Measuring the Amount of Methadone or Morphine in the Blood of Neonates, Infants & Children After Cardiac Surgery.

A Randomized, Double-blind, Controlled, Multi-site Study of the Pharmacokinetics and Pharmacodynamics of Methadone vs. Morphine During Mechanical Ventilation Following Cardiac Surgery in Neonates, Infants and Children

Study Population:

Neonates, infants and children from birth to 5 years of age undergoing cardiac surgery with CPB.

The use of methadone to provide analgesia may be increasing due to advantages compared to other commonly used opioid analgesic drugs. While efficacy of methadone has been reported in adults, there is a paucity of information in neonates and infants. In the latter population, fentanyl and morphine are most commonly used for opioid analgesia following major surgery, while methadone is frequently used for weaning of opioid dependent and tolerant patients, in spite of the paucity of knowledge of methadone pharmacology in this population. There are several clinical problems associated with fentanyl and morphine, and methadone may offer superior efficacy with fewer side effects than these agents. We propose to study the pharmacokinetics (PK) and pharmacodynamics (PD) of methadone in neonates and infants in the intensive care unit following cardiac surgery.

Study Overview

• Status: Completed
• Conditions: Pain
• Intervention / Treatment: Drug: Methadone; Drug: Morphine

Detailed Description

Treatment:

Fentanyl will be administered for intraoperative analgesia by the treating anesthesiologist in a dose range of 25 - 50 mcg/kg. No other intraoperative opioids will be given.

Subjects will receive intravenous methadone or morphine ("study drug") delivered by an initial IV "bolus" injection followed by a nurse-administered patient controlled analgesia (PCA) device for postoperative pain for a period of 24 hours. The initial dose of study drug will be 0.2 mg/kg IV administered following admission to the ICU after surgery. The study drug will then be given at a dose of 0.035 mg/kg IV as needed q30min via PCA. The study drug may be increased or decreased in increments of 20-25% according to the discretion of the investigator as needed to maintain a FLACC pain assessment tool < 4. Subjects will also receive lorazepam 0.025 mg/kg IV q2hr as needed for agitation as indicated by specific criteria. The study drug will be discontinued after 24 hours to facilitate "wash out" sampling and determination of elimination half-life. Beginning at 24 hours, fentanyl will be used for analgesia at an equianalgesic dose to be determined by the investigator based upon the current PCA "study drug" dose.

Measurements and Monitoring:

• Blood samples will be obtained for measurement of concentrations of methadone (methadone group) and morphine and its metabolites, morphine-3-glucuronide and morphine-6-glucuronide (morphine group), prior to administration of initial bolus dose (t = 0) and t = 5 min, 15 min, 30 min, 60 min, 2 hrs, 4 hrs and 6 hrs; thereafter, blood samples will be obtained for measurement every 6 hrs for up to 90 hrs according to availability of vascular access for phlebotomy.
• Continuous monitoring: temperature (rectal), electrocardiogram, heart rate, systemic arterial blood pressure, central venous blood pressure, respiratory rate, oxygen saturation (pulse oximetry)
• Intermittent recording (q1hr): urine output
• Lab Tests (at baseline[prior to study procedures] and 24 hours after initial dose of study medication): arterial blood gas tensions, arterial lactate, Hb/Hct, BUN/Cr, glucose, AST, ALT
• 12 lead ECG at hour 24 for determination of QTc.
• The Faces, Legs, Activity, Cry, Consolability (FLACC) Scale recoded every hour, and preceding every study medication PCA dose for 24 hours.
• Subject follow up at 90 hours to record time of extubation, re-intubation if necessary, and reason for re-intubation.

Primary Endpoints: Pharmacokinetics of methadone and morphine, including its metabolites (morphine-3-glucuronide and morphine-6-glucuronide)

Secondary Endpoints:

• Pain scores (FLACC) during the 24 hours study period
• Amount of study drug administered during the 24-hour dosing period
• Changes in heart rate, systemic arterial blood pressure and laboratory test values

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University School of Medicine
  • Colorado
    • Denver, Colorado, United States
      • University of Colorado
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Sciences University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 5 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Neonates, infants and children from birth through 5 years of age undergoing mechanical ventilation following cardiac surgery for congenital heart disease. Congenital heart lesions include "two ventricle repairs", including tetralogy of Fallot, transposition of the great arteries, "unobstructed" total anomalous pulmonary venous return, truncus arteriosus, atrioventricular canal defect and ventricular septal defect.

Exclusion Criteria:

Subjects will be excluded from the study because of prematurity (gestational age < 37 weeks), weight < 3.0 kg, severe hepatic dysfunction (elevation of conjugated bilirubin > 2, AST/ALT > 200 IU/L), significant renal dysfunction (serum Cr > 1.5 mg/dL), participation within 30 days of study entry or within 5 times the half-life, whichever is longer, in another investigational drug study, or previous participation in this study. Patients will be excluded if they have received opioids for more than 12 hours of the 48-hour period prior to surgery. In addition, patients will be excluded if they have a history of other clinically significant medical problems, which, in the opinion of the investigator, would interfere with study participation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Methadone; One half the Study patients will be randomized to receive a loading dose of IV methadone, followed by IV doses (given by the ICU nurse), on a PRN basis, for pain control for up to 24 hours during their postoperative course while they are intubated.	Drug: Methadone; 0.2 mg/kg (IV) for the Initial Loading Dose; followed by PRN ("as needed") doses (given by the ICU Nurses) starting at 0.035 mg/kg (IV) every 30 minutes, for postoperative pain. The PRN dose of methadone may be increased by the ICU doctors until the dose is adequate to relieve the patient's pain.
ACTIVE_COMPARATOR: Morphine; One half the Study patients will be randomized to receive a loading dose of IV morphine, followed by IV doses (given by the ICU nurse), on a PRN basis, for pain control for up to 24 hours during their postoperative course while they are intubated.	Drug: Morphine; 0.2 mg/kg (IV) for the Initial Loading Dose; followed by PRN ("as needed") doses (given by the ICU Nurses) starting at 0.035 mg/kg (IV) every 30 minutes, for postoperative pain. The PRN dose of morphine may be increased by the ICU doctors until the dose is adequate to relieve the patient's pain.; Other Names: MS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum Concentration of Morphine Including Its Metabolites (Morphine-3-glucuronide and Morphine-6-glucuronide)	0, 15, 30 minutes, 1, 2, 4, 6 hrs, every 6 hrs up to 24 hrs
Maximum Concentration of Methadone Including Its Metabolites (EDDP and EMDP)	0, 15, 30 minutes, 1, 2, 4, 6 hrs, every 6 hrs up to 24 hrs

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
•Pain Scores (FLACC) During the 24 Hours Study Period	Average of hourly FLACC score for each subject over 24 hours was calculated, followed by median and full range for total subjects in each arm. FLACC (Face, Leg, Activity, Cry, Consolability) score ranges from 0-10 with 0 representing no pain	24 hours
•Amount of Study Drug Administered During the 24-hour Dosing Period		24 hours

Collaborators and Investigators

• Sponsor: Stanford University
• Collaborators: University of Colorado, Denver; Oregon Health and Science University
• Investigators: Principal Investigator: Gregory Hammer, Stanford University

Publications and helpful links

General Publications

• Ward RM, Drover DR, Hammer GB, Stemland CJ, Kern S, Tristani-Firouzi M, Lugo RA, Satterfield K, Anderson BJ. The pharmacokinetics of methadone and its metabolites in neonates, infants, and children. Paediatr Anaesth. 2014 Jun;24(6):591-601. doi: 10.1111/pan.12385. Epub 2014 Mar 26.
• Elkomy MH, Drover DR, Glotzbach KL, Galinkin JL, Frymoyer A, Su F, Hammer GB. Pharmacokinetics of Morphine and Its Metabolites in Infants and Young Children After Congenital Heart Surgery. AAPS J. 2016 Jan;18(1):124-33. doi: 10.1208/s12248-015-9826-5. Epub 2015 Sep 9.

Study record dates

Study Major Dates

• Study Start: March 1, 2010
• Primary Completion (ACTUAL): June 1, 2012
• Study Completion (ACTUAL): June 1, 2012

Study Registration Dates

• First Submitted: March 25, 2010
• First Submitted That Met QC Criteria: March 25, 2010
• First Posted (ESTIMATE): March 29, 2010

Study Record Updates

• Last Update Posted (ACTUAL): September 18, 2017
• Last Update Submitted That Met QC Criteria: August 17, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Respiratory System Agents; Antitussive Agents; Morphine; Methadone
• Other Study ID Numbers: SU-03012010-5083; IRB Protocol # 16739