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.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Research Project (R01)
Project #
5R01RR018802-02
Application #
7125413
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Program Officer
Watson, William T
Project Start
2005-09-23
Project End
2009-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
2
Fiscal Year
2006
Total Cost
$355,202
Indirect Cost
Name
University of Wisconsin Madison
Department
Surgery
Type
Schools of Veterinary Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Smith, Lesley J; Kukanich, Butch K; Krugner-Higby, Lisa A et al. (2013) Pharmacokinetics of ammonium sulfate gradient loaded liposome-encapsulated oxymorphone and hydromorphone in healthy dogs. Vet Anaesth Analg 40:537-45
Krugner-Higby, Lisa; KuKanich, Butch; Schmidt, Brynn et al. (2011) Pharmacokinetics and behavioral effects of liposomal hydromorphone suitable for perioperative use in rhesus macaques. Psychopharmacology (Berl) 216:511-23
Schmidt, Jennifer R; Krugner-Higby, Lisa; Heath, Timothy D et al. (2011) Epidural administration of liposome-encapsulated hydromorphone provides extended analgesia in a rodent model of stifle arthritis. J Am Assoc Lab Anim Sci 50:507-12
Wunsch, L A; Schmidt, B K; Krugner-Higby, L A et al. (2010) A comparison of the effects of hydromorphone HCl and a novel extended release hydromorphone on arterial blood gas values in conscious healthy dogs. Res Vet Sci 88:154-8
Tu, Sheng; McGinnis, Tamara; Krugner-Higby, Lisa et al. (2010) A mathematical relationship for hydromorphone loading into liposomes with trans-membrane ammonium sulfate gradients. J Pharm Sci 99:2672-80
Paul-Murphy, Joanne R; Krugner-Higby, Lisa A; Tourdot, Renee L et al. (2009) Evaluation of liposome-encapsulated butorphanol tartrate for alleviation of experimentally induced arthritic pain in green-cheeked conures (Pyrrhura molinae). Am J Vet Res 70:1211-9
Krugner-Higby, Lisa; KuKanich, Butch; Schmidt, Brynn et al. (2009) Pharmacokinetics and behavioral effects of an extended-release, liposome-encapsulated preparation of oxymorphone in rhesus macaques. J Pharmacol Exp Ther 330:135-41
Shih, Andre; Miletic, Vjekoslav; Miletic, Gordana et al. (2008) Midazolam administration reverses thermal hyperalgesia and prevents gamma-aminobutyric acid transporter loss in a rodent model of neuropathic pain. Anesth Analg 106:1296-302, table of contents
KuKanich, B; Schmidt, B K; Krugner-Higby, L A et al. (2008) Pharmacokinetics and behavioral effects of oxymorphone after intravenous and subcutaneous administration to healthy dogs. J Vet Pharmacol Ther 31:580-3
Smith, L J; KuKanich, B; Hogan, B K et al. (2008) Pharmacokinetics of a controlled-release liposome-encapsulated hydromorphone administered to healthy dogs. J Vet Pharmacol Ther 31:415-22

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