The main sites of the analgesic action of oxycodone are the brain and spinal cord. The present study describes the concentrations of oxycodone and its metabolites in the brain and spinal cord after epidural administration to the ewe. Twenty pregnant ewes undergoing laparotomy were randomised into two groups to receive epidural oxycodone; infusion group (n=10, 0.1 mg·kg bolus followed by continuous infusion of 0.05 mg·kg ·h for five days) or repeated boluses group (n=10, 0.2+ 2×0.1 mg·kg bolus followed by a 0.2 mg·kg bolus every 12 hours for five days). After five days of oxycodone administration, arterial blood samples were collected, the sheep were euthanized, and a CSF sample and tissue samples from the cortex, thalamus, cerebellum and spinal cord were obtained for the quantification of oxycodone and its main metabolites. The median plasma and CSF concentration of oxycodone were 9.0 and 14.2 ng·mL after infusion and 0.4 and 1.1 ng·mL after repeated boluses. In the infusion group, the cortex, thalamus and cerebellum oxycodone concentration were 4-8-fold higher and in the spinal cord 1310-fold higher than in plasma. In the repeated boluses group, brain tissue concentrations were similar in the three areas, and in the spinal cord were 720-fold higher than in plasma. Oxymorphone was the main metabolite detected, which accumulated in the brain and spinal cord tissue. In conclusion, first, accumulation of oxycodone and oxymorphone in the CNS was observed, and second, high spinal cord concentrations suggest that epidural oxycodone may provide segmental analgesia. This article is protected by copyright. All rights reserved.