Pharmacokinetics of Oral Morphine and Pharmacogenomics of CYP2D6 and UGT2B7, in an Urban Pediatric Population Presenting for Elective Surgery

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2012 by University of British Columbia
Sponsor:
Information provided by (Responsible Party):
University of British Columbia
ClinicalTrials.gov Identifier:
NCT01071499
First received: February 17, 2010
Last updated: September 25, 2012
Last verified: September 2012
  Purpose

The purpose of this study is to identify and collect samples from children who have taken a single oral dose of the pain medication morphine, and to determine the genetic differences in the way children metabolize (break down in the body and how it affects them) morphine.


Condition Intervention Phase
Pain
Drug: Morphine
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Official Title: Pharmacokinetics of Oral Morphine and Pharmacogenomics of CYP2D6 and UGT2B7, in an Urban Pediatric Population (2 - 6 Years of Age) Presenting for Elective Surgery

Resource links provided by NLM:


Further study details as provided by University of British Columbia:

Primary Outcome Measures:
  • 1 mL blood sample will be obtained at 30, 60, 90, 120, 180 and 240 min after morphine administration. [ Time Frame: 4 hours ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Face, Legs, Activity, Cry and Consolability (FLACC) pain score [ Time Frame: 4 hours ] [ Designated as safety issue: No ]

Estimated Enrollment: 45
Study Start Date: March 2010
Estimated Study Completion Date: December 2012
Estimated Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 1
Subjects recruited will be block assigned to one of the three doses of morphine. Sampling will be done for 4 hrs to determine the key pharmacokinetic parameters.
Drug: Morphine
One dose of morphine (0.1 mg/kg)
Active Comparator: 2
Subjects recruited will be block assigned to one of the three doses of morphine. Sampling will be done for 4 hrs to determine the key pharmacokinetic parameters.
Drug: Morphine
One dose of morphine (0.2 mg/kg)
Active Comparator: 3
Subjects recruited will be block assigned to one of the three doses of morphine. Sampling will be done for 4 hrs to determine the key pharmacokinetic parameters.
Drug: Morphine
One dose of morphine (0.3 mg/kg)

Detailed Description:

Hypothesis:

Oral morphine will produce more reliable peak plasma morphine concentrations and more reliable analgesia than codeine, which is currently the drug of choice.

Background:

Codeine is the most commonly used oral opiate for analgesia in children. Codeine is a pro-drug that requires activation by the isozyme CYP2D6. Genetically determined variations in the activity of CYP2D6 can result in inappropriately low analgesic efficacy due to inadequate conversion of the drug in "poor-metabolizers" and conversely, adverse reactions such as respiratory depression and death in "ultra-metabolizers". In some ethnic groups as many as 40% of patients may be susceptible to concentration-dependent toxicity from greater than expected metabolism of codeine to morphine. We hypothesize that oral morphine is a feasible and safe alternative to codeine. The primary aim of this study is to define and trial an appropriate dose of morphine to provide children with effective and reliable perioperative analgesia with a minimum risk of adverse drug effects. A secondary aim is to investigate the pharmacogenetics of codeine and morphine metabolism in children.

Specific Objectives:

The pharmacokinetic properties of 3 (0.1 mg/kg, 0.2 mg/kg or 0.3 mg/kg) doses of oral morphine will be described. We will determine the dose of oral morphine that results in a peak plasma concentration that occurs within 60 - 90 min and results in the analgesic therapeutic range (10 - 40 ng/mL). Pharmacogenetic profiles for two key enzymes involved in codeine and morphine metabolism (CYP2D6 and UGT2B7) will be determined.

Methods:

After obtaining institutional review board approval, and written parental informed consent, we will recruit 45 children for Phase I aged 2-6 years undergoing elective surgery. A perceived ethnicity questionnaire will also be administered. Subjects recruited for Phase I will be block assigned to one of the three doses of morphine. In Phase I, sampling will be done for 4 hrs to determine the key pharmacokinetic parameters including Tmax, Cmax and AUC. Monitoring will occur throughout and analgesic efficacy and adverse effects will be measured post-operatively. All subjects will receive 24 hr telephone follow up for analgesic efficacy and adverse drug effects.

Data Analysis: All continuous parametric data (weight, age, BMI) will be analyzed using t-tests. Non-parametric ordinal data such as pain scores will be analyzed by the Mann-Whitney U test.

  Eligibility

Ages Eligible for Study:   2 Years to 6 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • 2 - 6 years of age
  • ASA 1 & 2 elective surgical patients - Procedures requiring opioid analgesia - Minimal hospital stay of 4 hrs
  • Informed consent

Exclusion Criteria:

  • Allergy or adverse reaction to morphine
  • Contraindication to morphine analgesia, such as a potential difficult airway -- Abnormal hepatic or renal function known by history or available laboratory results
  • Current regular opioid use
  • Surgical or anesthetic contraindication to oral premedication such as gastro-esophageal reflux disease
  • Children with a BMI of <10'ile or >90'ile
  • Declines study participation
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01071499

Contacts
Contact: Joanne Lim 604-875-2000 ext 6669 jlim2@cw.bc.ca

Locations
Canada, British Columbia
British Columbia Children's Hospital-Dept of Anesthesia Recruiting
Vancouver, British Columbia, Canada, V6H 3V4
Contact: Carolyn Montgomery       cmontgomery@cw.bc.ca   
Contact: Joanna Lim       jlim2@cw.bc.ca   
Principal Investigator: Carolyne Montgomery         
Sponsors and Collaborators
University of British Columbia
Investigators
Principal Investigator: Carolyne Montgomery, Dr. University of British Columbia
Study Director: Gillian Lauder, Dr. University of British Columbia
Study Director: Katherine Brand, Dr. University of British Columbia
Study Director: Bruce Carleton, Dr. University of British Columbia
Study Director: Gideon Koren, Dr. University of British Columbia
Study Director: Michael Rider, Dr. University of British Columbia
  More Information

No publications provided

Responsible Party: University of British Columbia
ClinicalTrials.gov Identifier: NCT01071499     History of Changes
Other Study ID Numbers: H09-03286
Study First Received: February 17, 2010
Last Updated: September 25, 2012
Health Authority: Canada: Health Canada

Keywords provided by University of British Columbia:
pharmacokinetics
pharmacogenetics
morphine
children

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

ClinicalTrials.gov processed this record on July 20, 2014