Osteoarthritis pain: pathogenesis and modern possibilities of therapy


DOI: https://dx.doi.org/10.18565/therapy.2020.3.117-127

Pilipovich A.A., Danilov Al.B.

I.M. Sechenov First Moscow State Medical University of the Ministry of Healthcare of Russia
Pain remains the main complaint of patients with osteoarthritis (OA). For many years, NSAIDs, which have shown their effectiveness (but are not free of disadvantages and limitations, especially with prolonged use) remain to be the first-line remedies for pain relieve in this disease. For this and some other reasons, there is a big demand for the development of new methods for the safe treatment of chronic pain in case of OA. Monoclonal antibodies are considered to be the most perspective treatment strategy for OA with pain component: two antibodies against nerve growth factor (NGF) – tanuzemab and fasinumab – are currently under active development. Substances with other mechanisms of action, including cytokine inhibitors, selective agonists of μ-, δ- and k-opioid receptors and others are under acive testing process now.
Besides pharmacological approach, the possibilities of interventional treatment, such as, for example, cryoneurolysis of peripheral nerves, are being actively studied, but the effectiveness profiles and long-term effects of such a therapy are requiring further studies. The possibilities of treating pain in OA are rapidly expanding. It is necessary to use a multidisciplinary approach for diagnostics and therapy, since symptomatic OA is a heterogeneous disease.
Keywords: cryoneurolysis, selective opioid receptor agonists, cytokine inhibitors, therapy of pain, SYSADOA, monoclonal antibodies, diclofenac, osteoarthritis, pain, NSAIDs
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Literature


  1. Karsdal M.A., Michaelis M., Ladel C. et al. Disease-modifying treatments for osteoarthritis (DMOADs) of the knee and hip: lessons learned from failures and opportunities for the future. Osteoarthritis Cartilage 2016; 24: 2013–21. doi: 10.1016/j.joca.2016.07.017.

  2. Zhang Y., Jordan J.M. Epidemiology of osteoarthritis. Clin Geriatr Med. 2010; 26: 355–69. doi: 10.1016/j.cger.2010.03.001.

  3. Global Burden of Disease Study C. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015; 386: 743–800. doi: 10.1016/S0140-6736(15)60692-4.

  4. Division UNDoEaSAP. World Population Prospects: The 2015 Revision, Key Findings and Advance Tables. 2016. https://esa.un.org/unpd/wpp/.

  5. Thomas E., Peat G., Croft P. Defining and mapping the person with osteoarthritis for population studies and public health. Rheumatology (Oxford). 2014; 53(2): 338–45. doi: 10.1093/rheumatology/ket346.

  6. Doherty M., Bijlsma J., Arden N. et al. Introduction : what is osteoarthritis? In: Doherty M, Bijlsma J, Arden N, Hunter DJ, Dalbeth N, editors. Oxford textbook of osteoarthritis and crystal Arthropathy. 3. Oxford: OUP; 2016: 3–12.

  7. Hannan M.T., Felson D.T., Pincus T. Analysis of the discordance between radiographic changes and knee pain in osteoarthritis of the knee. J Rheumatol. 2000; 27(6): 1513–17.

  8. Abramson S.B., Attur M. Developments in the scientific understanding of osteoarthritis. Arthritis Res Ther. 2009; 11(3): 227. doi: 10.1186/ar2655.

  9. Hunter D.J., Roemer F.W. Imaging: magnetic resonance imaging. In: Doherty M, Bijlsma J, Arden N, Hunter DJ, Dalbeth N, editors.Oxford textbook of osteoarthritis and crystal Arthropathy. 3. Oxford: OUP; 2016. Pp. 177–189.

  10. Mathiessen A., Conaghan P.G. Synovitis in osteoarthritis: current understanding with therapeutic implications. Arthritis Res Ther. 2017; 19(1): 18. doi: 10.1186/s13075-017-1229-9.

  11. Barr A.J., Campbell T.M., Hopkinson D. et al. A systematic review of the relationship between subchondral bone features, pain and structural pathology in peripheral joint osteoarthritis. Arthritis Res Ther. 2015; 17: 228–64. doi: 10.1186/s13075-015-0735-x.

  12. O’Neill T.W., Felson D.T. Mechanisms of osteoarthritis (OA) pain. Curr Osteoporos Rep. 2018; 16(5): 611–16. doi: 10.1007/s11914-018-0477-1.

  13. Callaghan M.J., Parkes M.J., Hutchinson C.E. et al. A randomised trial of a brace for patellofemoral osteoarthritis targeting knee pain and bone marrow lesions. Ann Rheum Dis. 2015; 74: 1164–70. doi: 10.1136/annrheumdis-2014-206376.

  14. Felson D.T., Chaisson C.E., Hill C.L. et al. The association of bone marrow lesions with pain in knee osteoarthritis. Ann Intern Med. 2001; 134: 541–49.

  15. Felson D.T., Niu J., Guermazi A. et al. Correlation of the development of knee pain with enlarging bone marrow lesions on magnetic resonance imaging. Arthritis Rheum. 2007; 56: 2986–92.

  16. Zhang Y., Nevitt M., Niu J. et al. Fluctuation of knee pain and changes in bone marrow lesions, effusions, and synovitis on magnetic resonance imaging. Arthritis Rheum. 2011; 63: 691–99. doi: 10.1002/art.30148.

  17. Roemer F.W., Javaid K.M., Guermazi A. et al. Anatomical distribution of synovitis in knee osteoarthritis and its association with joint effusion assessed on non-enhanced and contrast-enhanced MRI. Osteoarthr Cartil. 2010; 18: 1269–74. doi: 10.1016/j.joca.2010.07.008.

  18. Loeuille D., Chary-Valckenaere I., Champigneulle J. et al. Macroscopic and microscopic features of synovial membrane inflammation in the osteoarthritic knee: correlating magnetic resonance imaging findings with disease severity. Arthritis Rheum. 2005; 52: 3492–501.

  19. Hayashi D., Roemer F.W., Katur A. et al. Imaging of synovitis in osteoarthritis: current status and outlook. Semin Arthritis Rheum. 2011; 41(2): 116–30. doi: 10.1016/j.semarthrit.2010.12.003.

  20. Hill C.L., Gale D.G., Chaisson C.E. et al. Knee effusions, popliteal cysts, and synovial thickening: association with knee pain in osteoarthritis. J Rheumatol. 2001; 28: 1330–37.

  21. Hill C.L., Hunter D.J., Niu J. et al. Synovitis detected on magnetic resonance imaging and its relation to pain and cartilage loss in knee osteoarthritis. Ann Rheum Dis. 2007; 66: 1599–603.

  22. Baker K., Grainger A., Niu J. et al. Relation of synovitis to knee pain using contrast enhanced MRIs. Ann Rheum Dis. 2010; 69: 1779–83. doi: 10.1136/ard.2009.121426.

  23. O’Neill T.W., Parkes M.J., Maricar N. et al. Synovial tissue volume: a treatment target in knee osteoarthritis (OA). Ann Rheum Dis. 2016; 75: 84–90. doi: 10.1136/annrheumdis-2014-206927.

  24. Riis R.G., Gudbergsen H., Henriksen M. et al. Synovitis assessed on static and dynamic contrast-enhanced magnetic resonance imaging and its association with pain in knee osteoarthritis: a cross-sectional study. Eur J Radiol. 2016; 85(6): 1099–108. doi: 10.1016/j.ejrad.2016.03.017.

  25. Moisio K., Eckstein F., Chmiel J.S. et al. Denuded subchondral bone and knee pain in persons with knee osteoarthritis. Arthritis Rheum. 2009; 60: 3703–10. doi: 10.1002/art.25014.

  26. Hernandez-Molina G., Neogi T., Hunter D.J. et al. The association of bone attrition with knee pain and other MRI features of osteoarthritis. Ann Rheum Dis. 2008; 67: 43–47.

  27. Ashraf S., Wibberley H., Mapp P.I. et al. Increased vascular penetration and nerve growth in the meniscus: a potential source of pain in osteoarthritis. Ann Rheum Dis. 2011; 70: 523–29. doi: 10.1136/ard.2010.137844.

  28. Smelter E., Hochberg M.C. New treatments for osteoarthritis. Curr Opin Rheumatol. 2013; 25(3): 310–16. doi: 10.1097/BOR.0b013e32835f69b4.

  29. So A., Patel J., Jones A. Pain: mechanisms and management. In: Bijlsma JWJ, Hachulla E, editors. EULAR textbook of rheumatic diseases. 2. London: BMJ Publishing Group; 2015. Pp. 1332–53.

  30. Nicol G.D., Vasko M.R. Unravelling the story of NGF-mediated sensitization of nociceptive sensory neurons: ON or OFF the Trks? Mol Interv. 2007; 7(1): 26–41.

  31. Ghilardi J.R., Freeman K.T., Jimenez-Andrade J.M. et al. Neuroplasticity of sensory and sympathetic nerve fibers in the painful arthritic joint. Arthritis Rheum. 2012; 64: 2223–32. doi: 10.1002/art.34385.

  32. Brown M.T., Murphy F.T., Radin D.M. et al. Tanezumab reduces osteoarthritic hip pain. Results of a randomised, double-blind, placebo-controlled phase III trial. Arthritis Rheum. 2013; 65: 1795–803. doi: 10.1002/art.37950.

  33. Neogi T., Guermazi A., Roemer F. et al. Association of Joint Inflammation with pain sensitization in knee osteoarthritis: the multicenter osteoarthritis study. Arthritis Rheumatol. 2016; 68: 654–61. doi: 10.1002/art.39488.

  34. Arendt-Nielsen L. Pain sensitisation in osteoarthritis. Clin Exp Rheumatol. 2017; 35(Suppl 107): S68–S74.

  35. Hochberg M.C., Wohlreich M., Gaynor P. et al. Clinically relevant outcomes based on analysis of pooled data from 2 trials of duloxetine in patients with knee osteoarthritis. J Rheumatol. 2012; 39: 352–58. doi: 10.3899/jrheum.110307.

  36. Lee A.S., Ellman M.B., Yan D. et al. A current review of molecular mechanisms regarding osteoarthritis and pain. Gene. 2013; 527(2): 440–47. doi: 10.1016/j.gene.2013.05.069.

  37. Алексеева Л.И., Таскина Е.А., Кашеварова Н.Г. Остеоартрит: эпидемиология, классификация, факторы риска и прогрессирования, клиника, диагностика, лечение. Современная ревматология. 2019; 2: 9–21. [Alekseeva L.I., Taskina E.A., Kashevarova N.G. Osteoarthritis: epidemiology, classification, risk factors, and progression, clinical presentation, diagnosis, and treatment. Sovremennaya revmatologiya. 2019; 2: 9–21 (In Russ.)]. doi: 10.14412/1996-7012-2019-2-9-21.

  38. Bruyere O., Honvo G., Veronese N. et al. An updated algorithm recommendation for the management of knee osteoarthritis from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO). Semin Arthritis Rheum. 2019; 49(3): 337–50. doi: 10.1016/j.semarthrit.2019.04.008.

  39. Derry S., Conaghan P., Da Silva J. et al. Topical NSAIDs for chronic musculoskeletal pain in adults. Cochrane Database Syst Rev. 2016; 4: CD007400. doi: 10.1002/14651858.

  40. Parsaee S., Sarbolouki M.N., Parnianpour M. In-vitro release of diclofenac diethylammonium from lipid-based formulations. Int J Pharm. 2002; 241(1): 185–90.

  41. Ребров А.П., Никитина Н.М. Место Вольтарена Эмульгель в лечении заболеваний опорно-двигательного аппарата. РМЖ. 2008; 10: 670. [Rebrov A.P., Nikitina N.M. Voltaren Emulgel in treatment of diseases of the musculoskeletal system. Russkiy meditsinskiy zhurnal. 2008; 10: 670 (In Russ.)].

  42. Gan T.J. Diclofenac: an update on its mechanism of action and safety profile. Curr Med Res Opin. 2010; 26: 1715–31. doi: 10.1185/03007995.2010.486301.

  43. Пилипович А.А., Данилов Ал.Б. Терапия боли различного генеза: новые возможности диклофенака. Терапия. 2019; 4: 103–112. [Pilipovich A.A., Danilov Al.B. Therapy of pain of different genesis: new possibilities of diclofenac action. Terapiya. 2019; 4: 103–112 (In Russ.)]. doi: https://doi.org/10.18565/therapy.2019.4.103-112.

  44. Пилипович А.А. Остеоартроз: комплексный подход к лечению. РМЖ. Медицинское обозрение. 2014; 11: 835–837. [Pilipovich A.A. Osteoarthritis: integrated approach to the treatment. Russkiy meditsinskiy zhurnal. Meditsinskoe obozrenie. 2014; 11: 835–837 (In Russ.)].

  45. Roemer F.W., Miller C.G., West CR. et al. Development of an imaging mitigation strategy for patient enrolment in the tanezumab nerve growth factor inhibitor (NGF-ab) program with a focus on eligibility assessment. Semin Arthritis Rheum 2017; 47: 323–30. doi: 10.1016/j.semarthrit.2017.05.008.

  46. Schnitzer T.J., Marks J.A. A systematic review of the efficacy and general safety of antibodies to NGF in the treatment of OA of the hip or knee. Osteoarthritis Cartilage. 2015; 23 (Suppl 1): S8–17. doi: 10.1016/j.joca.2014.10.003.

  47. Schnitzer T.J., Ekman E.F., Spierings E.L. et al. Efficacy and safety of tanezumab monotherapy or combined with non-steroidal anti-inflammatory drugs in the treatment of knee or hip osteoarthritis pain. Ann Rheum Dis. 2015; 74: 1202–11. doi: 10.1136/annrheumdis-2013-204905.

  48. Chen J., Li J., Li R. et al. Efficacy and safety of tanezumab on osteoarthritis knee and hip pains: a meta-analysis of randomized controlled trials. Pain Med. 2017; 18: 374–85. doi: 10.1093/pm/pnw262.

  49. Miller R.E., Miller R.J., Malfait A.M. Osteoarthritis joint pain: the cytokine connection. Cytokine 2014; 70: 185–93. doi: 10.1016/j.cyto.2014.06.019.

  50. Levesque M.C., Chen S., Peterfy C. et al. Baseline characteristics of knee osteoarthritis subjects enrolled in the ILLUSTRATE-K study of the anti-interleukin-1alpha/beta dual variable domain immunoglobulin ABT-981 and factors associated with exclusion from the trial. Osteoarthritis Cartilage. 2017; 25: S350–51. doi: https://doi.org/10.1016/j.joca.2017.02.594.

  51. Kloppenburg M., Peterfy C., Haugen I. et al. OP0168 A phase 2a, placebo-controlled, randomized study of ABT-981, an anti-interleukin-1ALPHA and -1BETA dual variable domain immunoglobulin, to treat erosive hand osteoarthritis (EHOA). Ann Rheum Dis. 2017; 76 (Suppl 2): 122.

  52. Guedes V., Castro J.P., Brito I. Topical capsaicin for pain in osteoarthritis: a literature review. Reumatol Clin. 2018: 14(1): 40–45. doi: 10.1016/j.reuma.2016.07.008.

  53. Radnovich R., Scott D., Patel A.T. et al. Cryoneurolysis to treat the pain and symptoms of knee osteoarthritis: a multicenter, randomized, double-blind, sham-controlled trial. Osteoarthritis Cartilage. 2017; 25: 1247–56. doi: 10.1016/j.joca.2017.03.006.

  54. K161835. Silver Spring, MD: FDA, 2017. https://www.accessdata.fda.gov/cdrh_docs/pdf16/k161835.pdf.


About the Autors

Anna Al. Pilipovich, PhD, associate professor of the Department of nervous diseases of Institute of professional education of I.M. Sechenov First Moscow State medical University of the Ministry of Healthcare of Russia. Address: 119991, Moscow, 8/2 Trubetskaya Str. Tel.: +7 (495) 609-14-00. E-mail: aapilipovich@mail.ru
Alexey B. Danilov, MD, professor, head of the Department of nervous diseases of Institute of professional education of I.M. Sechenov First Moscow State medical University of the Ministry of Healthcare of Russia. Address: 119991, Moscow, 2/4 Bolshaya Pirogovskaya Str. Tel.: +7 (495) 609-14-00. E-mail: nervkafedra@gmail.com


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