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“How should I proceed and figure out what to do with our patients?” asked David T. Felson, MD, MPH, professor of medicine at Boston University School of Medicine, during OA Management Without Surgery in 2018, a session at the 2018 ACR/ARHP Annual Meeting. He also shared tips on how to interpret the effect size of clinical trial meta-analyses to see how available therapies work and compare to each other.
Pain is not patients’ only concern. Between 14% and 26% of patients with knee OA experience periodic knee buckling, and limit activity as a result, he said.1 “I had one patient who couldn’t go down to a basement and had to have her daughter come over to do her laundry,” he said. Her knees buckled when she walked downstairs, “and she was very scared she was going to fall.”
Patients with frequent, bothersome knee buckling should be referred to physical therapy (PT). “I don’t just refer patients to physical therapy. I instruct the physical therapist about exactly what I want.” To address muscle weakness that is the likely cause of the buckling, he prescribes functional closed-chain quadriceps strengthening and balance training. (Note: Chains are links of body parts, such as foot, ankle, knee and hip during walking. In a closed chain, the end of the chain farthest from the body is fixed, such as a squat where your feet are fixed and the rest of the leg chain moves.)
‘I don’t just refer patients to physical therapy. I instruct the physical therapist about exactly what I want.’ —David T. Felson, MD, MPH
To accurately interpret clinical trial data on medications for knee pain and other therapies, look at meta-analyses’ effect sizes, and watch for red flags that suggest publication bias, said Dr. Felson. Be skeptical of study results that seem too positive, trials that are not randomized and controlled, very small studies or markedly inconsistent results across studies. Trials with null results may never be published, and trials done in developing countries are overwhelmingly and suspiciously positive, he added.
Effect size in a trial is the average improvement in pain on the treatment minus the average improvement in pain while on placebo, divided by the standard deviation, he said. Dr. Felson offered a simple guide to gauge effect sizes of OA treatments: 0.2 to 0.5 is a small treatment effect, 0.5 to 0.8 is a moderate treatment effect, and 0.8 or greater is a large treatment effect. Total knee replacement surgery trials may have effect sizes of closer to 1.5, he said. Due to a strong placebo response in OA trials, look for effect sizes that show the treatment works better than placebo.
Sources of OA Knee Pain
Possible structural sources of knee OA pain include synovial thickening, effusions, bone marrow edema lesions (BMLs) and peri-articular lesions, said Dr. Felson.2-4 These are more easily seen through magnetic resonance imaging (MRI) than X-ray, and both valgus and varus knees may have BMLs, he said. Medial BMLs are related to joint malalignment.5
“These are trauma lesions. What they say is that there is so much stress in a localized area of the knee with that malalignment, they are actually causing damage to the bone. There’s an inflammatory or wound response. OA is like a series of little wounds,” he said. “Cartilage has no pain fibers in it. Cartilage is not a direct generator of pain. The way cartilage might generate pain is indirectly,” such as damaged cartilage releasing microscopic debris that eventually inflames the synovium, he said.
Current & Future Treatments
Acetaminophen, a conditional recommendation in the 2012 ACR recommendations for use of nonpharmacologic and pharmacologic therapies for knee OA pain, has a disappointing average effect size in trials of 0.23.6,7 He still recommends acetaminophen for patients who cannot tolerate non-steroidal anti-inflammatory drugs (NSAIDs), such as seniors. “I want to be as safe as I can be with my patients. But I don’t increase the dose, because there is no evidence to support that. Once they fail occasional acetaminophen, I don’t continue it,” he said.
However, NSAIDs are more effective for knee OA pain relief compared with acetaminophen, with a 0.29 effect size in a 2011 meta-analysis.8 “If acetaminophen fails or doesn’t work well, this is one of your choices,” he said. NSAIDs’ cardiovascular risks, particularly for older patients, vary depending on the drug.9 Oral diclofenac is dangerous, he stressed. “It puts people at increased risk of heart disease, mostly in people who are older whose main mortality risk is heart disease. I don’t use it,” he said. Topical diclofenac is a safer option with no systemic risks. Naproxen does not increase heart disease risk in many studies. “It needs to be in your portfolio of treatment. Not that it doesn’t have other side effects. It does. But with respect to risk of heart disease, it is entirely safe,” he said.
Nabumetone has a comparatively benign risk of upper gastrointestinal bleeding, and celecoxib is also safer option.10 He prefers to prescribe celecoxib at less than 400 mg a day to avoid an increase in heart disease risk.11 Consider topical NSAIDs over oral forms, he said. “Given the inefficacy of acetaminophen, I think these will surpass acetaminophen as a recommendation in the future. They are benign and work, although not terribly well, but mainly for hand OA and knee OA.”
Injections & Other Drugs
In a 2015 Cochrane review, intra-articular corticosteroids compared with placebo for knee OA pain had a small effect size of 0.3.12 Repeat injections significantly reduced cartilage thickness, according to a 2017 study, possibly because patients “felt so much better.13 They were much more active and they damaged their cartilage,” he said. “This doesn’t have anything to do with the effects of the steroid on cartilage. It has to do with the effect of activity on these knees.” Dr. Felson injects 80 mg of corticosteroids into the knees of his OA patients or 40 mg for diabetic patients, he said.
Intra-articular hyaluronic acid injections are ineffective for knee OA, although some patients may feel relief due to the placebo effect, he said.14 Glucosamine and chondroitin sulfate, although popular, also do not relieve OA knee pain.15 Opioids also do not work well for knee OA pain relief; a recent meta-analysis shows that opioids’ effect size is 0.36.16
Tanezumab, a humanized monoclonal antibody to nerve growth factor that targets the peripheral nerves, had an effect size of 0.8 in a 2010 randomized controlled trial, but the trial was stopped when patients in the active treatment group had rapid disease progression, likely due to overdoing physical activity when their pain subsided.17
Braces are effective treatments for malaligned joints, and in a 2015 meta-analysis, their effect size was 0.33.18 “Why are braces not the most popular treatment? The answer is that many patients won’t wear them or wear them for three hours a day or less,” he said. Suggest an over-the-counter knee brace before referring a patient to an orthotics specialist for a fitted brace due to the high cost, he suggested.
Exercise is also effective for knee pain, and if a patient is overweight, exercise with diet modification is even more effective, he said.19 He encourages his patients to do gentle squats at increasing depth as long as they are not in pain. “Exercise needs to be progressive,” he said. “You need to reinforce that with your patients.”
Susan Bernstein is a freelance medical journalist based in Atlanta.
- Felson DT, Niu J, McClennan C, et al. Knee buckling: Prevalence, risk factors, and associated limitations in function. Ann Intern Med. 2007 Oct 16;147(8):534–540.
- 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 Mar;63(3):691–699.
- Felson DT, Chaisson CE, Hill CL, et al. The association with bone marrow lesions with pain in knee osteoarthritis. Ann Intern Med. 2001 Apr 3;134(7):541–549.
- Hill CL, Gale DR, Chaisson CE, et al. Periarticular lesions detected on magnetic resonance imaging: Prevalence in knees with and without symptoms. Arthritis Rheum. 2003 Oct;48(10):2836–2844.
- Felson DT, McLaughlin S, Goggins J, et al. Bone marrow edema and its relation to progression of knee osteoarthritis. Ann Intern Med. 2003 Sep 2;139(5 Pt. 1):330–336.
- Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies for osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken). 2012 Apr;64(4):465–474.
- Neame R, Zhang W, Doherty M. A historic issue of the Annals: Three papers examine paracetamol in osteoarthritis. Ann Rheum Dis. 2004 Aug;63(8):897–900.
- Verkleij SP, Luijsterburg PA, Bohnen AM, et al. NSAIDs vs acetaminophen in knee and hip osteoarthritis: A systematic review regarding heterogeneity influencing the outcomes. Osteoarthritis Cartilage. 2011 Aug;19(8):921–929.
- Antman EM. Evaluating the cardiovascular safety of non-steroidal anti-inflammatory drugs. Circulation. 2017 May 23;135(21):2062–2072.
- Huang JQ, Sridhar S, Hunt RH. Gastrointestinal safety profile of nabumetone: A meta-analysis. Am J Med. 1999 Dec 13;107(6A):55S–61S.
- Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. N Engl J Med. 2016 Dec 29;375(26):2519–2529.
- Jüni P, Hari R, Rutjes AWS, et al. Intra-articular corticosteroid for knee osteoarthritis. Cochrane Database Syst Rev. 2015 Oct 22;(10):CD005328.
- McAlindon TE, LaValley MP, Harvey WF, et al. Triamcinolone vs saline on knee cartilage volume and pain in patients with knee osteoarthritis: A randomized clinical trial. JAMA. 2017 May 16;317(19):1967–1975.
- Lo GH, LaValley MP, McAlindon TE. Intra-articular hyaluronic acid in treatment of knee osteoarthritis: A meta-analysis. JAMA. 2003 Dec 17;290(23):3115–3121.
- Vlad SC, LaValley MP, McAlindon TE, Felson DT. Glucosamine for pain in osteoarthritis: Why do trial results differ? Arthritis Rheum. 2007 Jul;56(7):2267–2277.
- da Costa BR, Nüesch E, Kasteler R, et al. Oral or transdermal opioids for osteoarthritis of the knee or hip. Cochrane Database Syst Rev. 2014;9:CD003115.
- Lane NE, Schnitzer TJ, Birbara CA, et al. Tanezumab for the treatment of pain from osteoarthritis of the knee. New Engl J Med. 2010 Oct 14;363(16):1521–1531.
- Moyer RF, Birmingham TB, Bryant DM, et al. Valgus bracing for knee osteoarthritis: A meta-analysis of randomized trials. Arthritis Care Res (Hoboken). 2015 Apr;67(4):493–501.
- Messier SP, Loeser RF, Miller GD, et al. Exercise and dietary weight loss in overweight and obese older adults with knee osteoarthritis: The Arthritis, Diet, and Activity Promotion Trial. Arthritis Rheum. 2004 May;50(5):1501–1510.