This study presents a carboxylesterase enzyme 2 (CES2)-activated morphine prodrug that forms a subcutaneous depot and enables sustained prodrug release. In rats, the prodrug maintained steady plasma levels of morphine over 72 h without inducing opioid side effects. This prodrug may offer a safe and convenient alternative to repeated dosing of morphine, which is associated with toxicity (plasma peaks) and loss of efficacy (plasma troughs). The approach holds promise for improving care in neonatal abstinence syndrome.

Effective opioid management in neonatal abstinence syndrome (NAS) and opioid use disorder (OUD) requires maintaining low, stable plasma opioid levels to prevent withdrawal without central side effects. 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-L-E2-morphine, a prodrug that forms a zwitterionic subcutaneous depot for sustained morphine release is reported. In rats, a single subcutaneous dose of AG10-L-E2-morphine maintained plasma morphine levels for over 72 h 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-acting system could improve NAS care by enabling convenient dosing and early integration of nonpharmacologic strategies, ultimately reducing hospital stays and healthcare burden.