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Phd-Comelon-2021.Pdf Opioids in postoperative pain treatment Studies on analgesic efficacy and reduction of opioid-induced side effects Thesis for the degree philosophiae doctor Marlin Comelon, cand.med. Division of Emergencies and Critical Care Department of Anesthesiology Oslo University Hospital Ullevål, Norway & Institute of Clinical Medicine Faculty of Medicine University of Oslo Norway © Marlin Comelon, 2021 Series of dissertations submitted to the Faculty of Medicine, University of Oslo ISBN 978-82-8377-824-3 All rights reserved. No part of this publication may be reproduced or transmitted, in any form or by any means, without permission. Cover: Hanne Baadsgaard Utigard. Portrait photo: Amalie Huth Hovland Print production: Reprosentralen, University of Oslo. Table of contents 1. Acknowledgements...................................................................................................... 5 2. Abbreviations and acronyms ....................................................................................... 9 3. List of papers ............................................................................................................. 11 4. Synopsis ..................................................................................................................... 13 5. Norwegian summary .................................................................................................. 15 6. Introduction ............................................................................................................... 17 6.1 Pain physiology ....................................................................................................... 17 6.1.1 General considerations ...................................................................................... 17 6.1.2 Pathophysiology of hyperalgesia ...................................................................... 21 6.1.3 Effects of pain on different organ systems ....................................................... 22 6.2 Experimental pain.................................................................................................... 22 6.2.1 Experimental pain models ................................................................................ 25 6.3 Pathophysiology of pain in the postoperative setting .............................................. 27 6.4 Postoperative pain epidemiology ............................................................................ 29 6.5 Principles of pain management and opioids in postoperative care .......................... 29 6.5.1 Opioid pharmacology ....................................................................................... 30 6.5.2 Specific opioids ................................................................................................ 35 6.6 Opioid-induced side effects ..................................................................................... 38 6.6.1 General considerations ...................................................................................... 38 6.6.2 Opioid-induced constipation and postoperative ileus ....................................... 40 6.6.3 Nausea and vomiting ........................................................................................ 41 6.6.4 Opioid-induced hyperalgesia ............................................................................ 42 6.6.5 Other side effects .............................................................................................. 47 7. Aim and research questions ....................................................................................... 50 8. Material and methods ................................................................................................ 51 8.1 Study populations .................................................................................................... 51 8.2 Approvals and consent ............................................................................................ 52 8.3 Study design and interventions ................................................................................ 52 8.4 Study medicine and blinding ................................................................................... 54 8.5 Main outcome measures .......................................................................................... 55 8.5.1 Outcome measure - Pain ................................................................................... 55 8.5.2 Outcome measure - Constipation ...................................................................... 56 8.5.3 Outcome measures - Nausea and vomiting ....................................................... 57 8.6 Statistical analyses ................................................................................................... 57 3 9. Results ....................................................................................................................... 60 9.1 Paper I (Targiniq study) .......................................................................................... 60 9.2 Paper II (Tapentadol study) ..................................................................................... 60 9.3 Paper III (OIH study) .............................................................................................. 61 10. Discussion .................................................................................................................. 63 10.1 Main results ........................................................................................................... 63 10.1.1 Paper I ............................................................................................................. 63 10.1.2 Paper II ........................................................................................................... 67 10.1.3 Paper III .......................................................................................................... 70 10.2 Methodological considerations .............................................................................. 74 10.2.1 Bias, validity and reliability ............................................................................ 74 10.2.2 Study populations ........................................................................................... 76 10.2.3 Study design.................................................................................................... 77 10.2.4 Outcome measures .......................................................................................... 80 10.2.5 Statistical considerations ................................................................................ 85 10.3 Ethical considerations ............................................................................................ 90 10.4 Clinical implications.............................................................................................. 92 10.5 Future research and perspectives ........................................................................... 93 11. Conclusions ............................................................................................................... 96 12. References ................................................................................................................. 97 13. Reprints of Paper I - III ............................................................................................ 111 4 1. Acknowledgements First and foremost, I have to thank my perfect trio of supervisors: Harald Lenz, Johan Ræder and Audun Stubhaug. Harald has provided everything a Ph.D. student could wish for: time, availability, support, motivation, patience, hands-on participation, knowledge and some good laughs. Juggling the role as both my principal supervisor and my superior at the department initially might have been a challenge, but never noticed by me. Our attendance at international conferences together have been invaluable both research-wise and socially. I am truly grateful for the opportunity to have learned from Johan with his extensive research background but also his admirable carefree attitude toward most of life’s problems (quote: «Det ordner seg»; and it always does). Combined with his work ethics and impressive work capacity he has been a role model to live up to in research. Harald and Johan: thank you for noticing me and my capacities when I did not even know I was ready to start research myself. It has also been a pleasure to work with Audun and his vast research network. There is always an abundance of ideas every time we talk, and you have provided essential input at the most crucial of times. I feel fortunate to have done this thesis under the guidance of all three of you. I would like to express my immense gratitude to my superiors at the Department of Anesthesiology at Oslo University Hospital, Ullevål. Anne Bøen and Kristin Sem Thagaard have found solutions that made it possible to do research in parallel with clinical work throughout these nine years. Over the years many others have been my superiors too and I thank all of you for your flexibility, patience and support. It is a privilege to work in a department with so many outstanding colleagues, some of whom have contributed directly to my research. A special thanks goes out to Anders Holtan, Ivan Rimstad and Arne Skulberg. I would also like to thank Lars Øivind Høiseth and Torsten Eken for input, new ideas and tips on statistics during my thesis. Moreover, I appreciate all the talks I have had with fellow Ph.D. students in the department, either at the research seminars,
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