Treatment of Neonatal Abstinence Syndrome
Condition: Neonatal Abstinence Syndrome
MeSH terms: Neonatal Abstinence Syndrome; Syndrome
Study type: Interventional
Phase: Phase 4

Summary: 
      This study compares treatment of Neonatal Abstinence Syndrome (NAS) with two different drugs
      for the difference in the length of treatment. This is a randomized, open-label comparison of
      phenobarbital and methadone versus phenobarbital and diluted deodorized tincture of opium
      (dDTO) where phenobarbital is the initial drug used to stabilize neonatal withdrawal.
    

Detailed description: 
      a.Procedures: NAS scoring is currently done on infants meeting the inclusion criteria [IDD
      29:070]. NAS scores are initially done every 2 hours for 24 hours and then every 4 hours when
      awake or before feeding for the duration of observation or treatment.

      i. NAS scores may indicate more than withdrawal. Conditions such as colic, reflux, or
      baseline irritability may influence the baseline scores. Decisions made based on the NAS
      scores should take into account these factors and the baseline for the infant.

      b.Emergence of symptom, dosing, and initiation of treatment: Withdrawal is defined as at
      least 2 NAS scores >8 or 1 NAS score >12. Once withdrawal has emerged, the infant will be
      given: i. Phenobarbital 20 to 30 mg/kg to load divided in up to 3 doses over 24 hours and
      maintenance phenobarbital should be started at 2.5 mg/kg/dose administered Q 12h, 12 hours
      after the loading dose is ended. NAS scoring is continued and if scores remain <8 for a
      minimum of 5 days after starting phenobarbital, the infant is eligible for discharge.

      ii. If after phenobarbital treatment has been started, at least 2 NAS scores >8 or 1 NAS
      score >12, then a phenobarbital level will be drawn and a mini-load calculated to reach a
      level of 30 mg/dl. If withdrawal is not controlled or re-emerges after the mini-load dose,
      the infant will be randomized to one of the two arms of the study - methadone or dDTO.

      iii. Twins will be randomized together to the same arm. iv. Randomization will be stratified
      into mothers on narcotic treatment >3 months and those not in treatment or <3 months.
      Randomization will be done in blocks of 10 for each stratum.

      v. For both drugs, the neonatal preparation will be used. vi. The following is a dosing guide
      for methadone:

        1. The neonatal concentration is 1 mg/ml of methadone. It is administered orally every 12
           hours - standardized eventually to 0900 and 2100.

        2. For the first 24 hours, doses will be prescribed every 6 hours for 4 doses, using a
           sliding scale in response to the last NAS score:

           NAS Score Methadone dose 8-11 0.05 mg/kg/dose 12-15 0.1 mg/kg/dose >16 0.15 mg/kg/dose

        3. Maximum loading dose of methadone will be 0.15 mg/kg/dose Q 6 hour

        4. After the first 24 hours of treatment, the total methadone dose will be summed and that
           dose divided into two doses, given 12 hours apart. Subsequently, PRN doses of 0.05
           mg/kg/dose may be given every 6 hours for scores >8 X 2 and added to the next 24 hour's
           doses, divided every 12 hours, until NAS scores are consistently <8 for 48 hours.

        5. If at any point the maximum dose of methadone is reached and withdrawal is not
           controlled, then in the opinion of two neonatologists the patient can be crossed-over to
           the dDTO arm.

      vii. The following is a dosing guide for dDTO:

        1. The neonatal concentration is 1:24 dilution for a concentration of 0.4%, equivalent to
           0.4 mg/ml of morphine. It is administered orally every 4 hours - standardized eventually
           to 0400, 0800, 1200, 1600, 2000, 0000.

        2. The starting dose is determined by using a sliding scale in response to the last NAS
           score before starting:

           NAS Score dDTO dose 8-11 0.1 mg/kg/day 12-15 0.15 mg/kg/day >16 0.2 mg/kg/day

           For next day, the maintenance dose will return to the previous dose and given in 6
           divided doses given Q 4 hours.

           iv. For either methadone or dDTO, dosing will be held at this level and weaning will be
           resumed when the infant has NAS scores <8 for 48 hours.

           e. Holding of doses: Methadone or dDTO will be held for poor feeding, respiratory
           depression, or somnolence at any time in the protocol.

           f. Behavioral assessment: Behavioral assessment will be done by two methods. The first
           by actigraphy and the second by NINS, both during the second week of weaning. The latter
           will be done prior to a scheduled phenobarbital dose.

           g. Formula: A 24 kcal/ounce formula should be fed initially using either standard
           formula or by adding breast milk fortifier. During the weaning period, when weight gain
           is >30 grams/day for at least 2 days, formula will be changed to 20 kcal/ounce and
           weight gain monitored. If not sustained, then formula should be changed back to 24
           kcal/ounce.
    

Intervention name(s): Methadone; Diluted Deodorized Tincture of Opium
Intervention type(s): Drug; Drug
Intervention description(s): Concentration is 1mg/mL administered every 12 hours given on sliding scale in response to last NAS score.; Concentration is 1:24 dilution for a concentration of 0.4%
Other intervention name(s): Dolophine; Laudanum
Intervention MeSH terms: Methadone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Neonatal Abstinence Syndrome; Methadone; Diluted Deodorized Tincture of Opium; dDTO; Phenobarbital