Clinical trial NCT01071499: Pharmacokinetics of Oral Morphine and Pharmacogenomics of CYP2D6 and UGT2B7, in an Urban Pediatric Population Presenting for Elective Surgery
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Pain
Keywords: pharmacokinetics
pharmacogenetics
morphine
children
Lead sponsor: University of British Columbia
Sponsor class: OTHER
First posted: 2010-02-19
Enrollment: 43
Sex: ALL
Minimum age (years): 2
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

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.

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

Primary outcomes:
measure: 1 mL blood sample will be obtained at 30, 60, 90, 120, 180 and 240 min after morphine administration.
timeFrame: 4 hours
Secondary outcomes:
measure: Face, Legs, Activity, Cry and Consolability (FLACC) pain score
timeFrame: 4 hours
Other outcomes:
Locations:
city: Vancouver
country: Canada
facility: British Columbia Children's Hospital-Dept of Anesthesia
state: British Columbia
Study officials:
affiliation: University of British Columbia
name: Carolyne Montgomery, Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of British Columbia
name: Gillian Lauder, Dr.
role: STUDY_DIRECTOR
affiliation: University of British Columbia
name: Katherine Brand, Dr.
role: STUDY_DIRECTOR
affiliation: University of British Columbia
name: Bruce Carleton, Dr.
role: STUDY_DIRECTOR
affiliation: University of British Columbia
name: Gideon Koren, Dr.
role: STUDY_DIRECTOR
affiliation: University of British Columbia
name: Michael Rider, Dr.
role: STUDY_DIRECTOR
References:
citation: 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.