Neonatal Opioid Withdrawal Syndrome (NOWS) is a condition in which infants undergo withdrawal after exposure to prescription or non-prescription opioids such as methadone or heroin in utero. NOWS babies exhibit hyperirritability of the central nervous system and respiratory, gastrointestinal, and autonomic symptoms. These symptoms usually appear within 48 to 72 hours after birth. As of 2012, an infant with NOWS was born every 25 minutes in the US, accounting for more than $1.5 billion in national healthcare expenditures. Between 2000– 2012, national rates of NOWS increased 383% from 1.2 per 1000 births to 5.8 per 1000 births. These infants frequently require hospital stay in a neonatal intensive care unit (NICU) with an average hospital stay of 25 days at an average treatment cost of $66K. Currently, no nationwide standard of care exists for managing NOWS. Treatment of NOWS usually follows a multimodal regime centered on controlled withdrawal and replacement drug therapy with oral morphine. However, treatments that reduce the need for neurotoxic opioids are a high priority in this vulnerable population. In fact, a large multicenter randomized study of 898 infants demonstrated that, although morphine is effective in decreasing clinical signs of pain, it can cause significant acute adverse effects such as changes in heart and respiratory rate, hypotension, nasogastric feeds, and need for intravenous supplemental nutrition. Based on the vulnerability of the population and the potential for adverse effects, morphine should be used judiciously and cautiously. The American Academy of Pediatrics recommends attempting the use of non-pharmacologic treatment, which includes placing the infant in a dark and quiet environment, swaddling, rocking, breastfeeding, and providing high-calorie nutrition in frequent small feedings (known as Eat, Sleep, Console or ESC), among other techniques. When used appropriately, such non-pharmacological interventions have resulted in a reduction in length of stay, length of treatment (LOT), and percentage of infants requiring pharmacotherapy. With NOWS babies already under stress from opioid withdrawal, a non-pharmacological treatment may greatly benefit these patients, lowering the need for additional medications and potentially reducing their hospital stay. Our Phase I effort was the first study investigating the effects of transcutaneous auricular neurostimulation (tAN), as an adjunct therapy to oral morphine, in the reduction of the opioid withdrawal signs and symptoms in newborns with NOWS. Across all study participants, tAN was shown to be safe, well-tolerated, and facilitate the rapid weaning of oral morphine. If proven safe and effective in future trials, tAN may expand non-pharmacological treatment options for these infants. Building on our Phase I success, we propose to use our Roo™ tAN system as an adjunct therapy to reduce the signs and symptoms associated with NOWS.

Neonatal Opioid Withdrawal Syndrome (NOWS) is a condition in which infants undergo withdrawal after exposure to opioids such as methadone or heroin in utero. The current gold standard solution uses oral morphine and methadone which leads to many unwanted and harmful side effects to the infant. We propose a non- pharmacological adjunct treatment to help NOWS babies recover quicker while using less morphine.