The Use of Methadone in Newborn Infants
Condition: Premature Birth of Newborn; Critically Ill
MeSH terms: Premature Birth; Critical Illness
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      This proposed investigation will test the following hypotheses: 1) Enzymatic activity of
      CYP2B6 characterized by the formation clearance of methadone to EDDP (CLf,EDDP), is directly
      related to both gestational and postnatal age; 2) variations in the CYP2B6 gene (SNPs) are
      associated with variable activity of the CYP2B6 enzyme (as measured by the formation
      clearance, CLf,EDDP), and 3) the elimination rate of methadone and its major metabolite EDDP
      in neonates is dependent on the glomerular filtration rate and therefore on the stage of
      development (defined by both gestational and postnatal age). The investigators propose to
      develop a PK model for methadone dosing in neonates that takes into account both
      developmental stage and genetic variability. The long-term goal of the proposed
      investigations is to improve dosing of methadone in neonates exposed to opioids in utero or
      post-natally, leading to improved control of their withdrawal syndrome and decreased adverse
      drug reactions associated with the current use of methadone in these vulnerable patients.
      More immediately, the investigators will develop a PK model for methadone dosing based on
      relevant developmental and genetic characteristics. The acquired knowledge based on the
      proposed study will lead to a more efficacious treatment of pain or opiate withdrawal
      syndrome in newborn infants with a decreased chance of adverse drug reactions.
    

Detailed description: 
      The investigators will identify and recruit from the NICU of CNMC 60 preterm neonates
      uniformly distributed with respect to gestational age and encompassing GA's of from 22 to
      less than 43 weeks.

        -  Stratified Selection by Gestational Age (GA): The study neonates will be selected to
           achieve balance in the following GA strata: (22-24 wks, 25-26 wks, 27-28 wks, 29-30 wks,
           31-32 wks, 33-37 wks; 38-43 wks). Stratification will be done to ensure broad
           representation by GA. As described below, analyses will treat GA as a continuous
           variable.

        -  Randomization will assign a newborn infant to group 1 (n=30) or group 2 (n=30).

        -  Study medications: Methadone and inulin administration Blood and urine will be collected
           for the purposes of this research project. Blood will be drawn from the indwelling
           arterial catheter that already is in place for clinical purposes. The amount of blood
           obtained for all study related determinations will be minimized and kept at less than 3
           mL/kg of blood per 48 hour period. The study will last 60 hours for group 1 and 72 hours
           for group.

        -  DNA study 0.3ml whole blood will be collected from each subject

        -  PK study Blood samples (0.2 mL per sample) will be taken in 30 newborn infants at t=0,
           1, 4, 12, 36, 60 h (group 1) after the administration of one dose of methadone, and in
           30 newborn infants at t=0, 2, 8, 24, 48, 72 hr (group 2) after the administration of
           methadone. A total of 1.5 ml of blood will be collected from each subject

        -  Urine Collection Urine samples will be collected from each infant's diaper (wood pulp
           based study diapers) every 3-4 hours over the first 24 hour period or alternatively,
           from an indwelling urinary catheter placed based on clinical indications unrelated to
           the study protocol.
    

Intervention name(s): Methadone; Methadone
Intervention type(s): Drug; Drug
Intervention description(s): If the infant has been treated with morphine than substitute for that one study dose 0.1 mg morphine with 0.1 mg methadone, whereas if the infant has been treated with fentanyl substitute for that one study dose 1 μg fentanyl with 0.1 mg methadone.
Administration of inulin:
Inulin will be administered as a glucose 10%-inulin solution containing 25 gr. inulin/L, at an infusion rate of 0.6 mL/kg/h. After 24 h, the inulin clearance will be calculated.; If the infant has been treated with morphine than substitute for that one study dose 0.1 mg morphine with 0.1 mg methadone, whereas if the infant has been treated with fentanyl substitute for that one study dose 1 μg fentanyl with 0.1 mg methadone.
Administration of inulin:
Inulin will be administered as a glucose 10%-inulin solution containing 25 gr. inulin/L, at an infusion rate of 0.6 mL/kg/h. After 24 h, the inulin clearance will be calculated.
Other intervention name(s): inulin; inulin (Sinistrin)
Intervention MeSH terms: Methadone
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: NICU; Methadone; neonates