PROJECT SUMMARY / ABSTRACT The nationwide opioid epidemic includes women of child birthing age accounting for a dramatically increased number of infants being born with neonatal opioid withdrawal syndrome (NOWS). Currently there is no uniformly accepted treatment strategy for NOWS and the choice of primary medication, criteria for treatment, and dosing/weaning schedules vary between centers. Morphine is by far the most commonly used medication for NOWS treatment, followed by methadone. Buprenorphine is a promising drug but with limited studied in this patient population. Additionally, the screening tools used to diagnose NOWS and the appropriate threshold to initiate drug therapy have not been conclusively evaluated. When historical empirically derived drug treatment and weaning protocols have been modified and standardized, reductions of length of stay have been observed. Additionally, nonpharmalogical methods appear to be successful in reducing the symptoms of NOWS. In this application we present preliminary data of a pilot randomized controlled trial currently in progress in our nursery. It includes identifying infants with severe symptoms of NOWS via modified Finnegan scoring, then randomizing them to a standard morphine dosing/weaning schedule, or to an optimal morphine dosing strategy. The optimal morphine dosing strategy does not provide a scheduled dose of morphine, but only provides a dose of morphine when the withdrawal symptoms cannot be satiated through nonpharmacological means. Both study groups received all optimized nonpharmacological methods available to them. In the optimal morphine arm, we observed a large reduction in the use of morphine and in the duration of days receiving pharmacologic therapy. We speculate that the use of the optimal morphine dosing strategy limited the use of pharmacologic treatment to only times when nonpharmacologic interventions were not sufficient. This essentially provided the mother or other care givers time to recognize and adapt to the infant's withdrawal behaviors, enabling them to extinguish them via nonpharmacological means. The optimal morphine dosing strategy also prevented the infant's withdrawal from becoming too symptomatic by allowing morphine to be used when needed, yet not committing the infant to a prolonged scheduled course of morphine treatment and weaning when nonpharmacological measures could have sufficed. Thus, we favor a clinical trial that emphasizes the use of nonpharmacological methods to control withdrawal symptoms irrespective of the drug arm the infant is assigned. However, we favor including a more novel optimal dosing strategy arm rather than limiting the investigation to standard scheduled dosing/weaning arms.