THE PHARMACOLOGY OF OXYCODONE, Studies In Vitro, In Vivo and in Humans Kim K. Lemberg Institute of Biomedicine Pharmacology University of Helsinki Academic Dissertation To be publicly presented, with the permission of the Faculty of Medicine of the University of Helsinki, in Lecture Hall 2, Biomedicum Helsinki, on December12th, at 12 noon. Helsinki 2008 Supervised by: Professor Eija Kalso, MD. Ph.D. Pain Clinic, Department of Anaesthesiology and Intensive Care Medicine, Helsinki University Central Hospital Institute of Biomedicine, Pharmacology University of Helsinki Docent Vesa Kontinen, MD. Ph.D. Department of Anaesthesiology and Intensive Care Medicine, Helsinki University Central Hospital Institute of Biomedicine, Pharmacology University of Helsinki Reviewed by: Professor Klaus Olkkola, MD, Ph.D. Department of Anesthesiology, Intensive Care, Emergency Care and Pain Medicine Turku University Hospital Docent Petteri Piepponen, Pharm.D. Department of Pharmacology and Toxicology, School of Pharmacy University of Helsinki Opponent: Professor Mika Scheinin, MD, Ph.D. Department of Pharmacology, Drug Development and Therapeutics University of Turku Department of Clinical Pharmacology TYKSLAB Hospital District of Southwest Finland ISBN 978-952-92-4790-5 (paperback) ISBN 978-952-10-5126-5 (PDF) http://ethesis.helsinki.fi Helsinki University Print Helsinki 2008 2 To my wife Linda 3 Table of contents LIST OF ABBREVIATIONS..........................................................................................................................6 ABSTRACT .......................................................................................................................................................8 LIST OF ORIGINAL PUBLICATIONS.......................................................................................................9 1. INTRODUCTION...................................................................................................................................10 2. REVIEW OF THE LITERATURE .....................................................................................................12 2.1. Nociceptive pathways ............................................................................................................................12 2.2. Opioids and the opioidergic system......................................................................................................13 2.2.1. Opioid receptors..................................................................................................................................13 2.2.2. Pain modulation and the sites of opioid action .................................................................................16 2.2.3. Adverse effects and tolerance ............................................................................................................18 2.3. Pharmacokinetics of oxycodone............................................................................................................19 2.4. Pharmacodynamics of oxycodone and its metabolites .......................................................................22 2.5. The efficacy of oxycodone in different pain models.............................................................................24 2.5.1. Nociceptive pain .................................................................................................................................24 2.5.2. Inflammatory pain...............................................................................................................................25 2.5.3. Neuropathic pain .................................................................................................................................26 2.5.4. Visceral pain........................................................................................................................................28 2.6. Other effects of oxycodone ....................................................................................................................28 3. AIMS OF THE STUDY .........................................................................................................................30 4. MATERIALS AND METHODS ..........................................................................................................31 4.1. Ethical considerations ...........................................................................................................................31 4.2. Animals ...................................................................................................................................................31 4.3. Pain models ............................................................................................................................................32 4.3.1. Models of acute nociception ..............................................................................................................32 4.3.2. SNL model of neuropathic pain .........................................................................................................32 4.3.3. Models for mechanical and cold allodynia........................................................................................33 4.3.4. Carrageenan inflammation .................................................................................................................33 4.4. Assessment of other opioid effects ........................................................................................................34 4.5. Intrathecal cannulation .........................................................................................................................35 4 4.6. GTPγ[35S] autoradiography ..................................................................................................................35 4.7. Drugs ......................................................................................................................................................36 4.8. Clinical Study (Study IV) .......................................................................................................................37 4.8.1. Study design ........................................................................................................................................37 4.8.2. Determination of plasma oxycodone, three of its metabolites and paroxetine ..............................38 4.8.3. Patient genotyping ..............................................................................................................................39 4.9. Statistical analysis .................................................................................................................................39 5. RESULTS .................................................................................................................................................41 5.1. Oxycodone in models of acute nociception (Study I)..........................................................................41 5.2. Oxycodone in the SNL model of neuropathic pain (Study I)..............................................................42 5.3. The influence of the route of administration on effects of oxycodone (Study II) ..............................43 5.4. Pharmacodynamics of oxycodone in rats (Study II)............................................................................43 5.5. Oxycodone induced G-protein activation (Study II)............................................................................44 5.6. The role of noroxymorphone in the effects of systemic oxycodone in rats (Study III)......................44 5.7. Intrathecal administration of noroxymorphone in the rat (Study III) ..............................................45 5.8. The analgesic potency of oxycodone is independent of the CYP-2D6-mediated metabolism in humans (Study IV) .............................................................................................................................................46 6. DISCUSSION...........................................................................................................................................48 6.1. Methodological considerations.............................................................................................................48 6.2. Receptor pharmacology of oxycodone..................................................................................................49 6.3. Oxycodone-induced analgesia is route dependent ..............................................................................49 6.4. Oxycodone induced antinociception and analgesia after systemic administration..........................50 6.5. The role of metabolites in oxycodone-induced antinociception and analgesia ...............................51 6.6. Other pharmacological aspects ............................................................................................................53 7. CONCLUSIONS .....................................................................................................................................54 ACKNOWLEDGEMENTS ...........................................................................................................................55 REFERENCES ................................................................................................................................................57 ORIGINAL PUBLICATIONS......................................................................................................................73 5 LIST OF ABBREVIATIONS