The use of appropriate analgesic drugs for painful procedures is an essential part of the care of laboratory animals. Novel methods of time-release preparation for potent, pure agonist opioids such as oxymorphone and hydromorphone represent a significant refinement in the way in which these drugs are administered to both rodents and larger animals such as dogs and monkeys. Long-acting opioid preparations would also potentially decrease the risk of zoonotic disease transmission, especially in monkeys, by reducing the number of injections an animal must receive in the post-operative period. Liposome encapsulation of oxymorphone hydrochloride produces a preparation that provides blood concentrations of the drug for up to 3 days in rats, dogs, monkeys and mice. A single subcutaneous injection of liposomal oxymorphone prevents the development of neuropathic pain in rats in a sciatic nerve ligation model. Liposomal oxymorphone provides equivalent to superior relief of post-operative pain in rats after intestinal resection or transection compared with standard oxymorphone. A single injection of liposomal oxymorphone also provides superior pain relief to mice undergoing splenectomy compared to 3 injections of buprenorphine given every 12 hours.
The Specific Aims are: 1) to define the pharmacokenetics of liposomal oxymorphone and hydromorphone using HPLC methodology to separate the different metabolites, including those that are active in vivo in rats, dogs and rhesus monkeys, 2) To determine the side effects profile of liposomal oxymorphone and hydromorphone. Sedation scoring and respiratory gas monitoring will be used in rats and dogs, and cognitive behavioral tests will be used in rhesus monkeys, and 3) Test the analgesic efficacy of liposomal oxymorphone and hydromorphone in dogs, rats and rhesus monkeys. Initial observations will be done using standard analgesiometric tests. Effective dosages will then be used in clinical models of pain in animals. Liposomal oxymorphone and hydromorphone will be tested in a model of neuropathic pain in rats, in post surgical pain (thoracotomy) in dogs and in post surgical pain in rhesus monkeys (laparotomy and Caesarian Section). In clinical studies in post surgical dogs and rhesus monkeys, liposomal oxymorphone and hydromorphone will be compared with standard treatment regimens, including Fentanyl patch in dogs and buprenorphine in rhesus monkeys. If proven efficacious, these analgesic regimens would lead to a significant change in the post-surgical care of animals used in biomedical research and veterinary medicine.
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