A Compartmental Analysis for Morphine and Its Metabolites in Young Children After a Single Oral Dose.

Abstract

BACKGROUND AND OBJECTIVES:

Currently, the majority of the surgical procedures performed in paediatric hospitals are done on a day care basis, with post-operative pain being managed by caregivers at home. Pain after discharge of these post-operative children has historically been managed with oral codeine in combination with paracetamol (acetaminophen). Codeine is an opioid, which elicits its analgesic effects via metabolism to morphine and codeine-6-glucuronide. Oral morphine is a feasible alternative for outpatient analgesia; however, the pharmacokinetics of morphine after oral administration have been previously described only sparsely, and there is little information in healthy children.

METHODS:

The clinical trial included 40 children from 2 to 6 years of age, with an American Society of Anaesthesiologists physical status classification of 1 or 2, who were undergoing surgical procedures requiring opioid analgesia. Morphine was orally administered prior to surgery in one of three doses: 0.1 mg/kg, 0.2 mg/kg and 0.3 mg/kg. Blood samples were collected for plasma morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) concentrations at 30, 60, 90, 120, 180 and 240 min after administration. All analyses were performed with the non-linear mixed-effect modelling software NONMEM version 7.2, using the first-order conditional estimation (FOCE) method.

RESULTS:

A pharmacokinetic model was developed to simultaneously describe the plasma profiles of morphine and its metabolites M3G and M6G after a single dose of oral morphine in young children (2-6 years of age). The disposition of morphine, M3G and M6G in plasma was best described by a one-compartment model. M3G and M6G metabolite formation was best described by a delay transit compartment, indicating a delay in the appearance of these two major metabolites.

CONCLUSION:

This model provides a foundation on which to further evaluate the use of oral morphine and its safety in young children. Longer follow-up time for morphine oral doses and incorporation of other important covariates, such as phenotype, will add value and will help overcome the limitations of the presented population pharmacokinetic analysis.

• Authors: Nieves Velez de Mendizabal, Ricardo Jimenez-Mendez, Erin Cooke, Carolyne J Montgomery, Joy Dawes, Michael J Rieder, Katarina Aleksa, Gideon Koren, Carlos O Jacobo-Cabral, Rodrigo Gonzalez-Ramirez, Gilberto Castañeda-Hernandez, Bruce C Carleton
• Journal: Clinical pharmacokinetics (Clin Pharmacokinet) Vol. 54 Issue 10 Pg. 1083-90 (Oct 2015) ISSN: 1179-1926 [Electronic] Switzerland
• PMID: 25773480 (Publication Type: Clinical Trial, Journal Article, Randomized Controlled Trial)

Chemical References

• Analgesics, Opioid
• Morphine Derivatives
• morphine-6-glucuronide
• Morphine
• codeine-6-glucuronide
• Cytochrome P-450 CYP2D6
• morphine-3-glucuronide
• Codeine

Topics

• Administration, Oral
• Analgesics, Opioid (administration & dosage, blood, pharmacokinetics)
• Child
• Child, Preschool
• Codeine (analogs & derivatives, pharmacokinetics)
• Cytochrome P-450 CYP2D6 (genetics, metabolism)
• Female
• Humans
• Male
• Models, Biological
• Morphine (administration & dosage, blood, pharmacokinetics)
• Morphine Derivatives (blood)
• Pain, Postoperative (blood, drug therapy)
• Polymorphism, Genetic
• Tertiary Care Centers