Anti-inflammatory medication side-effects – accelerated knee osteoarthritis

Marc Darrow, MD. JD.

As we see more patients looking for alternatives to knee surgery and many of those people are being pain managed with anti-inflammatory medications or NSAIDs (non-steroidal anti-inflammatory medications) and painkillers, one question they all seem to have is: “What are these medications doing to my knees?”

The simple answer is, according to published research, they are destroying your knees. The research supporting this statement goes back for decades. In 1993 Dr. MJ Shield of the Department of Medical and Clinical Research, Searle, Bucks, United Kingdom, wrote in the European journal of rheumatology and inflammation (1) : “Growing evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs), while able to alleviate inflammation, may damage articular cartilage.” How? By preventing the growth of new cartilage.

Nothing has changed in 31 years. These medications are continually shown to accelerate knee damage.

But, while NSAIDS can make knees feel better in the short-term, more and higher doses are needed to in the long-term to achieve similar results. In the over 22 years that we have treated patients with knee problems, there has always been the instance when a patient will ask us if they can continue with their anti-inflammatory medications. The answer is typically no. When the patient asks why? We remind them that regenerative medicine techniques like the ones we use, count on the beneficial aspects of inflammation. Inflammation is the way Nature heals. If we stop the inflammation, we stop the healing.

This simple statement, that inflammation is Nature’s way of healing has been the subject of decades long debate in the medical community. Many doctors argue that you have to shut down inflammation to prevent more damage. For decades, cortisone became the weapon of choice. Cortisone as doctors would later find out, would destroy joints and contributed to the great surge in joint replacement surgeries.

But don’t you need to shut down inflammation to heal?

When someone comes into our office with a swollen knee, they will often discuss with us the problems of their knee pain with the thought that the inflammation is the cause of that pain. That is why, they often tell us, they are on anti-inflammatories, “to help the pain.” Therefore, before they come visit us, they have associated anti-inflammatories with reduction in knee pain. The question then is does knee inflammation really cause knee pain?

A group of medical researchers in Australia looked at inflamed knees. The researchers wanted to see what came first, knee inflammation or knee degenerative changes. In other words, did the inflammation cause the degenerative knee disease or did the degenerative knee disease cause the inflammation?

Knowing which came first would make a big difference for patients with knee pain and degenerative arthritis, and, towards helping doctors and patients understand a path of treatment. This treatment path would would move away from the use of anti-inflammatories as a primary step in “conservative care” of knee pain. The research team published their findings in The Journal of Rheumatology (2) to suggest:

“Knee cartilage and subchondral bone abnormalities predicted change in effusion-synovitis, but effusion-synovitis did not predict knee structural changes. These findings suggest that synovial inflammation is likely the result of joint structural abnormalities in established osteoarthritis.”

The knee damage that causes inflammation came first. Therefore chronic inflammation would make the knee worse and send the knee towards knee replacement. This study presents an interesting scenario that the inflammation causes knee degeneration and knee degeneration causes inflammation cycle has a starting point. Significant knee damage.

The greater knee pain could contribute to a new knee injury, which is often characterized by a destabilizing meniscal tear

Taking this idea further is this 2020 study (3) suggesting:

“Within 12 months before radiographic onset, adults with advanced knee osteoarthritis report more joint symptoms, frequent use of pain medication, frequent knee swelling, and daily knee pain compared with those who develop typical knee osteoarthritis. The greater knee pain could contribute to a new knee injury, which is often characterized by a destabilizing meniscal tear. The joint trauma may be a triggering event in a joint with an impaired ability to heal, which ultimately leads to joint failure.”

“medical management of hip and knee osteoarthritis, particularly with non-steroidal anti-inflammatory drugs, may carry higher mortality compared to surgery.” Surgery is dangerous. Anti-inflammatories are more dangerous.

This is from the Journal of orthopaedic surgery,(4) and university hospitals in the United Kingdom, The doctors in this study compared the long-term safety of taking anti-inflammatory medications with the long-term safety of knee and hip replacements. They are measuring side effects including mortality.

  • Mortality was the highest for naproxen (Aleve, Moltrin) and lowest for total hip replacement.
  • Highest gastrointestinal complications were reported for diclofenac (Voltaren) and lowest for total knee replacement
  • Ibuprofen had the highest renal complications.
  • Celecoxib (Celebrex) had the highest cardiovascular risk

The researchers said: “results of this study show that medical management of hip and knee osteoarthritis, particularly with non-steroidal anti-inflammatory drugs, may carry higher mortality compared to surgery.”

I have written an extensive article Dependency on painkillers may lead to unsuccessful knee replacement that will help shed more light on this subject.

Minor adverse effects

A May 2020 paper (6) wrote: “Despite an extensive body of research on non-steroidal anti-inflammatory drugs (NSAIDs) in osteoarthritis, the duration of their efficacy and timeline of adverse event onset have been understudied. (This research) is a systematic review and meta-analyses from 2 to 26 weeks to characterize the efficacy and adverse event trajectories of oral NSAIDs in knee osteoarthritis.

  • NSAIDs demonstrated moderate, statistically significant effects on pain that peaked at 2 weeks but the magnitude of the effects decreased over time. The results for function were similar. The incidence of gastrointestinal (GI) adverse event was significantly higher in NSAID users than placebo users as early as 4 weeks. The incidence of cardiovascular adverse event  in NSAID users was not significantly different from placebo. Most GI and cardiovascular adverse event were transient and of minor severity.

Conclusion: NSAIDs produced significant pain and function improvements that peaked at 2 weeks but decreased over time. The incidence of minor GI and cardiovascular adverse events consistently rose, reaching significance as early as 4 weeks. Clinicians should weigh the durability of efficacy with the early onset of minor adverse events along with patient tolerability and preferences when formulating an NSAID regimen.”

Should NSAIDs be given to patients 75 and older?

A June 2021 paper (8)  questioned whether of not NSAIDs should be given to patients 75 and older. Here is what the paper discussed: “Practitioners involved in the management of  osteoarthritis often have to manage very old patients, aged 75-80 years and above, as part of their daily practice. Treatment options are limited. In addition to education and physical treatments, which are at the forefront of all treatment recommendations but require a low level of symptoms to be implemented, many pharmacological options are proposed. Nonsteroidal anti-inflammatory drugs (NSAIDs) can be used as a second-line treatment but with great caution. However, the precise incidence of cardiovascular, renal, and gastrointestinal adverse events in very elderly patients is unclear. All of these risks are increased in the elderly. The relative risks can be extrapolated from various studies. However, what is the absolute risk according to age categorization? The answer to this question is important because NSAIDs should be used in very elderly patients with osteoarthritis only if full information has been provided and the decision to prescribe this treatment is shared between the patient and their doctor.”

“Use of specific medications may accelerate the progression of radiographic knee osteoarthritis.”

A January 2021 study (5) found the “Use of specific medications may accelerate the progression of radiographic knee osteoarthritis.” Of the different medications, including statins, anti-hypertensives, anti-depressant/anxiolytics/psychotropics, osteoporosis-related medication, diabetes-related medication, and NSAIDs, only the NSAIDs accelerate joint space loss and a worsening knee osteoarthritis condition.


Understanding the healing and destructive roles of knee inflammation

In the research I mentioned at the top of this article, doctors looked at the inflamed synovial membrane in the knees of 413 patients with painful osteoarthritis. The patients were almost equally divided into similar groups of women and men, and the average age was 63 years old.

The synovial membrane is a tissue that surrounds the knee and protects the joint capsule. In addition, to acting as a protective lining, the membrane secretes synovial fluid. Synovial fluid is a lubricant that helps the cartilage of the knee glide through normal range of motion.

When the synovial membrane becomes inflamed, it secrets inflamed synovial fluid.

Inflamed synovial fluid makes more inflammation.

While rheumatoid arthritis or immune disorder can cause synovitis, this study focuses on the development of synovitis as being caused by degenerative wear and tear arthritis..

Back to the the Australian research team. In the subject patients the doctors measured:

  • The inflamed fluid of the knee synovitis, cartilage defects, cartilage volume, and bone marrow lesions via magnetic resonance imaging.
  • Joint space narrowing and osteophytes (bone spurs) were assessed using radiograph.
  • Knee symptoms were assessed by using the popular Western Ontario and McMaster University (WOMAC) osteoarthritis index scoring system.

Here is the research conclusion:

Knee cartilage and subchondral bone abnormalities predicted change in effusion-synovitis (more inflammation), but effusion-synovitis (more inflammation) did not predict knee structural changes. These findings suggest that synovial inflammation is likely the result of joint structural abnormalities in established osteoarthritis. This means that that anti-inflammatory treatments are only suppressing inflammation, the degenerative damage to the knees continues.

A clear cut association between inflammation and pain could not be made

An April 2022 paper (7) reviewed the current medical literature on the relationship between inflammatory markers and pain in patients with knee osteoarthritis. Inflammatory markers were listed as effusion, synovitis, baker’s cysts, cytokines and C-reactive protein.  The researchers found that the strength of the association between inflammation and pain does not exceed the moderate level. Meaning a clear cut association between inflammation and pain could not be made. In fact the evidence was conflicting.

That knee swelling or inflammation causes knee pain is the subject of debate in the medical community. In a paper from 2011, doctors demonstrated the problems of what an MRI says is going on in the knee, how much swelling is going on in the knee, and then trying to determine if what the doctors were seeing was actually causing the knee pain.

In this 2011 paper (8) doctors systematically evaluates the association between MRI findings (cartilage defects, bone marrow lesions, osteophytes (bone spurs), meniscal lesion, effusion/synovitis, ligamentous (knee ligament) abnormalities, subchondral cysts and bone attrition) and pain in patients with knee osteoarthritis in order to establish the relevance of such findings when assessing an individual patient.

The doctors here found that bone marrow lesions and having pain when inflammation was present may indicate the source of the knee pain, however, while this evidence was moderate, other MRI findings were limited or conflicting. A strong recommendation connecting inflammation and pain could not be made.

Why use this 2011 as a benchmark to reviewing other research? Certainly things have changed for the better since 2011? No, not really. This is attested by the number of research papers using this research as a citation. Over 100.

NSAIDs reduce the effectiveness of Mesenchymal Stromal Cell Therapy

An April 2022 study (9) discussed how NSAIDs reduce the effectiveness of stem cell therapy. In this paper Mesenchymal Stromal Cell Therapy is used to describe stem cell therapy.

“Intra-articular injections of human mesenchymal stromal cells (hMSCs) have shown promise in slowing cartilage degradation in posttraumatic osteoarthritis. Clinical use of cell therapies for osteoarthritis has accelerated in recent years without sufficient scientific evidence defining best-use practices. Common recommendations advise patients to avoid nonsteroidal anti-inflammatory drug (NSAID) use before and after cell injection over concerns that NSAIDs may affect therapeutic efficacy. Recommendations to restrict NSAID use are challenging for patients, and it is unclear if patients are compliant.”

In this paper the researchers suggested that NSAIDs will reduce the efficacy of stem cells in treating  posttraumatic osteoarthritis. To demonstrate their hypothesis the researchers conducted animal research on rats. The rats had a surgery to remove their medical meniscus to accelerate the development of posttraumatic osteoarthritis. The lab rats received naproxen solution orally daily before (Pre-NSAID group) or after (Post-NSAID group) hMSC treatment, throughout the course of the experiment (Full-NSAID group), or received hMSCs without NSAIDs (No NSAID).

Results: Injection of human mesenchymal stromal cells attenuated cartilage degeneration associated with medial meniscus tear. Human mesenchymal stromal cells prevented proteoglycan loss, maintained smooth cartilage surfaces, reduced cartilage lesions, reduced mineralized osteophyte formation, and reduced pain by week seven. The Pre-NSAID group had decreased proteoglycan levels compared with the human mesenchymal stromal cells group, although there were no other significant differences. Thus, pretreatment with NSAIDs had minimal effects on the therapeutic benefits of human mesenchymal stromal cells injections. The Post-NSAID and Full-NSAID groups, however, exhibited significantly worse osteoarthritis than the human mesenchymal stromal cells-only group, with greater proteoglycan loss, surface roughness, osteophyte volume, and pain.

Clinical relevance: “This study supports” the clinical recommendation of avoiding NSAID use after human mesenchymal stromal cells injection but suggest that using NSAIDs before treatment may not substantially diminish the therapeutic efficacy of cell treatment.”

Moving away from anti-inflammatory treatments and moving towards pro-inflammatory treatments.

Treatments such as cortisone injections, Regenokine injections, NSAIDs (non-steroidal anti-inflammatories) may do more damage than good in some people. The inflammation is trying to heal damage, shutting off the inflammation makes MORE damage. This is why certain branches of medicine are  moving away from anti-inflammatory treatments and moving towards pro-inflammatory treatments.

1 Shield MJ. Anti-inflammatory drugs and their effects on cartilage synthesis and renal function. European journal of rheumatology and inflammation. 1993;13(1):7-16.
2 Wang X, Jin X, Blizzard L, Antony B, Han W, Zhu Z, Cicuttini F, Wluka AE, Winzenberg T, Jones G, Ding C. Associations Between Knee Effusion-synovitis and Joint Structural Changes in Patients with Knee Osteoarthritis. The Journal of Rheumatology. 2017 Sep 1:jrheum-161596.
3 Driban JB, Harkey MS, Barbe MF, Ward RJ, MacKay JW, Davis JE, Lu B, Price LL, Eaton CB, Lo GH, McAlindon TE. Risk factors and the natural history of accelerated knee osteoarthritis: a narrative review. BMC musculoskeletal disorders. 2020 Dec;21:1-1.
4 Aweid O, Haider Z, Saed A, Kalairajah Y. Treatment modalities for hip and knee osteoarthritis: A systematic review of safety. Journal of Orthopaedic Surgery. 2018 Nov 8;26(3):2309499018808669.
5 Perry TA, Wang X, Nevitt M, Abdelshaheed C, Arden N, Hunter DJ. Association between current medication use and progression of radiographic knee osteoarthritis: data from the Osteoarthritis Initiative. Rheumatology. 2021 Jan 27.—
6 Osani MC, Vaysbrot EE, Zhou M, McAlindon TE, Bannuru RR. Duration of symptom relief and early trajectory of adverse events for oral nonsteroidal antiinflammatory drugs in knee osteoarthritis: a systematic review and meta‐analysis. Arthritis care & research. 2020 May;72(5):641-51.
7 Dainese P, Wyngaert KV, De Mits S, Wittoek R, Van Ginckel A, Calders P. ASSOCIATION BETWEEN KNEE INFLAMMATION AND KNEE PAIN IN PATIENTS WITH KNEE OSTEOARTHRITIS: a systematic review. Osteoarthritis and Cartilage. 2021 Dec 27.
8 Yusuf E, Kortekaas MC, Watt I, Huizinga TW, Kloppenburg M. DO KNEE ABNORMALITIES VISUALISED ON MRI EXPLAIN KNEE PAIN IN KNEE OSTEOARTHRITIS? A SYSTEMATIC REVIEW. Annals of the rheumatic diseases. 2011 Jan 1;70(1):60-7.
9 Sok D, Raval S, McKinney J, Drissi H, Mason A, Mautner K, Kaiser JM, Willett NJ. NSAIDs Reduce Therapeutic Efficacy of Mesenchymal Stromal Cell Therapy in a Rodent Model of Posttraumatic Osteoarthritis. The American Journal of Sports Medicine. 2022 Apr;50(5):1389-98.
10 Cadet C, Maheu E, French AGRHUM Group (Association Geriatric and RHeUMatology). Non-steroidal anti-inflammatory drugs in the pharmacological management of osteoarthritis in the very old: prescribe or proscribe?. Therapeutic advances in musculoskeletal disease. 2021 Jun;13:1759720X211022149.




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