Pharmacokinetics of Oral Morphine and Pharmacogenomics of CYP2D6 and UGT2B7, in an Urban Pediatric Population Presenting for Elective Surgery
Condition: Pain
Study type: Interventional
Phase: Phase 2/Phase 3

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.
    

Intervention name(s): Morphine; Morphine; Morphine
Intervention type(s): Drug; Drug; Drug
Intervention description(s): One dose of morphine (0.1 mg/kg); One dose of morphine (0.2 mg/kg); One dose of morphine (0.3 mg/kg)
Intervention MeSH terms: Morphine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Other
Keywords: pharmacokinetics; pharmacogenetics; morphine; children