PROJECT SUMMARY/ABSTRACT The number of infants exposed to opioids prenatally in the US remains high, with one infant born exposed to opioids every 15 minutes. Optimal treatment for exposed infants who develop neonatal opioid withdrawal syndrome (NOWS) has not been established, and randomized comparative effectiveness trials of medications for NOWS are critically needed. Cincinnati Children’s Hospital Medical Center (CCHMC) is uniquely suited to participate as a clinical site in such a multicenter randomized comparative effectiveness trial. The CCHMC Perinatal Institute is a large regional perinatal center, providing population-based clinical service for approximately 25,000 newborns each year. Intrauterine exposure to opioids in the Cincinnati region was approximately 26 per 1000 live births in 2020, with 10.3 per 1000 developing NOWS requiring pharmacologic treatment. The proposed PI for this study Stephanie Merhar, proposed alternate PI Scott Wexelblatt, and proposed follow-up PI Jennifer McAllister all have extensive experience in clinical care, quality improvement, and clinical research in the NOWS population. The Cincinnati team will provide significant intellectual contributions to the design of the study, recruit a large number of infants with NOWS to participate, and continue our tradition of excellent follow-up rates to retain infants in the study to age 2. The expertise and experience of the investigators and support staff, along with the facilities and population available for study at CCHMC, make CCHMC a strong site for this proposed study.