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

NCT ID: NCT01071499

Last Updated: 2017-07-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 43 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-03-31
• Study Completion Date: 2012-11-30

Brief Summary

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.

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.

Conditions

Pain

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: OTHER
• Blinding Strategy: NONE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Morphine

Intervention Type: DRUG

One dose of morphine (0.1 mg/kg)

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.

Group Type: ACTIVE_COMPARATOR

Morphine

Intervention Type: DRUG

One dose of morphine (0.2 mg/kg)

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.

Group Type: ACTIVE_COMPARATOR

Morphine

Intervention Type: DRUG

One dose of morphine (0.3 mg/kg)

Interventions

Morphine

One dose of morphine (0.1 mg/kg)

Intervention Type: DRUG

Morphine

One dose of morphine (0.2 mg/kg)

Intervention Type: DRUG

Morphine

One dose of morphine (0.3 mg/kg)

Intervention Type: DRUG

Eligibility 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

• Minimum Eligible Age: 2 Years
• Maximum Eligible Age: 6 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University of British Columbia

OTHER

Sponsor Role: lead

Responsible Party

Carolyne Montgomery

Principle Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Carolyne Montgomery, Dr.

Role: PRINCIPAL_INVESTIGATOR

University of British Columbia

Gillian Lauder, Dr.

Role: STUDY_DIRECTOR

University of British Columbia

Katherine Brand, Dr.

Role: STUDY_DIRECTOR

University of British Columbia

Bruce Carleton, Dr.

Role: STUDY_DIRECTOR

University of British Columbia

Gideon Koren, Dr.

Role: STUDY_DIRECTOR

University of British Columbia

Michael Rider, Dr.

Role: STUDY_DIRECTOR

University of British Columbia

Locations

British Columbia Children's Hospital-Dept of Anesthesia

Vancouver, British Columbia, Canada

Countries

Canada

References

Velez de Mendizabal N, Jimenez-Mendez R, Cooke E, Montgomery CJ, Dawes J, Rieder MJ, Aleksa K, Koren G, Jacobo-Cabral CO, Gonzalez-Ramirez R, Castaneda-Hernandez G, Carleton BC. A Compartmental Analysis for Morphine and Its Metabolites in Young Children After a Single Oral Dose. Clin Pharmacokinet. 2015 Oct;54(10):1083-90. doi: 10.1007/s40262-015-0256-4.

Reference Type: DERIVED

PMID: 25773480 (View on PubMed)

Other Identifiers

H09-03286

Identifier Type: -

Identifier Source: org_study_id