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

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

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 18-24 months

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

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)

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