Beckwée, DNijs, JBierma-Zeinstra, SMALeemans, LLeysen, LPuts, SRice, DSchiphof, DBautmans, I2024-01-312024-01-312024-01-10BMJ open, ISSN: 2044-6055 (Print); 2044-6055 (Online), BMJ, 14(1), e074258-. doi: 10.1136/bmjopen-2023-0742582044-60552044-6055http://hdl.handle.net/10292/17168INTRODUCTION: Muscle strengthening training (MST) and behavioural graded activity (BGA) show comparable effects on knee osteoarthritic (KOA) pain, but the mechanisms of action remain unclear. Both exercise-induced anti-inflammation and central sensitisation are promising pathways for pain relief in response to exercise therapy in patients with KOA: MST has the potential to decrease inflammation and BGA has the potential to decrease central sensitisation. Hence, this study aims to examine inflammation and central sensitisation as mediators for the effect of MST and/or BGA on pain in patients with KOA. METHODS AND ANALYSIS: The Knee OsteoArthritis PAIN trial started on 10 January 2020 (anticipated end: April 2024). The three-arm clinical trial aims to recruit 90 KOA patients who will be randomly allocated to 12 weeks of (1) MST, (2) BGA or (3) care as usual. Assessments will be performed at baseline, 13 and 52 weeks after finishing the intervention. Outcomes, including pain (Knee injury and Osteoarthritis Outcome Score), were chosen in line with the OARSI recommendations for clinical trials of rehabilitation interventions for OA and the IMMPACT/OMERACT recommendations for the assessment of physical function in chronic pain clinical trials. Inflammation as well as features of central sensitisation (including conditioned pain modulation, offset analgesia, temporal summation of pain and event-related potentials following electrical stimulation), will be considered as treatment mediators. A multiple mediators model will be estimated with a path-analysis using structural equation models. In July 2023, all 90 KOA patients have been included and 42 participants already finished the study. ETHICS AND DISSEMINATION: This study obtained ethics approval (B.U.N. 143201941843). Unravelling the mechanisms of action of exercise therapy in KOA will not only be extremely valuable for researchers, but also for exercise immunology and pain scientists and clinicians. TRIAL REGISTRATION NUMBER: NCT04362618.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions.http://creativecommons.org/licenses/by-nc/4.0/Chronic PainMusculoskeletal disordersREHABILITATION MEDICINE4201 Allied Health and Rehabilitation Science32 Biomedical and Clinical Sciences3202 Clinical Sciences42 Health SciencesChronic PainPain ResearchRehabilitationClinical Trials and Supportive ActivitiesClinical ResearchArthritis6 Evaluation of treatments and therapeutic interventions6.1 PharmaceuticalsMusculoskeletal1103 Clinical Sciences1117 Public Health and Health Services1199 Other Medical and Health Sciences32 Biomedical and clinical sciences42 Health sciences52 PsychologyHumansOsteoarthritis, KneeExercise TherapyInflammationChronic PainPain ManagementRandomized Controlled Trials as TopicHumansOsteoarthritis, KneeExercise TherapyInflammationChronic PainPain ManagementRandomized Controlled Trials as TopicJournal ArticleOpenAccess10.1136/bmjopen-2023-074258