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 52 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, CYP2B6, CYP2C8, CYP2c19, and CYP2D6 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.

• Pain
• Analgesia
• Newborn

• Drug: Methadone
  Methadone HCl oral solution 5 mg/ml Methadone HCl inject 10 ml/ml (will require dilution)
  Other Name: Dolophine, Methadose, Methadose Oral
• Drug: Methadone
  Methadone HCl oral solution 5 mg/ml Methadone HCl inject 10 ml/ml (will require dilution) Single dose
  Other Name: Dolophine, Methadose, Methadose Oral

• Scheme 1: Experimental
  Patients who are feeding or not feeding and mechanically ventilated, 1 week or more of age and at 29 0/7wks to 48 6/7 wks PMA, treated with i.v. bolus doses of methadone, fentanyl or morphine with an arterial or venous line in place for sampling will be studied for 36 hr. Sampling will include 6 pK samples of 0.5 ml of blood/sample for infants 1.5-2.699kg and 6 pK samples of 1.0 ml of blood/sample for infants >2.699 kg. ECG monitoring will occur prior to study dose administration to determine a baseline recording. Three patients will be enrolled in each of the following groups 1A, 1B, 1C, 1D, 1E based on PMA. Should ventilation need to occur or hypotension requiring treatment, dosages for Treatment Scheme 2 will be reduced (50%) and additional patients will be studied in Treatment Scheme 1 to insure that the lower parenteral dose is well tolerated and effective.
  Intervention: Drug: Methadone
• Scheme 2: Experimental
  Patients 29 0/7wks to 48 6/7 wks PMA, with i.v. bolus doses of methadone, fentanyl or morphine, with an arterial or venous line in place for sampling, tolerating feeds for at least 3 days before study and will be studied twice, once after i.v. methadone and once after enteral methadone, separated by 24hrs after the end of sampling after the first dose. 4-5 samples will be obtained after the 1st dose and 5-6 samples after the 2nd dose depending on PMA and weight. Patients will be divided into 12 groups based on PMA and sampling times. Groups are numbered to indicate their sampling schedule (2, 3, 4, 5), followed by an alphabetical letter to indicate PMA (G, H, J, K, L with "I" omitted since it will look like the number 1), followed by the number 1 or 2 to indicate whether this follows dose 1 or 2.
  Intervention: Drug: Methadone

Inclusion Criteria:

1. Patients must be in the NICU or PICU with continuous cardiorespiratory monitoring
2. PMA between 29 0/7 to 48 6/7 weeks (EGA at birth (wks) + postnatal age wks) at the start of study
3. Weight >1499 gm at the time of enrollment
4. Postnatal age of 1 week or more
5. Arterial or venous catheter suitable for blood sampling with a separate i.v. infusion site is preferred, but not essential
6. Currently being treated with methadone bolus doses or fentanyl or morphine in bolus doses or by infusion for clinical indications and expected to be treated for at least 1-2 more days with opioids for study of single dose pharmacokinetics and to be treated for 3-5 days more during the study of bioavailability
7. Hematocrit ≥35%
8. Parental permission

9. Approval by the patient's attending physician

   Treatment Scheme 1, studied for 48 hours, 12 hour ECG before a dose and 36 hour ECG and kinetic sampling after a single i.v. dose of methadone

10. Feeding or not feeding

11. Mechanically ventilated

    Treatment Scheme 2, studied for 24 to 48 hours after a single i.v. dose of methadone AND again after a single enteral dose of methadone at least 24 hours after the end of sampling after the first dose; order of doses is randomized

12. Tolerating enteral feeding for 3 consecutive days before study

Exclusion Criteria:

1. Liver dysfunction with ALT or AST >2x ULN
2. Gastrointestinal malformation or dysfunction that might interfere with enteral drug absorption
3. Congenital anomalies or other conditions thought to be incompatible with life
4. Arrhythmias, excluding bradycardia associated with apnea
5. Unstable cardiorespiratory status
6. Serum K+ <3.0 mEq/L
7. QTc[H] >0.449 ms using Hodges correction =QT + 1.75(rate - 60)
8. Family history of unexplained early cardiac deaths, syncope, or long QT syndrome in primary relatives: siblings, parents, grandparents, or aunts/uncles
9. Treatment with inhibitors and inducers of CYP3A4, CYP2B6, CYP2D6 and PGP including: amiodarone, carbamazepine, ciprofloxacin, clarithromycin, clotrimazole, dexamethasone, erythromycin, ethosuximide, fluconazole, fluoxetine, fluvoxamine, grapefruit juice, indinavir, itraconazole, ketoconazole, metronidazole, miconazole, nelfinavir, paroxetine, phenobarbital, phenytoin, quercetin, quinidine, rifabutin rifampin, ritonavir, saquinavir, sulfadimidine, sulfinpyrazone, troleandomycin

• Children's Research Institute
• Children's Hospital of Philadelphia
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)