Development of a polymeric naltrexone delivery system would give an effective means for treatment of opiate addiction. A novel approach involves synthesis and characterization of a biodegradable polymeric prodrug of naltrexone covalently coupled to poly(amino acids). Modification of the drug gave several prodrugs including: naltrexone-3-acetate (N3A), naltrexone-3,14-diacetate, naltrexone-14-acetate (N14A), and naltrexone-3-acetate-14-hemisuccinate (N3A14HS). Prodrugs were characterized by infrared and nuclear magnetic resonance spectroscopy. Hydrolysis rates of these esters were determined in phosphate buffer. Prodrugs were coupled via either ester or carbonate bonds to random copolymers of hydroxy-propyl-L-glutamine (HPG) with L-leucine (Leu) having compositions (HPG.-Leu) of 90:10, 80:20, 70:30, 60:40, and 50:50. Copolymers were synthesized by the base catalyzed polymerization of the amino acid N-carboxyanhydrides and had molecular weights between 45,000 and 100,000 as determined by viscometric analysis and wide-angle light scattering. In vitro studies showed rate and duration to be dependent upon copolymer composition, drug loading, covalent linkage type, and geometry of the devices. Subcutaneous injection of these polymeric prodrugs into rats as suspensions of particles led to plasma naltrexone levels that were relatively constant after exhibiting initial bursts. Conjugates of N3A and N14A directly bound to P(HPG50/Leu50) via carbonate bonds exhibited nearly constant naltrexone plasma levels for 1 month.