1. Methadone vs. Morphine in the Treatment of Neonatal Abstinence Syndrome: A Randomized Clinical Trial
Jonathan Davis, MD
Chief of Newborn Medicine
The Floating Hospital for Children at Tufts Medical Center
Professor of Pediatrics
Tufts University School of Medicine

2. Neonatal Abstinence Syndrome (NAS)
NAS is a complex disorder with many factors contributing to the incidence & severity
There is significant variability in NAS expression, especially with the need and response to treatment
Concerns about safety and efficacy of NAS treatments; no pharmacologic therapy is approved by the FDA
Significant uncertainty - who to treat, when to treat, how to treat, how to wean, and the optimal agent(s)
Current treatments of NAS are costly & require lengthy hospitalization - we need to establish best practices

3. Improving Outcome in NAS
Randomized, double-blind, intent to treat clinical trial
Infants born to mothers receiving methadone or buprenorphine for an OUD or opioids for chronic pain (CoC issued by FDA)
Treatment initiated if Finnegan scores ≥ 8 for 2 consecutive scores (4h apart), or ≥ 12 for 1 score
Infants randomized to morphine (preservative free) or methadone (compounded powder)
Length of hospital stay and treatment were measured
Bayley III Neurodevelopmental Examinations at months

4. Methods
Concerns by FDA over 10% alcohol content in commercial methadone solution
Required methadone powder to be compounded (DEA approval)
Needed to hire GLP Laboratory (Boston Analytical)
Testing protocol developed and approved by FDA
Took 1 year and approximately $20,000 to complete
Solution needed to be stable for 2 weeks after compounding
Extensive stability testing (pH, Assay, Appearance, Impurities and Microbial Enumeration Testing and Absence of Specified Organisms)
Primary outcome – relative mean number of days; adjusted for by site and maternal opioid

6. Methadone:Morphine Relative Mean Number of Days
Length of Stay: 14% lower with methadone treatment (95% CI 0, 26%); difference of 2.9 days (p=0.046)
Length of Stay Due to NAS: 14% lower with methadone treatment (95% CI 3, 23%); difference of 2.7days (p=0.01)
Length of Treatment: 14% lower in methadone treated infants (95% CI 3, 27%); a difference of 2.3 days (p=0.02)
Phenobarbital Use: 17.2% with methadone treatment vs. 29.7% with morphine (p=0.07)

7. Conclusions
Short term outcomes were better with 3x/day methadone than 6x/day morphine
A safe neonatal formulation for methadone is needed
Only 13 adverse events were recorded (equal between groups) and responded well to dosage decreases
Longer term follow-up shows no differences
Most mothers refused to participate – didn’t like methadone or confidentiality language used in consent
Data will be submitted to FDA for approval of these drugs for the treatment of NAS