title: Pain control via opioid analgesic-local anesthetic loaded IPNs.
abstract: 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 Higuchi's 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.
authors.affiliation: Middle East Technical University, Department of Biological Sciences, Biotechnology Research Unit, Ankara 06531, Turkey.
authors.forename: Dilek Sendil
authors.initials: DS
authors.lastname: Keskin
authors.forename: Donald L
authors.initials: DL
authors.lastname: Wise
authors.forename: Vasif
authors.initials: V
authors.lastname: Hasirci
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000627:therapeutic use*; D000779:Anesthetics, Local / Q000008:administration & dosage* / Q000627:therapeutic use*; D000818:Animals; D002045:Bupivacaine / Q000008:administration & dosage / Q000627:therapeutic use; D003061:Codeine / Q000008:administration & dosage / Q000627:therapeutic use; D003692:Delayed-Action Preparations; D016503:Drug Delivery Systems; D004343:Drug Implants; D005079:Excipients; D005260:Female; D004091:Hydromorphone / Q000008:administration & dosage / Q000627:therapeutic use; D008026:Ligation; D009020:Morphine / Q000008:administration & dosage / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D010147:Pain Measurement / Q000187:drug effects; D011091:Polyesters; D011102:Polyhydroxyethyl Methacrylate; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D020426:Sciatic Neuropathy / Q000150:complications; D012995:Solubility; D000094122:Polyhydroxybutyrates
chemical_list: D000701:Analgesics, Opioid; D000779:Anesthetics, Local; D002045:Bupivacaine; D003061:Codeine; D003692:Delayed-Action Preparations; D004343:Drug Implants; D005079:Excipients; D004091:Hydromorphone; D009020:Morphine; D011091:Polyesters; D011102:Polyhydroxyethyl Methacrylate; C052620:poly(3-hydroxybutyrate)-co-(3-hydroxyvalerate); D000094122:Polyhydroxybutyrates