Pain is a major clinical problem of osteoarthritis (OA). Recently, OA has been thought to be a disease of the whole joint with both destruction of cartilage and inflammatory components such as synovitis and bone marrow lesions. Clinical studies have documented a significant inflammatory soft tissue contribution to the severity and frequency of OA pain. Both clinical and experimental studies have provided evidence for the sensitization of pain pathways during OA, involving pronounced changes in joint nociceptors and changes of the nociceptive processing in the spinal cord, brainstem, and thalamocortical system. Additionally, evidence has been provided for neuropathic pain components in OA models. Concerning molecular mechanisms of OA pain and potential options for pain therapy, studies on nerve growth factor, cytokines, sodium channel blockers, hyaluronic acid preparations, and others are addressed in this review.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Breivik H, Collett B, Ventafridda V, et al. Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur J Pain. 2006;10:287–333.
Felson DT. Developments in the clinical understanding of osteoarthritis. Arthritis Res Ther. 2009;11:203.
Konttinen YT, Sillat T, Barreto G, et al. Osteoarthritis as an autoinflammatory disease caused by chondrocyte-mediated inflammatory responses. Arthritis Rheum. 2012;64:613–6.
Goldring MB, Otero M. Inflammation in osteoarthritis. Curr Opin Rheumatol. 2011;23:471–8.
Bondeson J, Blom AB, Wainwright S. The role of synovial macrophages and macrophage-produced mediators in driving inflammatory and destructive responses in osteoarthritis. Arthritis Rheum. 2010;62:647–57.
• 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;63:691–9. This paper reports important data on the sources of pain in patients with knee OA.
Ordeberg G. Evidence of sensitization to pain in human osteoarthritis. In: Felson DT, Schaible H-G, editors. Pain in osteoarthritis. Hoboken: Wiley Blackwell; 2009. p. 199–209.
Hochman JR, Gagliese L, Davis AM, Hawker GA. Neuropathic pain symptoms in a community knee OA cohort. Osteoarthritis Cartilage. 2011;19:647–54.
Eckstein F, Cotofana S, Wirth W, et al. Greater rates of cartilage loss in painful knees than in pain-free knees after adjustment for radiographic disease stage. Arthritis Rheum. 2011;63:2257–67.
Wittoek R, Cruyssen BV, Verbruggen G. Predictors of functional impairment and pain in erosive osteoarthritis of the interphalangeal joints. Arthritis Rheum. 2012;64:1430–6.
Schaible H-G. Joint pain – Basic mechanisms. In: McMahon SB, Koltzenburg M, editors. Wall and Melzack´s textbook of pain. 6th ed. Oxford: Elsevier; 2012. in press.
Im H-J, Kim J-S, Li X, et al. Alteration of sensory neurons and spinal response to an experimental osteoarthritis pain model. Arthritis Rheum. 2010;62:2995–3005.
Ivanavicius SP, Ball AD, Heapy CG, et al. Structural pathology in a rodent model of osteoarthritis is associated with neuropathic pain: increased expression of ATF-3 and pharmacological characterisation. Pain. 2007;128:272–82.
Orita S, Ishikawa T, Miyagi M, et al. Pain-related sensory innervation in monoiodoacetate-induced osteoarthritis in rat knees that gradually develops neuronal injury in addition to inflammatory pain. BMC Musculoskelet Disord. 2011;12:134.
Liu P, Okun A, Guo R-C, et al. Ongoing pain in the MIA model of osteoarthritis. Neurosci Lett. 2011;493:72–5.
Ferland CE, Levrty S, Beaudry F, Vachon P. Gait analysis and pain response of two rodent models of osteoarthritis. Pharmacol Biochem Behav. 2011;97:603–10.
Malfait AM, Ritchie J, Gil AS, et al. ADAMTS-5 deficient mice do not develop mechanical allodynia associated with osteoarthritis following medial meniscal destabilization. Osteoarthritis Cartilage. 2010;18:572–80.
Schaible H-G, Richter F, Ebersberger A, et al. Joint pain. Exp Brain Res. 2009;196:153–62.
Schuelert N, McDougall JJ. Grading of monosodium iodoacetate-induced osteoarthritis reveals a concentration-dependent sensitization of nociception in the knee joint of the rat. Neurosci Lett. 2009;465:184–8.
McDougall JJ, Andruski B, Schuelert N, et al. Unravelling the relationship between age, nociception and joint destruction in naturally occurring osteoarthritis of Dunkin Hartley guinea pigs. Pain. 2009;141:222–32.
Schaible H-G, Ebersberger A, Natura G. Update on peripheral mechanisms of pain: beyond prostaglandins and cytokines. Arthritis Res Ther. 2011;13:210.
•• Lane NE, Schnitzer TJ, Birbara CA, et al. Tanezumab for the treatment of pain from osteoarthritis of the knee. N Engl J Med. 2010;363:1521–31. This study shows for the first time the use of a monoclonal antibody to NGF in pain treatment in patients with moderate to severe OA pain.
Nagashima H, Suzuki M, Araki S, et al. Preliminary assessment of the safety and efficacy of tenazumab in Japanese patients with moderate to severe osteoarthritis of the knee: a randomized, double-blind, dose-escalation, placebo-controlled study. Osteoarthritis Cartilage. 2011;19:1405–12.
Schnitzer TJ, Lane NE, Birbara C, et al. Long-term open-label study of tanezumab for moderate to severe osteoarthritis. Osteoarthritis Cartilage. 2011;19:639–46.
Bennett D. NGF, sensitization of nociceptors. In: Schmidt RF, Willis WD, editors. Encyclopedia of pain, volume 2. Berlin, Heidelberg New York, Tokyo: Springer; 2007. p. 1338–42.
McNamee KE, Burleigh A, Gompels LL, et al. Treatment of murine osteoarthritis with TrkAd5 reveals a pivotal role for nerve growth factor in non-inflammatory joint pain. Pain. 2010;149:386–92.
Richter F, Natura G, Loeser S, et al. Tumor necrosis factor-α (TNF-α) causes persistent sensitization of joint nociceptors for mechanical stimuli. Arthritis Rheum. 2010;62:3806–14.
Schaible H-G, Segond von Banchet G, Boettger MK, et al. The role of proinflammatory cytokines in the generation and maintenance of joint pain. Ann N Y Acad Sci. 2010;1193:60–9.
Boettger MK, Leuchtweis J, Kümmel D, et al. Differential effects of locally and systemically administered soluble glycoprotein 130 on pain and inflammation in experimental arthritis. Arthritis Res Ther. 2010;12:R140.
Attur M, Belitskaya-Lévy I, Oh C, et al. Increased interleukin-1ß gene expression in peripheral blood leukocytes is associated with increased pain and predicts risk for progression of symptomatic knee osteoarthritis. Arthritis Rheum. 2011;63:1908–17.
Schuelert N, McDougall JJ. Involvement of Nav1.8 sodium channels in the transduction of mechanical pain in a rodent model of osteoarthritis. Arthritis Res Ther. 2012;14:R5.
Schuelert N, Zhang C, Mogg AJ, et al. Paradoxical effects of the cannabinoid CB(2) receptor agonist GW405833 on rat osteoarthritic knee joint pain. Osteoarthritis Cartilage. 2010;18:1536–43.
Zhang W, Robertson J, Jones AC, Dieppe PA, Doherty M. The placebo effect and its determinants in osteoarthritis: meta-analysis of randomised controlled trials. Ann Rheum Dis. 2008;67:1716–23.
Boettger MK, Kümmel D, Harrison A, Schaible H-G. Evaluation of long-term antinociceptive properties of of stabilized hyaluronic acid preparation (NASHA) in an animal model of repetitive joint pain. Arthritis Res Ther. 2011;13:R110.
Jorgensen A, Stengaard-Pedersen K, Simonsen O, et al. Intra-articular hyaluronan is without clinical effect in knee osteoarthritis: a multicentre, randomised, placebo-controlled, double blind study of 337 patients followed for 1 year. Ann Rheum Dis. 2010;69:1097–102.
Chevalier X, Jerosch J, Goupille P, et al. Single, intraarticular treatment with 6 ml hylan G-F 20 in patients with symptomatic primary osteoarthritis of the knee: a randomised, multicentre, double-blind, placebo controlled trial. Ann Rheum Dis. 2010;69:113–9.
Berenbaum F, Grifka J, Cazzaniga J, et al. A randomised, double-blind, controlled trial comparing two intra-articular hyaluronic acid preparations differing by their molecular weight in symptomatic knee osteoarthritis. Ann Rheum Dis. doi:10.1136/annrheumdis-2011-200972.
Gomis A, Miralles A, Schmidt RF, Belmonte C. Intra-articular injections of hyaluronan solutions of different elastoviscosity reduce nociceptive nerve activity in a model of osteoarthritic knee joint of the guinea pig. Osteoarthritis Cartilage. 2009;17:798–804.
Ashraf S, Mapp PI, Walsh DA. Contributions of angiogenesis to inflammation, joint damage, and pain in a rat model of osteoarthritis. Arthritis Rheum. 2011;63:2700–10.
Arendt-Nielsen L, Nie H, Laursen MB, et al. Sensitization in patients with painful knee osteoarthritis. Pain. 2010;149:573–81.
Rahman W, Bauer CS, Bannister K, et al. Descending serotoninergic facilitation and the antinociceptive effects of pregabalin in a rat model of osteoarthitic pain. Mol Pain. 2009;5:45.
Sagar DR, Staniaszek LE, Okine BN, et al. Tonic modulation of spinal hyperexcitability by the endocannabinoid receptor system in a rat model of osteoarthritis pain. Arthritis Rheum. 2010;62:3666–76.
Telleria-Diaz A, Schmidt M, Kreusch S, et al. Spinal antinociceptive effects of cyclooxygenase inhibition during inflammation: involvement of prostaglandins and endocannabinoids. Pain. 2010;148:26–35.
Kosek E, Ordeberg G. Lack of pressure pain modulation by heterotopic noxious conditioning stimulation in patients with painful osteoarthritis before, but not following surgical pain relief. Pain. 2000;88:69–78.
Gwilym SE, Keltner JR, Warnaby CE, et al. Psychophysical and functional imaging evidence supporting the presence of central sensitization in a cohort of osteoarthritis patients. Arthritis Rheum. 2009;61:1226–34.
Kulkarni B, Bentley DE, Elliott R, et al. Arthritic pain is processed in brain areas concerned with emotions and fear. Arthritis Rheum. 2007;56:1345–54.
Gwilym SE, Filippini N, Douaud G, et al. Thalamic atrophy associated with painful osteoarthritis of the hip is reversible after arthroplasty. Arthritis Rheum. 2010;62:2930–40.
Rodriguez-Raecke R, Niemeier A, Ihle K, et al. Brain gray matter decrease in chronic pain is the consequence and not the cause of pain. J Neurosci. 2009;29:13746–50.
Hess A, Axmann R, Rech J, et al. Blockade of TNF-α rapidly inhibits pain responses in the central nervous system. PNAS. 2011;108:3731–36.
No potential conflicts of interest relevant to this article were reported.
About this article
Cite this article
Schaible, HG. Mechanisms of Chronic Pain in Osteoarthritis. Curr Rheumatol Rep 14, 549–556 (2012). https://doi.org/10.1007/s11926-012-0279-x
- Bone marrow lesion
- Brain atrophy
- Central sensitization
- COX-2 inhibitor
- Descending facilitation
- Descending inhibition
- Hyaluronic acid
- Joint nociceptor
- Joint pain
- MIA model
- Microglial activation
- Nerve growth factor
- Peripheral sensitization
- Sodium channel blocker
- TRPV1 channel
- Chronic pain