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ToxSci Advance Access published online on November 30, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl178
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received July 20, 2006
Accepted November 21, 2006

Safety Evaluation

Oxymorphone Hydrochloride, A Potent Opioid Analgesic, Is Not Carcinogenic In Rats Or Mice

Dana L. Shuey 1 *, Cindy Woodland 2, Claudine Tremblay 2, Richard Gregson 2, and Ronald J. Gerson 1

1 Endo Pharmaceuticals Inc., 100 Endo Blvd., Chadds Ford, PA 19350
2 Charles River Laboratories, Preclinical Services, 22022, Transcanadienne, Senneville, Quebec, CANADA H9X 3R3

* To whom correspondence should be addressed.
Dana L. Shuey, E-mail: shuey.dana{at}endo.com


  Abstract

Despite their long history of chronic use, little information is available regarding the carcinogenicity of opioid analgesics. Oxymorphone is a potent morphinan-type mu-opioid analgesic used for treatment of moderate-to-severe pain. Oxymorphone was tested for carcinogenicity in Crl:CD®IGS BR rats and CD-1 mice. Oxymorphone hydrochloride was administered orally once daily for 2 years to rats at doses of 2.5, 5 and 10 mg/kg/day (males) and 5, 10 and 25 mg/kg/day (females), and mice at 10, 25, 75 and 150 mg/kg/day (65 animals/sex/group; 100 animals/sex in controls). In rats, survival was generally higher than controls in oxymorphone-treated groups, attributable to lower body weight gain. In mice, survival was generally higher than controls in females at all doses and males given ≤25 mg/kg/day, but lower in males given ≥75 mg/kg/day due to a high incidence of obstructive uropathy. Opioid-related clinical signs and reduced body weight gain occurred in both species throughout the study. Nonneoplastic findings associated with oxymorphone pharmacology included ocular and pulmonary changes in rats considered secondary to inhibition of blinking and mydriasis, and antitussive activity, respectively, and urinary tract and renal findings in mice considered secondary to urinary retention. There was no target organ toxicity, and no increase in any neoplastic lesions attributed to oxymorphone. Plasma oxymorphone levels achieved in these studies exceeded those in patients taking high therapeutic doses of oxymorphone (AUC0-24hr values up to 5.6-fold and 64-fold in rats and mice, respectively). Oxymorphone is not considered to be carcinogenic in rats or mice under the conditions of these studies.

Keywords: opioids; carcinogenicity; analgesics.
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