Project Summary/Abstract The Neonatal Opioid Withdrawal Syndrome (NOWS) Pharmacological Treatments Comparative Effectiveness Trial is a multisite study that examine the long- and short-term outcomes for neonates with NOWS that require pharmacological treatment. The neonates will be randomized to three medications: buprenorphine, methadone and morphine. Short term outcomes are anticipated to include length of hospital stay and length of pharmacological treatment, with longer term outcomes including neonatal growth and neurodevelopment. The common protocol will be developed by a steering committee composed of the principal investigators from each participating clinical center. The trial will be designed to control for relevant clinical variables including the type of maternal opioid used, maternal polysubstance use including tobacco, the use of nonpharmacological treatments for NOWS, and the use of adjunctive nonopioid medications. The follow-up plan will be developed as part of the protocol and will extend until at least 24 months of age and include the use of specific neurodevelopmental assessment tools including the Bayley Scales of Infant and Toddler Development 4th Edition. The trial is designed to determine the optimal pharmacological treatment including the specific medication dosing and weaning regimen. The University of New Mexico Clinical Center will include infants treated for NOWS across all neonatal care sites including the mother baby unit where dyadic room-in care is provided, the intermediate care nursery, and the neonatal intensive care unit. The standardization of pharmacological treatment for NOWS is anticipated to have significant public health benefits including decreasing length of hospital stay, decreasing cost of treatment, and potentially improving long term neurodevelopmental outcomes.