Faculty of Health Sciences Department of Community Medicine Use of analgesics in the general population Trends, persistence, high-risk use and associations with pain sensitivity — Per-Jostein Samuelsen A dissertation for the degree of Philosophiae Doctor – May 2016 Use of analgesics in the general population: Trends, persistence, high-risk use and associations with pain sensitivity Per-Jostein Samuelsen Department of Community Medicine UiT – The Arctic University of Tromsø and Regional Medicines Information and Pharmacovigilance Center (RELIS) University Hospital of North Norway Tromsø, Norway 2016 Front page photo (slightly cropped): “Spring is in the air” by Randi Hausken (https://www.flickr.com/photos/46406832@N00/3455539162/) Creative Commons BY-SA 2.0 (https://creativecommons.org/licenses/by-sa/2.0/) The photo shows the blooming of a willow tree (Norwegian: selje). CONTENTS Summary .................................................................................................................................................. i Acknowledgements ................................................................................................................................. ii Abbreviations ......................................................................................................................................... iii List of papers .......................................................................................................................................... iv 1 Background ..................................................................................................................................... 1 1.1 What this dissertation is about ................................................................................................. 1 1.2 History of analgesic use........................................................................................................... 1 1.3 Definition of analgesics ........................................................................................................... 2 1.3.1 Analgesics ....................................................................................................................... 2 1.3.2 Non-steroidal anti-inflammatory drugs ........................................................................... 2 1.3.3 Other analgesics and antipyretics .................................................................................... 3 1.3.4 Opioids ............................................................................................................................ 3 1.4 Pain .......................................................................................................................................... 4 1.4.1 Definition of pain ............................................................................................................ 4 1.4.2 Pain mechanisms ............................................................................................................. 4 1.4.3 Experimental pain ............................................................................................................ 6 1.5 Mechanism of action of analgesics .......................................................................................... 7 1.5.1 Non-steroidal anti-inflammatory drugs ........................................................................... 7 1.5.2 Paracetamol ..................................................................................................................... 7 1.5.3 Opioids ............................................................................................................................ 7 1.6 Benefits and risks of analgesic use .......................................................................................... 8 1.6.1 Effectiveness and efficacy of analgesics ......................................................................... 8 1.6.2 Risks of analgesic use ...................................................................................................... 8 1.7 Literature search ...................................................................................................................... 9 1.8 Sales of analgesics ................................................................................................................. 10 1.9 Prevalence of analgesic use ................................................................................................... 11 1.10 Trends in analgesic use .......................................................................................................... 11 1.11 Persistent analgesic use ......................................................................................................... 19 1.12 High-risk use of analgesics .................................................................................................... 19 1.13 Risk factors for analgesic use ................................................................................................ 20 1.14 Pain sensitivity and analgesic use .......................................................................................... 21 2 Purpose and aims ........................................................................................................................... 23 3 Materials and methods ................................................................................................................... 24 3.1 Data sources .......................................................................................................................... 24 3.1.1 The Tromsø Study ......................................................................................................... 24 3.1.2 The Norwegian Prescription Database .......................................................................... 25 3.2 Central variables .................................................................................................................... 25 3.2.1 Outcome variables: Analgesic use ................................................................................. 25 3.2.2 Exposure variables/independent variables ..................................................................... 29 3.3 Study design .......................................................................................................................... 32 3.3.1 Paper I ............................................................................................................................ 32 3.3.2 Paper II-III ..................................................................................................................... 33 3.4 Directed acyclic graphs ......................................................................................................... 34 3.5 Statistical analysis ................................................................................................................. 35 3.5.1 Paper I ............................................................................................................................ 35 3.5.2 Paper II .......................................................................................................................... 36 3.5.3 Paper III ......................................................................................................................... 36 3.5.4 Software ......................................................................................................................... 36 3.6 Ethics ..................................................................................................................................... 36 4 Results ........................................................................................................................................... 37 4.1 Paper I.................................................................................................................................... 37 4.2 Paper II .................................................................................................................................. 38 4.3 Paper III ................................................................................................................................. 38 5 Discussion ..................................................................................................................................... 39 5.1 Discussion of main findings .................................................................................................. 39 5.1.1 Prevalence and trends in analgesic use .......................................................................... 39 5.1.2 Persistent analgesic use ................................................................................................. 41 5.1.3 High-risk use ................................................................................................................. 43 5.1.4 Risk factors for analgesic use ........................................................................................ 45 5.1.5 Pain sensitivity and analgesic use .................................................................................. 46 5.2 Methodological considerations .............................................................................................. 47 5.2.1 Selection bias and external validity ............................................................................... 47 5.2.2 Information bias and recall ............................................................................................ 49 5.2.3 Missing data