Osteoarthritis is the leading musculoskeletal cause of disability in western society. General practitioners are central in the management of patients with osteoarthritis.
To review the literature on factors associated with pain in osteoarthritis and discuss the implications of these findings for management.
It is well known that there is a modest correlation between X-ray changes and pain, mainly because an X-ray is a poor measure of what is happening in the joint. For example, in the knee, there is consistent evidence that bone marrow lesions, synovitis/effusions and cartilage defects are associated with knee pain and cartilage loss. In addition, muscle strength and obesity are predictors of pain, even in structurally normal knees. Lastly, central factors and genetic factors have been implicated in the pain experience. Thus, osteoarthritis is an umbrella term for a number of pathways that lead to very similar pain and structural outcomes, which is leading to lesion-specific therapies, indicating the importance of trying to pinpoint causes of pain in the individual.
Osteoarthritis as a public health problem
Osteoarthritis is the most common form of arthritis and the incidence is increasing markedly due to an ageing population. It is a whole-joint problem that leads to cartilage loss and, eventually, joint failure. In Australia, it is one of the most frequent causes of pain, loss of function and disability in adults. It is pain that drives the patient to seek help, interferes with quality of life and accounts for up to 30% of the variance in quality-of-life scores in people aged 50–80 years living in Hobart.1 The aim of this article is to review the literature on factors associated with pain and discuss the implications of these findings for therapy, with a focus on the knee.
Radiographs and knee pain
There have been many studies of knee pain.2 A systematic review of the literature showed that 15–76% of patients with knee pain were found to have radiographic osteoarthritis, and 15–81% of those with radiographic knee osteoarthritis had pain.2 Overall, there is a modest but significant correlation between the degree of radiographic change and knee pain, which is most consistent for osteophytes.2 However, a study from our group reported a significant association between osteophytes and pain but this disappeared after adjustment for muscle strength, BMI and a number of factors assessed on MRI scanning,3 suggesting that osteophytes may be a reflection of the disease process but not a key player.
MRI features and knee pain
Bone marrow lesions
There is strong and increasing evidence from studies in humans that bone has an important role in the pathogenesis of osteoarthritis.4 In particular, bone marrow lesions (BMLs), have been recognised as a key feature of knee osteoarthritis.5–7 A number of studies have linked BMLs with knee pain.3,5–7 There are now two papers that show a significant correlation between change in BMLs and change in pain, both in unselected community living6 and osteoarthritis populations,7 suggesting a potential target for therapy. Indeed, a report of a proof-of-principle trial done in those with only BMLs demonstrated that zoledronic acid (a potent bone-acting bisphosphonate) could decrease both pain and BML size over 6 months.8 Another trial of chondroitin sulphate in patients who had knee osteoarthritis showed a decrease in BML size over 12 months but no change in pain.9
Cartilage defects are very common, being present in high proportions in many studies.4 Cartilage is aneural and therefore defects in cartilage should not be associated with pain. Despite this, there is consistent evidence that they are associated with pain,3,10–14 and that this is largely independent of other structural factors. Cartilage defects correlate strongly with BMLs, suggesting that BMLs and cartilage defects are closely related but both have independent associations with pain. This may be mediated by substance P nociceptive fibres15 or superinduction of cyclooxygenase 2 and prostaglandins.16 Weight loss may improve defects.17
The association between meniscal pathology and pain remains controversial and may reflect site-specific associations. Any meniscal damage was associated with knee pain but not after adjustment for radiographic osteoarthritis.18 In a study from our institution, meniscal tear at the lateral posterior and anterior horns, but not other sites, was significantly associated with questionnaire-assessed pain, stiffness and function scores.19 In another study, macerated tears were associated with pain.14 Again, weight loss may improve cartilage loss in those with meniscal tear.20
The evidence links local inflammation (measured as synovitis and/or effusions) with pain.21 Further, in two studies, changes in synovitis (but not effusion severity) were associated with fluctuations in knee pain in patients with knee osteoarthritis,22,23 suggesting that synovitis may be the key factor and effusion a consequence of synovitis. C‑reactive protein (CRP) levels in serum are also predictive of knee pain development over 5 years24 (even though they are within the normal range) and this association is independent of all measured knee structural abnormalities in that study, suggesting systemic inflammation is also important. In terms of therapy, this opens up a number of options. Corticosteroid injections are effective for pain in knee osteoarthritis but seem to be most effective for effusions.25 Thus, it would seem logical to preferentially give corticosteroid injections to those with effusions. Non-steroidal anti-inflammatory drugs (NSAIDs) help to manage pain in osteoarthritis but there is limited data on who may benefit most from the use of these agents.26
Other knee structures
There is generally consistent evidence that knee bone size, subchondral bone density, meniscal extrusion and cartilage volume are not associated with pain3 (also Jones G et al, unpublished data).
Obesity is a very strong, independent correlate of knee pain and is consistently associated with knee pain in many studies.3,11,27 There is Level 1 evidence that weight loss improves knee symptoms,26 although interestingly, there is a stronger correlation between weight gain and worsening pain than between weight loss and improvements in pain, suggesting limited reversibility.28 Nevertheless, in the overweight patient with limited structural pathology, weight loss should be the main objective.
Similarly to obesity, muscle weakness, especially in the quadriceps, is independently associated with pain in cross-sectional3 and longitudinal studies.29 There is Level 1 evidence that strengthening and aerobic exercises help to manage pain in knee and hip osteoarthritis.26 Whether these therapies work better in those with weaker muscles is unknown.
Central factors and genetics
It is clear that pain in osteoarthritis is also modulated by a number of central factors, such as depression, catastrophisation (the tendency to view or present a situation as considerably worse than it actually is), self-efficacy and a positive attitude.30–32 Recently, there have been studies implicating specific genes associated with pain processing in pain. These include genes for the transient receptor potential cation channel, subfamily V, member 1 (TRPV1); catechol-O-methyltransferase (COMT); and proprotein convertase gene 6 (PCSK6).33–35 There is limited data about therapy but evidence suggests that duloxetine (a serotonin and noradrenaline re-uptake inhibitor) has a modest but significant effect on pain in osteoarthritis of the knee.36
A woman aged 65 years, who is a retired gardener, presents with a 5-year history of progressive mechanical knee pain and swelling. She has some night pain and morning stiffness of 15 minutes. Before your consultation, she had tried full-dose paracetamol, glucosamine sulfate, rose hip vital, fish oil, physiotherapy, conservative weight loss programs and ibuprofen (in doses up to 800 mg/day). None of the treatments has been particularly beneficial and she finds it hard to walk more than 100 metres or climb stairs.
She has a background history of lumbar spondylolisthesis, hypertension (well controlled on an angiotensin converting enzyme inhibitor and diuretic), hypercholesterolaemia (on atorvastatin), obesity (BMI 38 kg/m2) and smoking. There is a strong family history of rheumatoid arthritis: her grandmother, father and aunt had this condition.
Examination shows an overweight woman with a full range of movement in both knees. She has small effusions, crepitus on movement and some medial bony enlargement and tenderness. Her muscles seem a little weak but you are unsure if this is due to pain. Hip movements are normal.
Radiographs show grade 1 (mild) joint space narrowing. Basic blood tests, including erythrocyte sedimentation rate (ESR), CRP, creatine kinase (CK) and rheumatoid factor, are normal. You diagnose osteoarthritis of the knees and consider a number of initial management strategies.
You consider NSAIDs in therapeutic doses are risky given her antihypertensive regime. Stopping her atorvastatin for a month may improve muscle function and pain but is unlikely to help the knee inflammation. You decide to drain the fluid from her knees and give her intra-articular corticosteroid injections (eg. 80 mg methylprednisolone) into each knee. This gives her 10 weeks of relief so you repeat this regimen approximately every 3 months.
After 2 years, the injections stop helping so you decide that further injections are unlikely to be worthwhile. She asks what other options are available. You discuss surgically assisted weight loss and joint replacement but she is not interested in either option. She is interested in a trial of zoledronic acid reported in a recent publication so you refer her for a rheumatology opinion.
An MRI scan shows a large medial plateau lesion (Figure 1). Six months after receiving zoledronic acid, a repeat MRI scan shows total resolution of the bone marrow lesion (Figure 2). However, the patient says there has been little, if any, change in pain.
Figure 1. MRI scan at baseline
Figure 2. MRI scan 6 months later
You again discuss options and take the view that lap banding may be more appropriate than joint replacement in this case given the significant obesity, the relatively mild joint changes and the literature suggesting overweight people have less successful joint replacement outcomes. She agrees to have lap banding done and loses 36 kg over 18 months. Her pain score is now 2/10 and she is on no pain medication and doing all the activities she wants to do. You leave follow up open depending on progress.
- Osteoarthritis is an umbrella term for a number of processes that lead to pain and/or cartilage loss.
- It is clear that osteoarthritis is an active process rather than merely wear and tear.
- Treatment should be tailored to the individual as same size does not fit all.
- Targeting subchondral bone has the most potential to modify osteoarthritis given failure of most therapies aimed at cartilage.
Competing interests: Graeme Jones has board membership on Novartis, Roche, Amgen, Abbott, Merck Sharpe & Dohme, Bristol–Myer Squibb, UCB, Pfizer, Janssen and Servier, and has received honoraria for educational presentations from Servier and MSD. He has also received honoraria from Novartis, Roche, Amgen, Abbott, MSD, BMS, UCB, Pfizer, Janssen and Servier for consultancy and lectures.
Provenance and peer review: Commissioned; externally peer reviewed.
- Laslett LL, Quinn S, Winzenberg T, Sanderson K, Cicuttini FM, Jones G. A prospective study of the impact of musculoskeletal pain and radiographic osteoarthritis on health related quality of life in community dwelling older people. BMC Musculoskelet Disord 2012;13:168.
- Bedson J, Croft PR. The discordance between clinical and radiographic knee osteoarthritis: a systematic search and summary of the literature. BMC Musculoskelet Disord 2008;9:116.
- Zhai G, Blizzard L, Srikanth V, et al. Correlates Of Knee Pain In Older Adults: Tasmanian Older Adult Cohort Study. Arthritis Rheum 2006;55:264–71.
- Ding C, Cicuttini F, Jones G. Tibial subchondral bone size and knee cartilage defects: relevance to knee osteoarthritis. Osteoarthr Cartil 2007;15:479–86.
- Felson DT, Chaisson CE, Hill CL, et al. The association of bone marrow lesions with pain in knee osteoarthritis. Ann Intern Med 2001;134:541–49.
- Dore D, Quinn S, Ding C, et al. Natural history and clinical significance of MRI-detected bone marrow lesions at the knee: a prospective study in community dwelling older adults. Arthritis Res Ther 2010;12:R223.
- Felson DT, 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.
- Laslett LL, Doré D, Quinn S, et al. Zoledronic acid reduces knee pain and bone marrow lesions over one year: a randomised controlled trial. Ann Rheum Dis 2012;71:1322–28.
- Wildi LM, Raynauld JP, Martel-Pelletier J, et al. Chondroitin sulphate reduces both cartilage volume loss and bone marrow lesions in knee osteoarthritis patients starting as early as 6 months after initiation of therapy: a randomised, double-blind, placebo-controlled pilot study using MRI. Ann Rheum Dis 2011;70:982–89.
- Sowers MF, Hayes C, Jamadar D, et al. Magnetic resonance- detected subchondral bone marrow and cartilage defect characteristics associated with pain and X-ray-defined knee osteoarthritis. Osteoarthr Cartil 2003;11:387–93.
- Zhai G, Cicuttini F, Ding C, Scott F, Garnero P, Jones G. Correlates of knee pain in younger subjects. Clin Rheumatol 2006;26:75–80.
- Torres L, Dunlop DD, Peterfy C, et al. The relationship between specific tissue lesions and pain severity in persons with knee osteoarthritis. Osteoarthr Cartil 2006;14:1033–40.
- Link TM, Steinbach LS, Ghosh S, et al. Osteoarthritis: MR imaging findings in different stages of disease and correlation with clinical findings. Radiology 2003;226:373–81.
- Sowers M, Karvonen-Gutierrez CA, Jacobson JA, Jiang Y, Yosef M. Associations of anatomical measures from MRI with radiographically defined knee osteoarthritis score, pain, and physical functioning. J Bone Joint Surg Am 2011;93:241–51.
- Fortier LA, Nixon AJ. Distributional changes in substance P nociceptive fiber patterns in naturally osteoarthritic articulations. J Rheumatol 1997;24:524–30.
- Amin AR, Attur M, Patel RN, et al. Superinduction of cyclooxygenase-2 activity in human osteoarthritis-affected cartilage. Influence of nitric oxide. J Clin Invest 1997;99:1231–37.
- Ding C, Cicuttini F, Scott F, Cooley H, Boon C, Jones G. Natural history of knee cartilage defects and factors influencing change. Arch Intern Med 2006;166:651–58.
- Englund M, Niu J, Guermazi A, et al. Effect of meniscal damage on the development of frequent knee pain, aching, or stiffness. Arthritis Rheum 2007;56:4048–54.
- Ding C, Martel-Pelletier J, Pelletier J-P, et al: Is meniscal tear an osteoarthritis risk factor? A cross-sectional study of associations between meniscal tear and knee structure, radiographic changes and symptoms in a largely non-osteoarthritic cohort. J Rheumatol 2007;34:776–84.
- Teichtahl A, Wluka A, Wang Y, et al. The longitudinal relationship between changes in body weight and changes in knee cartilage and pain among community-based adults with and without meniscal tears. Ann Rheum Dis In press 2013.
- Lo GH, McAlindon TE, Niu J, et al. Bone marrow lesions and joint effusion are strongly and independently associated with weight-bearing pain in knee osteoarthritis: data from the osteoarthritis initiative. Osteoarthr Cartil 2009;17:1562–69.
- 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.
- Hill CL, Hunter DJ, 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.
- Stannus O, Jones G, Cicuttini F, et al. Associations between serum levels of inflammatory markers and change in knee pain over 5 years in older adults: a prospective cohort study. Ann Rheum Dis In press 2013.
- Smith MD, Wetherall M, Darby T, et al. A randomized placebo-controlled trial of arthroscopic lavage versus lavage plus intra-articular corticosteroids in the management of symptomatic osteoarthritis of the knee. Rheumatology 2003;42:1477–85.
- Zhang W, Nuki G, Moskowitz RW, et al. OARSI recommendations for the management of hip and knee osteoarthritis: part III: Changes in evidence following systematic cumulative update of research published through January 2009. Osteoarthr Cartil 2010;18:476–99.
- Soni A, Kiran A, Hart DJ, et al. Prevalence of reported knee pain over twelve years in a community-based cohort. Arthritis Rheum 2012;64:1145–52.
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- Amin S, Baker K, Niu J, et al. Quadriceps strength and the risk of cartilage loss and symptom progression in knee osteoarthritis. Arthritis Rheum 2009;60:189–98.
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- Valdes AM, De Wilde G, Doherty SA, et al. The Ile585Val TRPV1 variant is involved in risk of painful knee osteoarthritis. Ann Rheum Dis 2011;70:1556–61.
- van Meurs JB, Uitterlinden AG, Stolk L, et al. A functional polymorphism in the catechol-O-methyltransferase gene is associated with osteoarthritis-related pain. Arthritis Rheum 2009;60:628–29.
- Malfait AM, Seymour AB, Gao F, et al. A role for PACE4 in osteoarthritis pain: evidence from human genetic association and null mutant phenotype. Ann Rheum Dis 2012;71:1042–48.
- Hochberg MC, Wohlreich M, Gaynor P, Hanna S, Risser R. 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.