1. Recomendations for the medicamentous treatment of chronic inflammatory rheumatic disease pain Dušan Logar Dpt.of Rheumatology, University Clinical Centre, Ljubljana

2. Rheumatoid arthritis RA is a chronic, inflammatory, systemic, autoimmune disease Mainly polyarticular disease Chronic inflammation in synovial membrane of affected joints The specific cause of RA is unknown, but the immune response is well characterised

5. Pain in RA 71% adults who are taking methotrexate, biologics or both, continued to report pain 55% these individuals had to modify their daily household activities Arthritis Foundation Survey – 500 adult RA patients

6. Pain in RA The extent of disability associated with chronic pain can vary from none to severe, and pain continue in the absence of tissue damage

7. Interplay of various factors causing RA pain Cytokines Mechanical factors Glial cells Central sensitization Circadian rythm of various hormons Inflammatory mediators Synovial fluid byochemical changes Neural-immune system interplay

8. Cells involved in articular inflammation

9. Molecules involved in peripheral sensitization Tissue damageInflammationSympathetic terminals Sensitisizing cocteil BRADYKININEPROSTAGLANDINESCYTOKINES NALEUCOTRIENESNERVE GROWTH FACTORS Hydrogen ionsHISTAMINENEUROPEPTIDES Potassium ionsPURINESPROTEASES Direct action on nociceptors Sensitization of primary aferent neurons Transduction sensitivity

10. IL-1β and TNF-α : Proinflammatory Cytokines in the Rheumatoid Joint Neutrophils Osteoclasts Bone Cartilage Osteoblasts Chondrocytes Bone TNF-  IL- 11 Synovial space IL-6 PGE 2 IL-8 High endothelial venule Synovial membrane Capsule Pannus OsteoblastsOsteoclasts PGE 2 = prostaglandin-E 2 Dinarello C, Moldawer L. Proinflammatory and Anti-inflammatory Cytokines in Rheumatoid Arthritis: A Primer for Clinicians. 3rd ed. Thousand Oaks, Ca, USA: Amgen Inc.; 2001.

11. Interplay of various factors causing RA pain Cytokines Mechanical factors Glial cells Central sensitization Circadian rythm of various hormons Inflammatory mediators Synovial fluid byochemical changes Neural-immune system interplay

12. Interplay of various factors causing RA pain Cytokines Mechanical factors Glial cells Central sensitization Circadian rythm of various hormons Inflammatory mediators Synovial fluid byochemical changes Neural-immune system interplay

13. Inflammmatory rheumatic disease pain Macrophage PERIPHERAL SENSITIZATION CENTRAL SENSITIZATION PHENOTYPIC SWITCH Neutrophil granulocyte ARTHRITIS Mast cell

14. CORRECTIVE JOINT OPERATIONS PATIENT EDUCATION, PHYSICAL THERAPY, ORTHOSES, BALNEOTHERAPY DAMAGE OF JOINT STRUCTURES PARACETAMOL AND/OR NSAR, PARACETAMOL/TRAMADOL, OPIOIDS PAIN INFLAMMATION GLUCOCORTICOIDS DMARs, BIOLOGICS Zdravljenje bolečine pri revmatoidnem artritisu Treatment of chronic inflammatory rheumatic disease pain

15. Pharmacological approaches NSAIDs DMARDs Biologics Intraarticular long acting steroids opioids

16. Pharmacological approaches NSAIDs DMARDs Biologics Intraarticular long acting steroids opioids

17. NSARDs Effectivness evaluation after 14 days Concommitant prescription of second NSARD is not allowed Risk of prescription NSARD with long t/ 2 to older patients Low dose therapy in children and old adults Do not to ignore contraindications:  active ulcer disease  ischaemic heart disease  asthma, urticaria, angioedema  advanced kidney disease

18. Pharmacological approaches NSAIDs DMARDs Biologics Intraarticular long acting steroids opioids

19. DMARDs Sulphasalasine Antimalarials Methotrexate Leflunomide Cyclosporine A

20. Pharmacological approaches NSAIDs DMARDs Biologics Intraarticular long acting steroids opioids

21. Biologics Infliximab Etanercept Adalimumab Rituximab Tociluzumab

22. Pharmacological approaches NSAIDs DMARDs Biologics Intraarticular long acting steroids opioids

23. Pharmacological approaches NSAIDs DMARDs Biologics Intraarticular long acting steroids opioids

24. Opioids Treatment failure of therapy with NSARDs Contraindications for NSARDs Contraindications for corrective joint operation Patient long waiting on corrective joint operation

25. Conclusions I 65 % patients with RA state pain as the most important symptom of the disease For 75 % of patients the still acceptable pain is graded with VAS between 0.5 and 2.0 Agressive treatment of RA with DMARDs and biologics decreases the need of analgetic use Future: targeted treatment with:  Drugs that have influence on various ionic channels  α-2 agonists  Drugs that have influence on prostaglandine and opioid receptors in spinal cord

26. Conclusions II Pain that is consistenly present in any rheumatic condition should be considered a specific disease entity, which should be actively managed in parallel with the rheumatic complaint Fitzcharles MA, Shir Y. New concept in rheumatic pain. Rheum Dis Clin North Am 2008;34: 267-83.