Relief of chronic pain is an important clinical problem requiring special care and approaches. The present study was designed for the construction of a controlled release system for local application of analgesics (hydromorphone (HM), morphine (M), and codeine (C)) and a local anesthetic, bupivacaine (BP). An interpenetrating network (IPN) drug release system was prepared by using a biocompatible, biodegradable copolyester, poly(3-hydroxybutyrate-co-3- hydroxyvalerate) (PHBV) and another biocompatible but synthetic, nondegradable polymer, poly (2- hydroxyethyl methacrylate), (PHEMA). In situ release kinetics of the IPN system was first order for BP but could not be fitted to any known equation for the other drugs. Complete release from the IPNs occurred within a considerably short time (24 h for 80 % of the drugs) most probably due to the significant hydrophilicity of PHEMA. In order to slow down the release rate these IPNs were coated with PHBV. Release from these coated IPNs (cIPN) resulted in rates that could be described by Higuchis equations. In vivo measurement of antinociceptive efficacy was carried out in rats with tail flick and paw-withdrawal tests after inducing chronic pain created by sciatic nerve ligation at the right side. Control groups received placebo implants. In vivo studies showed potent, prolonged (2-3 days) antinociception at the site of injury (right paw) for strong opioids (HM and M) and about 2 days for the weak opioid (C) and local anesthetic (BP). In all cases the release rate was found to be as important as the antinociceptive potency. The weakest opioid analgesic of those evaluated (C) had a higher first day antinociception than its stronger counterpart M, probably due to its higher initial concentration that was expected from its faster release rate in the in situ experiments.
Keywords: phbv, phema, morphine, hydromorphone, codeine, bupivacaine, controlled release, interpenetrating network
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