Methadone Pharmacokinetics and Cardiac Effects in Newborns

Overview

The Primary objectives of this proposal are to determine the population kinetics for methadone and its enantiomers in preterm newborns and infants at 29 weeks to 48 weeks post menstrual age (PMA) who are 1 week old and older and establish any correlations of the kinetics with PMA to determine the bioavailability for enterally administered methadone in these newborns and young infants. The secondary objectives of this proposal are to explore possible genotypic changes in CYP3A4-3A7-3A5, CYP2B6, CYP2C8, CYP2C19, and CYP2D6 and PGO on the kinetics of methadone in neonates and young infants and to test the safety of methadone in this population by correlating the plasma concentrations of the methadone enantiomers, S-methadone and R-methadone, with changes in cardiac repolarization by measurement of corrected QT, heart rate, and blood pressure.

Painful procedures are frequent during the NICU care of sick newborns. Newborns are capable of perceiving pain by the time in fetal development when they reach our current limits of viability around 23-24 weeks post menstrual age.1 Painful procedures include suctioning during mechanical ventilation, thoracostomy tube placement, heel lance and venipuncture for blood sampling, and care following surgical procedures such as PDA ligation and bowel resection. Simons et al recently reported on the number of painful procedures in a large NICU in Rotterdam and provided a review of the frequency of such procedures from other NICU's.2 This review shows that before discharge from the NICU, newborns may experience as many as 376 painful procedures and as many as 61 painful procedures in a single day (or more if all procedures were not observed or reported). The most frequent procedures were heel lance and suctioning, both associated with the need for mechanical ventilation. Topical treatment of pain from heel lance has not been successful with EMLA3 or tetracaine.4 During initial NICU care for infants supported with mechanical ventilation, systemic analgesia is usually provided with parenteral treatment with fentanyl or morphine. Most neonates are extubated soon after birth, and continued systemic treatment with analgesics is not needed. Other neonates have problems associated with chronic pain or continued painful procedures, such as surgical problems, chronic lung disease, airway anomalies, pulmonary hypoplasia and pulmonary hypertension following ECMO and congenital diaphragmatic hernia repair. These patients often require mechanical ventilation for weeks and sometimes months. During that prolonged care, systemic analgesia is changed to enteral dosing to reduce risks of infection associated with central catheters and to reduce the number of intravenous catheter insertions. Morphine and fentanyl administered enterally do not provide reliable systemic concentrations and effects due to first-pass metabolism. Fentanyl undergoes first-pass metabolism by CYP3A4 during passage through the intestines and liver. Morphine undergoes first pass hepatic metabolism primarily by UGT2B7. In addition for morphine, one of its major metabolites, the 3-glucuronide, is anti-analgesic and can cause dysphoria. An effective and well-characterized systemic analgesic that can be administered enterally is needed for the care of infants who require prolonged analgesic treatment and methadone can meet those needs. Methadone treatment in adults provides effective systemic analgesia after enteral administration through binding to the mu opioid receptor with a wide range of reported half-lives of 5 to 130 hrs,5 2 to 50 hrs,6 and 33 to 46 hrs; 7 and bioavailability ranging from 41 to 95%.8, 9 Recently, methadone was reported to prolong QTc in adults receiving large doses of methadone during chronic treatment, often with additional predisposing factors for QT prolongation. Methadone is dispensed in a racemic mixture whose enantiomers have different potency for analgesia and for binding to the myocardium to potentially prolong QT. In addition the different enantiomers exhibit complex kinetics in adults as they undergo metabolism, primarily by CYP3A4, CYP2B6, and CYP2C19. This study will evaluate kinetics and bioavailability of methadone enantiomers and its effects on QT of neonates and young infants.