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A fivefold increase in neonatal opioid withdrawal syndrome (NOWS) has accompanied the increase in opioid use. The Eating, Sleeping, Consoling care approach (ESC) has been shown to improve outcomes for infants with NOWS and is quickly becoming the standard of care for infants affected by opioid use disorder. Quality improvement initiatives following the implementation of ESC provide some evidence to suggest that symptom-based (i.e., as needed, PRN, just in time) dosing of opioid medications for infants with significant withdrawal may be an effective alternative to using a traditional scheduled opioid taper approach. These initiatives have shown reduced length of hospital stay and decreased postnatal opioid exposure when compared to scheduled opioid dosing for infants with NOWS who receive pharmacologic treatment. It is unknown if the findings from these quality improvement initiatives are generalizable, and little is known about the safety of this approach in a diverse population. The purpose of this manuscript is to describe the design and rationale for an ongoing study to evaluate the effect of symptom-based opioid dosing compared to traditional scheduled opioid taper on short-term outcomes for infants with NOWS.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods\/design<\/jats:title>\n            <jats:p>In this ongoing multi-center two-period cluster crossover randomized controlled trial, 24 sites within the USA were randomized at the site level into one of two sequences. Prior to randomization, sites were stratified by care approach used (ESC vs. usual care) and these strata were independently randomized. All study sites will provide care based on their random allocation. Data will be collected under waiver of consent for in-hospital and short-term outcomes for eligible infants. A minimum of 480 infants will be enrolled. We hypothesize that use of symptom-based dosing will safely reduce the length of time until infants with NOWS and at risk for pharmacological treatment are medically ready for discharge when compared to infants treated with a scheduled opioid taper.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Discussion<\/jats:title>\n            <jats:p>This trial is uniquely and efficiently designed to establish the efficacy, safety, and generalizability of the symptom-based dosing approach to opioid treatment for NOWS.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Trial registration<\/jats:title>\n            <jats:p>\n              <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT05980260?term=NCT05980260&amp;rank=1\" ext-link-type=\"uri\">NCT05980260<\/jats:ext-link>; registered July 27, 2023.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s13063-025-09035-x","type":"journal-article","created":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T13:59:45Z","timestamp":1756303185000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Optimizing pharmacologic treatment for neonatal opioid withdrawal syndrome (OPTimize NOW): a symptom-based dosing approach study protocol for a multi-center, cluster crossover design randomized controlled trial"],"prefix":"10.1186","volume":"26","author":[{"given":"Leslie W.","family":"Young","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Denise C.","family":"Babineau","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abhik","family":"Das","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"DeMauro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Walter K.","family":"Kraft","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Scott","family":"Lorch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michele C.","family":"Walsh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"Merhar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lori A.","family":"Devlin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research and the National Institutes of Health (NIH) Helping to End Addiction Long-term (HEAL) Initiative","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,8,27]]},"reference":[{"key":"9035_CR1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2020-029074","author":"SW Patrick","year":"2020","unstructured":"Patrick SW, et al. 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