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Current treatments rely on frequent opioid dosing, such as oral morphine every few hours for up to 3 weeks in NAS, leading to plasma level fluctuations and increased risk of toxicity or withdrawal. Herein, the design and characterization of AG10\u2010L\u2010E2\u2010morphine, a prodrug that forms a zwitterionic subcutaneous depot for sustained morphine release is reported. In rats, a single subcutaneous dose of AG10\u2010L\u2010E2\u2010morphine maintained plasma morphine levels for over 72\u2009h without inducing respiratory depression, even at high doses. The prodrug is stable in human plasma and specifically activated by liver carboxylesterase enzyme 2 (CES2), supporting its safety and translational potential. This long\u2010acting system could improve NAS care by enabling convenient dosing and early integration of nonpharmacologic strategies, ultimately reducing hospital stays and healthcare burden.<\/jats:p>","DOI":"10.1002\/cmdc.202500499","type":"journal-article","created":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T16:10:20Z","timestamp":1755533420000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design of a Long\u2010Acting Morphine Prodrug for Safe Opioid Delivery"],"prefix":"10.1002","volume":"20","author":[{"given":"Hana S.","family":"Alhamadsheh","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences Thomas J. Long School of Pharmacy University of the Pacific  Stockton CA 95211 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roshanak","family":"Rahimian","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences Thomas J. Long School of Pharmacy University of the Pacific  Stockton CA 95211 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miki","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences Thomas J. Long School of Pharmacy University of the Pacific  Stockton CA 95211 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4325-7044","authenticated-orcid":false,"given":"Mamoun M.","family":"Alhamadsheh","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences Thomas J. Long School of Pharmacy University of the Pacific  Stockton CA 95211 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9710-4951","authenticated-orcid":false,"given":"Hala","family":"Aldawod","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences Thomas J. Long School of Pharmacy University of the Pacific  Stockton CA 95211 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,8,18]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1600879"},{"key":"e_1_2_8_2_2","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2020-029074"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2017-3520"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1177\/8755122516657566"},{"key":"e_1_2_8_5_1","first-page":"Cd002059","volume":"7","author":"Zankl A.","year":"2021","journal-title":"Cochrane Database Syst. Rev."},{"key":"e_1_2_8_5_2","unstructured":"b) University of North Carolina Department of Pediatrics Clinical Care & Clinical Pathways (CCCP). Treatment Guidelines for Neonatal Abstinence Syndrome [Internet].https:\/\/www.med.unc.edu\/pediatrics\/cccp\/wp\u2010content\/uploads\/sites\/1156\/2025\/06\/UNC\u2010NAS\u2010Guidelines_11_2017.pdf. 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