locations

• Chile
  • Metropolitana
    • Santiago, Metropolitana, Chile, 8320000
      • Pontificia Universidad Catolica de Chile

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 105 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / 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

What is the study measuring?

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.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Body fat	Body fat (kilograms) by body impedance analysis.	Once, before the anesthetic induction in the operating toom.
Level of satisfaction with pain management: 10-point scale	10-point scale: very unsatisfied to very satisfied.	Since the admission to the recovery room up to 2 hours.
Lean Mass	Lean mass (kilograms) by body impedance analysis.	Once, before the anesthetic induction in the operating toom.
Total water	Total water (kilograms) by body impedance analysis.	Once, before the anesthetic induction in the operating toom.

Collaborators and Investigators

• Sponsor: Pontificia Universidad Catolica de Chile
• Investigators: Principal Investigator: Maria F Elgueta, MD, Associate Professor

Publications and helpful links

General Publications

• 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. doi: 10.1097/00000542-199906000-00003.
• Hilmer SN, McLachlan AJ, Le Couteur DG. Clinical pharmacology in the geriatric patient. Fundam Clin Pharmacol. 2007 Jun;21(3):217-30. doi: 10.1111/j.1472-8206.2007.00473.x.
• Gagnon B, Almahrezi A, Schreier G. Methadone in the treatment of neuropathic pain. Pain Res Manag. 2003 Fall;8(3):149-54. doi: 10.1155/2003/236718.
• 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. doi: 10.1097/00000542-199701000-00004.
• Sadean MR, Glass PS. Pharmacokinetics in the elderly. Best Pract Res Clin Anaesthesiol. 2003 Jun;17(2):191-205. doi: 10.1016/s1521-6896(03)00002-8.
• Shafer SL. The pharmacology of anesthetic drugs in elderly patients. Anesthesiol Clin North Am. 2000 Mar;18(1):1-29, v. doi: 10.1016/s0889-8537(05)70146-2.
• Kaiko RF, Wallenstein SL, Rogers AG, Grabinski PY, Houde RW. Narcotics in the elderly. Med Clin North Am. 1982 Sep;66(5):1079-89. doi: 10.1016/s0025-7125(16)31383-9. No abstract available.
• Singleton MA, Rosen JI, Fisher DM. Pharmacokinetics of fentanyl in the elderly. Br J Anaesth. 1988 May;60(6):619-22. doi: 10.1093/bja/60.6.619.
• 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. doi: 10.1097/00000542-198503000-00005.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): September 3, 2019
• Primary Completion (Actual): July 13, 2022
• Study Completion (Actual): July 13, 2022

Study Registration Dates

• First Submitted: August 5, 2020
• First Submitted That Met QC Criteria: August 21, 2020
• First Posted (Actual): August 25, 2020

Study Record Updates

• Last Update Posted (Actual): December 21, 2023
• Last Update Submitted That Met QC Criteria: December 20, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Elderly; Postoperative Pain; Methadone
• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Pain, Postoperative; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Respiratory System Agents; Antitussive Agents; Methadone
• Other Study ID Numbers: 190510001

Drug and device information, study documents

• 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