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While the short\u2010term effects of NOWS are well\u2010characterized, long\u2010term physiological and molecular consequences remain unclear. First\u2010line NOWS treatments include non\u2010pharmacological interventions; however, most infants who require medication are primarily treated with more opioids, such as morphine, weaned over time. This practice may be counterintuitive given recent preclinical evidence linking prenatal opioid exposure (POE) to neuroinflammation, as well as cognitive deficits in both preclinical and clinical studies. Identifying alternative non\u2010opioid therapeutic agents may be essential for future NOWS management. This scoping review evaluated non\u2010opioid therapeutics for opioid withdrawal symptoms (OWSx) across clinical and preclinical populations to identify candidate agents for future NOWS treatment research. Forty\u2010one articles met inclusion criteria, encompassing 16 different drug classes, with particular attention to alpha\u20102\u2010agonists, enzyme inhibitors, NMDA receptor antagonists, and unregulated dietary supplements. Among these empirical studies, several promising therapeutics emerged, with a few demonstrating efficacy on par with standard opioid treatments. However, despite promising results, definitive conclusions from many studies were limited by small sample sizes, inconsistent methodologies, or confounding variables. Furthermore, most agents remain untested in neonatal populations, leaving critical safety and dosing parameters unknown. This underscores the need for rigorous, translational research of these agents, including neonatal safety, efficacy, pharmacokinetics, and pharmacodynamics, ideally benchmarked against standard\u2010of\u2010care treatments. Addressing these gaps is crucial for developing effective NOWS treatment and improving outcomes for this vulnerable population.<\/jats:p>","DOI":"10.1111\/cts.70581","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T06:01:01Z","timestamp":1778479261000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Scoping Review of Non\u2010Opioid Therapeutics for Opioid Withdrawal: Translational Relevance to Neonatal Opioid Withdrawal Syndrome (\n                    <scp>NOWS<\/scp>\n                    ) Research"],"prefix":"10.1111","volume":"19","author":[{"given":"Sara L.","family":"Mills\u2010Huffnagle","sequence":"first","affiliation":[{"name":"Pennsylvania State University, Pennsylvania State College of Medicine  Hershey Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oliver M.","family":"Lowden","sequence":"additional","affiliation":[{"name":"Pennsylvania State University  State College Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0725-6386","authenticated-orcid":false,"given":"Rhea E.","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Pennsylvania State University, Pennsylvania State College of Medicine  Hershey Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Taryn E.","family":"McFadden","sequence":"additional","affiliation":[{"name":"Pennsylvania State University, Pennsylvania State College of Medicine  Hershey Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4549-3617","authenticated-orcid":false,"given":"Jennifer E.","family":"Nyland","sequence":"additional","affiliation":[{"name":"Pennsylvania State University, Pennsylvania State College of Medicine  Hershey Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,5,10]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.mm6932a2"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.24991"},{"key":"e_1_2_10_4_1","volume-title":"Neonatal Abstinence Syndrome","author":"Anbalagan S. 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