Improving Outcomes in Neonatal Abstinence Syndrome
Condition: Neonatal Abstinence Syndrome; Neonatal Opioid Withdrawal
MeSH terms: Neonatal Abstinence Syndrome; Syndrome
Intervention: Neonatal Morphine Solution; Methadone; Phenobarbital
Intervention description: Infants randomized to this arm will receive neonatal morphine solution (0.2mg/mL) for first line therapy. Infants will be scored using the standardized Finnegan scoring system and will be initiated on treatment if they have 2 consecutive scores greater than or equal to 8 or 1 score greater than 12. Dosing will be weight and symptom based. A "double dummy" design will be used - each infant will be ordered for both a methadone/placebo study drug at 0.4 mg/mL and a morphine/placebo study drug at 0.2 mg/mL. Starting doses will range from 0.3mg/kg/day to 0.9mg/kg/day divided every 4 hours depending on the severity of the Finnegan scores. Doses will be increased to a maximum of 0.9mg/kg/day for continued scores generally >8 caused primarily by worsening NAS. Infants will be weaned by 10% of the maximum dose once every 24 - 48 hours and the medication will be discontinued once at 25% of the maximum dose.; Infants randomized to this group will receive methadone oral solution (0.4mg/mL) for first line therapy. Infants will be scored using the standardized Finnegan scoring system and will be initiated on treatment if they have 2 consecutive scores greater than or equal to 8 or 1 score greater than or equal to 12. Dosing will be weight and symptom based. Starting doses will range from 0.3mg/kg/day to 0.9mg/kg/day divided every 8 hours depending on the severity of the Finnegan scores. To maintain blinding of the two study arms, a "double dummy" design will be used - each infant will receive both methadone/placebo study drug at 0.4 mg/mL and a morphine/placebo study drug at 0.2 mg/mL. Doses will be increased to a maximum of 0.9mg/kg/day for continued scores generally >8 caused primarily by worsening NAS as needed. Infants will be weaned by 10% of the maximum dose once every 24-48 hours and the medication will be discontinued once at 25% of the maximum dose.; A second line medication will be added once the infant reaches maximum doses of the study drug (morphine or methadone) for continued scores generally >8. Infants will be loaded with 20mg/kg of phenobarbital with the option to re-load with 10mg/kg q8-12 hours for 2 more doses if needed for continued high scores. Maintenance therapy of 5mg/kg/day will be initiated 12 - 24 hours after the last loading dose. Phenobarbital trough levels will be monitored with goal levels of 20 - 30 mcg/mL.
Phenobarbital will be weaned only after the infant has been weaned off of the study drug. Weaning will begin 48 hours after the study drug has been stopped by 20% of the maximum total daily dose every 3 days for scores <8. An infant may be discharged home 48 - 72 hours after the first wean. The remaining wean will be outlined in the discharge prescription, and followed up on by study staff with the goal of the phenobarbital discontinuation within a 2 week period.
Intervention MeSH terms: Morphine; Methadone; Phenobarbital; Pharmaceutical Solutions
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 117.0
Sex: All
Healthy volunteers: No
Keywords: Neonatal Abstinence Syndrome; Opioids

Summary:

      1: SPECIFIC Aim I: To compare treatment options for neonatal abstinence syndrome (NAS) due to
      in-utero narcotic exposure. One hundred eighty four full-term infants with a diagnosis of NAS
      requiring medications will be studied. Infants will be randomized to receive either morphine
      or methadone. It is hypothesized that morphine treated infants will do better and require
      fewer days in the hospital compared to methadone treated infants.

      2. SPECIFIC Aim II: To evaluate the effects of NAS treatment on long-term neurodevelopmental
      outcome. Infants will be evaluated with development testing at 18 months of age. It is
      hypothesized that morphine treated infants will have better neurodevelopmental outcomes. It
      is also hypothesized that neurobehavioral abnormalities identified at two weeks of age will
      correlate with neurodevelopmental impairment at 18 months.

      3: SPECIFIC Aim III: To determine if common genetic variations in the genes involving
      narcotic action contribute to the severity of NAS. A DNA sample will be obtained from all
      infants and analyzed for differences in 3 key genes. This will then be correlated with
      short-term and long-term outcomes.
    

Eligibility criteria:

        Inclusion criteria:

          1. Mother receiving methadone or buprenorphine (BPH) from a licensed physician or drug
             treatment program, or an opioid prescribed by a licensed health care worker for
             treatment of chronic pain.

          2. Need for treatment of NAS by Finnegan Scoring criteria

          3. Gestational age >37 weeks at birth defined by best obstetrical estimate

          4. Medically stable in the opinion of the Attending Physician

          5. Mother receiving "adequate" or "intermediate" prenatal care from a qualified physician
             or midwife as defined by the Prenatal Care Adequacy Index

          6. Singleton pregnancy

          7. Mother able to provide informed consent

          8. Infant able to take oral medications

        Exclusion criteria:

          1. Gestation <37 weeks at entry defined by best obstetrical estimate

          2. Major congenital abnormalities including genetic syndromes

          3. Serious medical illness such as sepsis, asphyxia, seizures, or respiratory failure

          4. Mother abusing alcohol during pregnancy (average of 3 or more drinks per week in the
             last 30 days)

          5. Multiple gestations

          6. Mother received "inadequate" prenatal care as defined by the Prenatal Care Adequacy
             Index.