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

This study has been completed.
Sponsor:
Collaborators:
University of Colorado, Denver
Oregon Health and Science University
Information provided by (Responsible Party):
Gregory Hammer, Stanford University
ClinicalTrials.gov Identifier:
NCT01094522
First received: March 25, 2010
Last updated: June 5, 2012
Last verified: June 2012
  Purpose

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.


Condition Intervention Phase
Pain
Drug: Methadone
Drug: Morphine
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Stanford University:

Primary Outcome Measures:
  • Pharmacokinetics [ Time Frame: 24 hours ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Pharmacodynamics [ Time Frame: 24 hrs ] [ Designated as safety issue: Yes ]

Enrollment: 48
Study Start Date: March 2010
Study Completion Date: June 2012
Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: MS

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
  Eligibility

Ages Eligible for Study:   up to 5 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.

  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01094522

Locations
United States, California
Stanford University School of Medicine
Stanford, California, United States, 94305
United States, Colorado
University of Colorado
Denver, Colorado, United States
United States, Oregon
Oregon Health & Sciences University
Portland, Oregon, United States, 97239
Sponsors and Collaborators
Stanford University
University of Colorado, Denver
Oregon Health and Science University
Investigators
Principal Investigator: Gregory Hammer Stanford University
  More Information

No publications provided by Stanford University

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Gregory Hammer, Professor of Anesthesia and Pediatrics, Stanford University
ClinicalTrials.gov Identifier: NCT01094522     History of Changes
Other Study ID Numbers: SU-03012010-5083, IRB Protocol # 16739
Study First Received: March 25, 2010
Last Updated: June 5, 2012
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Morphine
Methadone
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Pharmacologic Actions
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Central Nervous System Agents
Therapeutic Uses
Antitussive Agents
Respiratory System Agents

ClinicalTrials.gov processed this record on October 16, 2014