Aalborg Universitet Peripheral and Central Effects of Morphine and the Impact of Methylnaltrexone in Human Experimental Pain Models Brokjær, Anne DOI (link to publication from Publisher): 10.5278/vbn.phd.med.00020 Publication date: 2015 Document Version Publisher's PDF, also known as Version of record Link to publication from Aalborg University Citation for published version (APA): Brokjær, A. (2015). Peripheral and Central Effects of Morphine and the Impact of Methylnaltrexone in Human Experimental Pain Models. Aalborg Universitetsforlag. Ph.d.-serien for Det Sundhedsvidenskabelige Fakultet, Aalborg Universitet https://doi.org/10.5278/vbn.phd.med.00020 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. ? Users may download and print one copy of any publication from the public portal for the purpose of private study or research. ? You may not further distribute the material or use it for any profit-making activity or commercial gain ? You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us at [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from vbn.aau.dk on: September 26, 2021 PERIPHERAL AND CENTRAL EFFECTS OF MORPHINE AND THE IMPACT OF METHYLNALTREXONE IN HUMAN EXPERIMENTAL PAIN MODELS PAIN IN HUMAN EXPERIMENTAL OF METHYLNALTREXONE AND THE IMPACT EFFECTS OF MORPHINE AND CENTRAL PERIPHERAL PERIPHERAL AND CENTRAL EFFECTS OF MORPHINE AND THE IMPACT OF METHYLNALTREXONE IN HUMAN EXPERIMENTAL PAIN MODELS BY ANNE BROKJÆR DISSERTATION SUBMITTED 2015 Peripheral and Central Effects of Morphine and the Impact of Methylnaltrexone in Human Experimental Pain Models Ph.D. thesis by Anne Brokjær November 2014 Thesis submitted: November 7, 2014 PhD supervisor: Asbjørn Mohr Drewes PhD committee: Pharm D, PhD, Associate Professor Parisa Gazerani (chairman) Aalborg University PhD, Associate Professor Anne-Marie Heegaard University of Copenhagen Professor, Dr.med. Frank Petzke Universitätsklinikum Göttingen PhD Series: Faculty of Medicine, Aalborg University ISSN (online): 2246-1302 ISBN (online): 978-87-7112-276-3 Published by: Aalborg University Press Skjernvej 4A, 2nd floor DK – 9220 Aalborg Ø Phone: +45 99407140 [email protected] forlag.aau.dk © Copyright: Anne Brokjær Printed in Denmark by Rosendahls, 2015 Acknowledgements ........................................................................................................................................... 4 List of papers ..................................................................................................................................................... 6 Abbreviations .................................................................................................................................................... 7 English summary ............................................................................................................................................... 8 Danish summary .............................................................................................................................................. 10 1 General introduction ..................................................................................................................................... 12 1.1 Pain ........................................................................................................................................................ 12 1.1.2 Impact of pain ................................................................................................................................. 12 1.2 The pain system ..................................................................................................................................... 13 1.2.1 The primary afferent ....................................................................................................................... 13 1.2.2 Sensory transmission ...................................................................................................................... 14 1.2.3 Innervation of the gastrointestinal tract .......................................................................................... 16 1.3 Pharmacological pain management ....................................................................................................... 17 1.3.1 Opioids ........................................................................................................................................... 17 1.3.2 Opioid antagonists .......................................................................................................................... 21 1.4 Experimental human pain models ......................................................................................................... 22 1.4.1 Opioids in experimental pain models ............................................................................................. 22 1.4.2 Sex differences in pain perception .................................................................................................. 23 2 Objectives ..................................................................................................................................................... 24 2.1 Hypotheses and aims ............................................................................................................................. 24 2.1.1 Study I ............................................................................................................................................ 24 2.1.2 Study IIa ......................................................................................................................................... 25 2.1.3 Study IIb ......................................................................................................................................... 25 3 Methods and key results ............................................................................................................................... 26 3.1 Study conduct ........................................................................................................................................ 26 3.2 Study population .................................................................................................................................... 26 3.3 Study I ................................................................................................................................................... 27 3.3.1 Methods .......................................................................................................................................... 27 3.3.2 Key results ...................................................................................................................................... 34 3.4 Study II .................................................................................................................................................. 36 3.4.1 Methods .......................................................................................................................................... 36 3.4.2 Key results ...................................................................................................................................... 43 4 Discussion..................................................................................................................................................... 45 2 4.1 Study I ................................................................................................................................................... 45 4.2 Study IIa ................................................................................................................................................ 46 4.3 Study IIb ................................................................................................................................................ 48 4.4 Methodological considerations .............................................................................................................. 48 4.4.1 Study population ............................................................................................................................. 48 4.4.2 Rectal drug administration .............................................................................................................. 49 4.4.3 The experimental procedure ........................................................................................................... 49 4.4.4 Study design ................................................................................................................................... 50 5 Conclusions .................................................................................................................................................. 51 6 Future perspectives ....................................................................................................................................... 52 7 Reference list ................................................................................................................................................ 54 3 Acknowledgements First and foremost I would like to express my