ToxSci Advance Access originally published online on November 30, 2006
Toxicological Sciences 2007 96(1):162-173; doi:10.1093/toxsci/kfl178
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Oxymorphone Hydrochloride, a Potent Opioid Analgesic, Is Not Carcinogenic in Rats or Mice
* Endo Pharmaceuticals Inc., Chadds Ford, Pennsylvania 19350
Charles River Laboratories, Preclinical Services, Senneville, Quebec, Canada H9X 3R3
1 To whom correspondence should be addressed at Endo Pharmaceuticals Inc., 100 Endo Blvd., Chadds Ford, PA 19350. Fax: (484) 840-4291. E-mail: shuey.dana{at}endo.com.
Received July 20, 2006; accepted November 21, 2006
 |
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 per sex per group; 100 animals per 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 (Area under the curve [AUC0–24 h] 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.
Key Words: opioids; carcinogenicity; analgesics.