Project Summary Many infants exposed to opioids antenatally develop Neonatal Opioid Withdrawal Syndrome (NOWS). The overarching goal of the HEAL Initiative: Neonatal Opioid Withdrawal Syndrome Pharmacological Treatments Comparative Effectiveness Trial – Clinical Sites (UG1 Clinical Trial Required) as stated in RFA-HD-21-031 is to design and implement a multi-center, comparative effectiveness, randomized controlled trial (RCT) to assess the optimal pharmacological treatment for NOWS. Our clinical site at the University of Alabama at Birmingham (UAB) is a Regional Perinatal Center with a Comprehensive Addiction in Pregnancy Program (CAPP) that can enroll a large cohort of infants with NOWS. UAB is also actively enrolling in the UAB Outcomes of Babies with Opioid Exposure (OBOE) in response to HEAL Initiative: Antenatal Opioid Exposure Longitudinal Study Consortium (RFA- HD-19-025) and the ACT NOW Weaning study. As a center in the NICHD Neonatal Research Network (NRN) for >25 years, our clinical site has long-standing established productive collaborations with many other clinical centers. Our center has an excellent track record of enrollment in clinical studies (#1 or 2 in most NRN trials) with successful follow-up to 2 years of age and beyond, with trained certified examiners for neurodevelopment. Our investigational pharmacy has worked with us on multiple trials. Therefore, there is demonstrated adequacy of clinical, administrative and data organizational management facilities. For this delayed onset clinical trial, the final protocol will be developed in coordination with the other Clinical Sites and the DCC. We clearly express our intent to participate in a cooperative manner with the other Clinical Centers, the DCC, the NIH, and the DSMC in all aspects of research in a manner consistent with the terms of the award. The Specific Aims are: Specific Aim 1: To develop a protocol in coordination with the other Clinical Sites and the DCC, to compare morphine, methadone, and buprenorphine, while taking into account non-pharmacologic factors and adjunct therapies for the management of neonatal opioid withdrawal syndrome. Specific Aim 2: To recruit and enroll infants with neonatal opioid withdrawal syndrome at our clinical site in the randomized controlled trial, and measure important short-term outcomes by hospital discharge. Specific Aim 3: (A) To determine important neurodevelopmental and other clinical, social, and environmental outcomes in enrolled infants at two-year follow-up outcomes; and (B) In collaboration with the other Clinical Sites and the DCC, to disseminate findings of the clinical trial and help develop evidence-based clinical practice guidelines.