Effectiveness of repeated administration of a new oral naltrexone controlled-release system on morphine analgesia

Naltrexone hydrochloride, an opioid antagonist used as an adjunct to the maintenance of the opioid-free state for detoxified individuals, was introduced into the polymeric structure of Eudragit L30D, an anionic copolymer based on polymethacrylic acid and ethylacrylate. From the results of a preclinical study, this complexation technique can be considered as a useful tool in the design of oral controlled-release systems (naltrexone-Eudragit L) capable of inducing long-lasting effects in-vivo. The biopharmaceutical characterization of the naltrexone-Eudragit L complex in comparison with naltrexone hydrochloride using the mouse hot-plate model has been previously carried out. The results showed a longer effect, an enhancement of 23.47% of the area under the curve of the inhibition of analgesic activity vs time, and a delay of 51.80% in the t1/2 value induced by the complex, compared with those induced by conventional naltrexone. In this study, a regimen of chronic administration of naltrexone-Eudragit L was established. Thus, in an 8-day treatment (4 doses in alternate days) this oral controlled-release system effectively antagonized the analgesic effect of morphine for 8 h, whereas naltrexone hydrochloride has to be administered over 16 days (8 doses in alternate days) to induce the same effect. In the 16-day schedule the complex-induced antagonism lasted over 14 h after administration.