Clinical trial NCT01723722: Treatment of Neonatal Abstinence Syndrome
Official title: Treatment of Neonatal Abstinence Syndrome: Evaluation of Efficacy of Phenobarbital in Combination With Either Methadone or Diluted Deodorized Tincture of Opium as Stabilizing and Tapering Regiments
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Neonatal Abstinence Syndrome
Keywords: Neonatal Abstinence Syndrome
Methadone
Diluted Deodorized Tincture of Opium
dDTO
Phenobarbital
Lead sponsor: Eastern Maine Medical Center
Sponsor class: OTHER
First posted: 2012-11-08
Enrollment: 40
Sex: ALL
Minimum age (years): 1
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: Inclusion Criteria:

* Evidence of opioid withdrawal clinically as defined by 2 NAS scores \>8 or 1 NAS score \>12 over a 4 to 8 hour time period, AND
* Gestation \>=35 weeks at entry defined by best obstetrical and physical exam criteria, AND
* Medically stable condition, other than in opioid withdrawal, in the opinion of the attending neonatologist, AND EITHER,
* Meconium or urine drug screen positive for opioids on mother or newborn, OR
* Known maternal prescription of opioids for chronic pain management during at least the last trimester of pregnancy, OR
* Known maternal prescription of opioids for treatment of addiction, OR
* Suspected or admitted abuse with opioid drugs
* Infants of mothers with a medical or psychiatric diagnosis will not be excluded, unless the maternal diagnosis precludes informed consent

Exclusion Criteria:

* Gestation \<35 weeks at entry defined by best obstetrical and physical exam criteria.
* Hypoglycemia, hypomagnesaemia, or hypocalcaemia until corrected.
* Serious medical illness such as sepsis, pneumonia, hyperthyroidism, meningitis, intracranial hemorrhage, perinatal depression, or respiratory failure requiring admission to the NICU.
* Evidence of major congenital anomalies or genetic syndromes that impact the neonatal course.

Primary outcomes:
measure: Length of Treatment With Opioid Medication
timeFrame: Up to 12 months
Secondary outcomes:
Other outcomes:
Locations:
city: Bangor
country: United States
facility: Eastern Maine Medical Center
state: Maine
Study officials:
affiliation: Eastern Maine Medical Center
name: Mark S. Brown, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Zankl A, Martin J, Davey JG, Osborn DA. Opioid treatment for opioid withdrawal in newborn infants. Cochrane Database Syst Rev. 2021 Jul 7;7(7):CD002059. doi: 10.1002/14651858.CD002059.pub4.