Purpose Following the report that continuous exposure of naltrexone (NTX) to drug-dependent pregnant women is safe and effective, the work was designed to develop NTX-loaded controlled delivery systems capable of making NTX available from 1 month to 4 months or greater by a single parenteral administration. Such drug-delivery systems will be useful in alleviating problems such as fetal alcohol syndrome in pregnant women and other problems associated with alcoholism. Methods These studies were designed to investigate in vitro drug availability and microsphere degradation (investigated by gel permeation chromatography(GPC) peak areas of water-soluble fragments released into incubation medium, changes in molecular weight with degradation time, and changes in the glass transition temperature with degradation time) of NTX-loaded poly(D,L-lactide-co-glycolide) (PDLLAGA) microspheres. Results Data showed that in vitro drug availability and degradation were affected by the initial molecular weight of the copolymers, the type of copolymers (lactide-co-glycolide ratio), the source of the polymer (the manufacturer), and the nature of the drug (anhydrous versus regular NTX). Conclusion Drug-development scientists interested in NTX-loaded microspheres for the design of controlled release devices using these polyesters should take adequate cognizance of the variables that affect drug availability from NTX-loaded microspheres. The copolymers are suitable for the fabrication of NTX-loaded microspheres capable of sustained drug release from 30 to 150 days.