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From the *Institute of Biomedicine, Pharmacology, Department of Oral Radiology, Institute of Dentistry, Faculty of Pharmacy, Division of Pharmaceutical Chemistry, University of Helsinki, and Department of Anaesthesiology and Intensive Care Medicine, Helsinki University Central Hospital, Helsinki, Finland.
Address correspondence and reprint requests to Kim Lemberg, DDS, Institute of Biomedicine/Pharmacology, P. O. Box 63, FI-00014 University of Helsinki, Finland. Address e-mail to kim.lemberg{at}helsinki.fi.
BACKGROUND: Noroxymorphone is one of the major metabolites of oxycodone. Although oxycodone is commonly used in the treatment of acute and chronic pain, little is known about the antinociceptive effects of noroxymorphone. We present an in vivo pharmacological characterization of noroxymorphone in rats.
METHODS: The antinociceptive properties of noroxymorphone were studied with thermal and mechanical models of nociception in rats.
RESULTS: Intrathecal noroxymorphone (1 and 5 µg/10 µL) induced a significantly longer lasting antinociceptive effect compared with oxycodone (200 µg/10 µL) and morphine (1 and 5 µg/10 µL). Pretreatment with subcutaneous naloxone (1 mg/kg) 15 min before intrathecal drug administration significantly decreased the antinociceptive effect of both noroxymorphone and morphine, indicating an opioid receptor-mediated antinociceptive effect. In the hotplate, paw pressure, and tail flick tests, subcutaneous noroxymorphone was inactive in doses of 5, 10, and 25 mg/kg. Also, no effect on motor function was observed in the rotarod test with doses studied. No antihyperalgesic effect was observed in the carrageenan model for inflammation in rats with subcutaneous noroxymorphone 25 mg/kg.
CONCLUSIONS: The results of this study indicate that noroxymorphone is a potent µ-opioid receptor agonist when administered intrathecally. The lack of systemic efficacy may indicate reduced ability of noroxymorphone to penetrate the blood–brain barrier due to its low calculated logD value (log octanol/water partition coefficient). Thus, noroxymorphone should have a negligible role in analgesia after systemic administration of oxycodone. Because of its spinal efficacy and long duration of effect, noroxymorphone is an interesting opioid for spinal analgesia with a low potential for abuse. Its safety for spinal administration should be assessed before clinical use.
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