Pharmacokinetics of Morphine and Its Metabolites in Infants and Young Children After Congenital Heart Surgery

Abstract

ABSTRACT. The objective of this study was to characterize morphine glucuronidation in infants and children following cardiac surgery for possible treatment individualization in this population. Twenty children aged 3 days to 6 years, admitted to the cardiovascular intensive care unit after congenital heart surgery, received an intravenous (IV) loading dose of morphine (0.15 mg/kg) followed by subsequent intermittent IV bolus doses based on a validated pain scale. Plasma samples were collected over 6 h after the loading dose and randomly after follow-up doses to measure morphine and its major metabolite concentrations. A population pharmacokinetic model was developed with the non-linear mixed effects software NONMEM. Parent disposition was adequately described by a linear two-compartment model. Effect of growth (size and maturation) on morphine parameters was accounted for by allometric body weight-based models. An intermediate compartment with Emax model best characterized glucuronide concentrations. Glomerular filtration rate was identified as a significant predictor of glucuronide formation time delay and maximum concentrations. Clearance of morphine in children with congenital heart disease is comparable to that reported in children without cardiac abnormalities of similar age. Children 1-6 months of age need higher morphine doses per kilogram to achieve an area under concentration-time curve comparable to that in older children. Pediatric patients with renal failure receiving morphine therapy are at increased risk of developing opioid toxicity due to accumulation of morphine metabolites.

Decreased Morphine Clearance in Neonates With Hypoxic Ischemic Encephalopathy Receiving Hypothermia

“…This is the first study to describe the population pharmacokinetics of morphine and its glucuronide metabolites in neonates with HIE receiving hypothermia. Similar to previous morphine population pharmacokinetic models in neonates without HIE and young children, morphine pharmacokinetics were adequately described by a 2‐compartment model for morphine and 1‐compartment model for each of the metabolites . The major study finding was that morphine clearance was markedly lower in neonates with HIE receiving hypothermia compared with reports in full‐term normothermic neonates <7 days old without HIE .…”

“…For example, the pharmacokinetics of morphine in neonates is already known to be highly variable, and therefore, variation in morphine pharmacokinetics in neonates with HIE receiving hypothermia is expected. In addition, kidney function is known to impact elimination of the active M6G metabolite . However, neonates with HIE receiving hypothermia represent a distinct and vulnerable population from a pharmacologic perspective, and extrapolation of dose strategies from nonasphyxiated, normothermic neonates are likely inappropriate .…”

Drug metabolism in early infancy: opioids as an illustration

“…One-, two-, and three-compartmental models are observed, reflecting differences in sample times. Discrepancy can be observed in clearance values, whereas 10 studies reported morphine values, per kg or scaled (allometric, per 70 kg) [62,[76][77][78][79][80]83,84,86,90], © three studies reported morphine elimination clearances as elimination clearance of the metabolites (M3G and M6G) values [81,82,85].…”

“…This will be preceded by background information concerning pain management in neonates ( © Section 1.1) (targeted indication for these drugs) as well as the patterns of enzyme maturation (Sections 1.2, 2, and 3). Those opioids were selected as both 90 have different metabolic pathways and are transformed by different iso-enzymes. Fentanyl undergoes phase I metabolism (Cytochrome P450 3A4, CYP3A4), whereas morphine undergoes phase II (UDP-glucuronosyltransferase-2B7, UGT2B7) metabolism.…”

Pediatric Cardiac Surgery and Pain Management: After 40 Years in the Desert, Have We Reached the Promised Land?

“…Pediatric patients with renal dysfunction receiving morphine therapy are at increased risk of developing opioid toxicity due to accumulation of morphine metabolites. 42 Remifentanil is a very short-acting, pure mu receptor agonist that is equipotent to fentanyl. Its rapid onset and offset times make it particularly useful for procedural and short-term analgesia and anesthesia.…”