When NSAIDs make pain worse and other side-effects

Ross Hauser, MD

There are countless articles on the internet describing the use of NSAIDs in treating chronic inflammation. This article will focus on one aspect of NSAIDs. How they can make your pain worse. We are going to span many years of research and bring you up to 2021 research that demonstrates NSAIDs can cause more pain.

NSAIDs prevent healing and send patients to joint replacement surgery is not a new idea, Caring Medical published research of 2010

In 2010, I published the following paper in the Journal of Prolotherapy. The Acceleration of Articular Cartilage Degeneration in Osteoarthritis by Nonsteroidal Anti-inflammatory Drugs. (1) In this research I stated:

The use of this nonsteroidal anti-inflammatory medication has been shown in scientific studies to accelerate the articular cartilage breakdown in osteoarthritis. The use of this product poses a significant risk in accelerating osteoarthritis joint breakdown. Anyone using this product for the pain of osteoarthritis should be under a doctor’s care and the use of this product should be with the very lowest dosage and for the shortest duration of time. If NSAID use continues, then most likely the exponential rise in degenerative arthritis and subsequent musculoskeletal surgeries, including knee and hip replacements as well as spine surgeries, will continue to rise as well.

NSAIDs and the acceleration of the arthritis process

NSAIDs are truly anti-inflammatory in their mechanism of action. Since all tissues heal by inflammation, one can see why long-term use of these medications will have harmful effects. Osteoarthritis and other chronic pain disorders are not ibuprofen or other NSAID deficiency. Their chronic long-term use will not cure, and will actually hamper soft tissue healing and accelerate the arthritic process.

In my 2010 study that I referenced above, I concluded the research with these thoughts:

“The lay public for whom NSAIDs are prescribed and recommended by both healthcare professionals and drug manufacturers should be aware that long-term NSAID use is detrimental to articular cartilage. Specifically, be informed that NSAIDs will likely worsen the osteoarthritis disease for which it is prescribed. Physicians, allied health care professionals, and drug manufacturers should be required to inform the lay public that NSAID use can accelerate osteoarthritis articular cartilage degeneration. A strict warning label on these medications should read as follows:

The use of this nonsteroidal anti-inflammatory medication has been shown in scientific studies to accelerate the articular cartilage breakdown in osteoarthritis. Use of this product poses a significant risk in accelerating osteoarthritis joint breakdown. Anyone using this product for the pain of osteoarthritis should be under a doctor’s care and use of this product should be with the very lowest dose and for the shortest possible duration of time.

One of the basic tenants of medicine is stated in the Hippocratic oath, “I will prescribe regimens for the good of my patients according to my ability and my judgment and never do harm to anyone.” For doctors to uphold this statement in the treatment of their osteoarthritis patients, it would necessitate the almost complete banning of the use of NSAIDs for this condition. If this does not occur, then most likely the exponential rise in degenerative arthritis and subsequent musculoskeletal surgeries, including knee and hip replacements, as well as spine surgeries, will continue for decades to come.”

The Effect of NSAIDs on Joints

Acceleration of radiographic progression of osteoarthritis.

Decreased joint space width.
Increased joint forces/loads.
Increased risk of joint replacement.
Inhibition of chondrocyte proliferation.
Inhibition of collagen synthesis.
Inhibition of glycosaminoglycan synthesis.
Inhibition of prostagalandin synthesis.
Inhibition of proteoglycan synthesis.
Inhibition of synthesis of cellular matrix components.

Do Anti-inflammatory medications damage your joints? Stop and slow healing?

I need to work

You may be saying to yourself: I am working a physically demanding job, this is why I am taking the anti-inflammatories. My joints are all swelled up, I can’t bend my knee because it is so puffy. My shoulder is sloshy around, I can hear all the water in it when I try to move it. I can’t tie my shoes because my ankle is always swelled up, I am wearing a size 12 boot and I am a size 9 shoe. What else am I supposed to do? I know these things are bad for me, my doctor who prescribed them told me that they are bad for me and we need to look at options. I need to go to work today.

Hopefully, we can share some answers further in this article.

I am waiting for eventual surgery

You may be saying to yourself: I am waiting for surgery, I have a lot of pain and I do not want to get on opioids or narcotics, I see the NSAIDs as the lesser of two evils. My doctor has already told me that I need a knee replacement, there is no other option. Please see our article on alternatives to knee replacement. There may be an option. One thing that research, as we will look at below does point out. If you are in a situation of joint erosion, NSAIDs will make it worse. I even published a paper on that. See below.

I need to take anti-inflammatories because all the other medical treatments did not work.

You may be saying to yourself, what else am I supposed to do? Nothing has worked, I had a surgery that left me worse off.

I want to keep playing or training.

You may be saying to yourself, I need to keep playing, I will deal with my issues after the season and then decide on what type of treatments or surgery I should get to repair the damage. What is really the harm? What is really the damage I am doing?

NSAIDs – What is really the damage? NSAIDs make your knees worse by thinning out your cartilage

The following is a small sample of the research that was published in the last two months. The side effects of NSAIDs can fill pages and pages.

January 2021 research (2) led by the University of Oxford says: “Use of specific medications may accelerate the progression of radiographic knee osteoarthritis.”

Here are the learning points of this research:

A the start of the study people with radiological evidence of knee osteoarthritis, greater than grade 2 level were selected. Data from patient medication habits were collected. Those who took medications prior to the x-ray were assessed for up to six years.
Study conclusion: In current users of NSAIDs, (knee joint space) loss was increased compared with current non-users in participants with radiographic knee osteoarthritis.

NSAIDs – What is really the damage? NSAIDs may cause organ failure

January 2021: Published in the medical journal Pain and Therapy: (3)
- Researchers examined the side effects of NSAIDs on kidney function and renal failure in patients with osteoarthritis and/or chronic low back pain.
- 180,371 patients, NSAIDs were prescribed as first-line analgesics in 89.3%. (Nine out of ten people got NSAIDs as the first-line treatment for their chronic pain)
- The risk for kidney-related adverse side-effects or renal failure was seen more in elderly patients and in those with diabetes, hypertension, and other cardiovascular diseases.
- Study conclusion: “Risk of renal events significantly increased with prolonged and consistent NSAID use with age, and in patients with certain comorbidities. Careful NSAID use is recommended in patients with chronic kidney disease and those at high risk for chronic kidney disease.

NSAIDs – What is really the damage? NSAIDs may cause joint replacement failure

December 2020: NSAIDs contribute to poorer outcomes after hip replacement.
- Published in the Journal of Orthopaedics (4) “Although the reported clinical outcomes of total hip arthroplasty (replacement) for hip osteoarthritis are satisfactory, not all patients are completely satisfied. Thus, there is interest in predicting postoperative satisfaction before surgery. The influence of comorbidities and preoperative medications on the incidence of complications and duration of hospitalization following total hip arthroplasty has become apparent.”

While there is more research, this paper may get the message home better than others.

A December 2020 study in the American Journal of Therapeutics (5) suggests: “There is convincing evidence that NSAIDs administered locally in and around the joint reduce postoperative pain scores and opioid consumption in patients undergoing total joint arthroplasty, yet further research is required regarding the risks of potential chondrotoxicity and the inhibition of bone and soft-tissue healing with locally administered NSAIDs.”

In other words, after the knee or hip or shoulder replacement, it may be better to help patients with their postoperative pain with NSAIDs than narcotic opioid medication. BUT, there may be risks that the NSAIDs may lead to a possible joint replacement failure because it is basically dissolving bone and inhibiting soft tissue repair.

Non-steroidal anti-inflammatory drugs, may carry higher mortality compared to surgery

An August 2018 paper from doctors at the Luton and Dunstable University Hospital and University College Hospital in London, wrote in the Journal of orthopaedic surgery,(18) about their observations in their comparison of the long-term safety of anti-inflammatory medications consumption with the long-term safety outcomes of knee and hip replacements. Here are the leraning points which suggest that taking anti-inflammatory medications was harmful than under going replacement surgery.

Cause of patient death was highest for naproxen and lowest for total hip replacement.
Highest gastrointestinal complications were reported for diclofenac and lowest for total knee replacement.
Ibuprofen had the highest renal complications.
Celecoxib (Celebrex) carried the highest cardiovascular risk.

The researchers concluded: “(The) 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.”

Understanding inflammation in healing: Chronic inflammation will continue trying to heal something it can’t.

To understand the above studies and why you have may still be experiencing pain despite increased dosage is to understand that you have passed the point of pain management and repair homeostasis in your painful or spine. Homeostasis simply means balance. You are degenerating faster than your body can heal.

Understanding inflammation in healing: Chronic inflammation will continue trying to heal something it can’t.

The body’s healing response is inflammation. Inflammation fixes injuries. Inflammation will turn on and continue staying on until the joint injury is healed. If you have reached the point of j your joint and spine breaking down faster than your body can fix it then the inflammatory mechanism will be stuck in the “open” position, chronic inflammation will continue trying to heal something it can’t.

Naturally occurring inflammation is filled with quick-acting chemicals. Let’s stress that these are quick acting and not “long-term.” One characteristic of inflammation is its use of powerful corrosives to remove dead and dying tissue.

If inflammation becomes chronic, naturally occurring powerful corrosives start eating away at your joint. This is the degenerative process.

And as far back as 1995, a classic study from the University of North Carolina, School of Medicine, Division of Orthopaedic Surgery, Sports Medicine section found how detrimental NSAIDs use was in healing soft tissue. The paper also stated a fact that many researchers in this field are still wondering, “Despite the lack of scientific data, NSAIDs are widely used, often as the mainstay of treatment.”(6) More than twenty five years later – little has changed.

This was later supported in the medical research which not only showed how NSAIDs destroyed joints but any treatments ability to fix that damage as well.

Doctors in Canada wrote in the journal Arthritis Research & Therapy: (7) NSAIDs makes pain worse and interfere with the body’s healing capabilities. NSAIDs do this by inhibiting the immune systems ability to regrow bone. Further, residual NSAID presence in the joints may weaken the bone, causing structural instability. This is supported by research from McGill University reporting on Naproxen’s effect on bone healing.
This research is from doctors at Maastricht University Medical Centre and Boston University. This study published in the journal Public Library of Science One (8) is a discussion of the NSAID COX-2 inhibitor. (COX or cyclooxygenase, are two enzymes (COX-1 and COX 2) that promote inflammation). COX inhibitors shut off inflammation and directly cause suppression of cartilage cell growth and natural repair of articular cartilage growth.
Doctors at Oxford University, writing in the journal Maturitas (9) examining elderly patients with non-healing bone fractures found the treatment of post-fracture pain with NSAIDs put the patient at the greatest risk for non-union of the fracture and questioned whether stem cell therapy was introduced into treatment could help these patients.
In the Journal of Gastroenterology and Hepatology, (10) researchers examined the digestive and gastrointestinal distress caused by NSAIDs and found that they may have their origin in the patient’s low anti-oxidant inner milieu. In other words, the immune system is too compromised to fight off the NSAIDs’ side effects including ulcers. This can also suggest that the immune system is too compromised to heal joints.

Clearly, NSAIDs inhibit and suppress the growth of bone and collagen, the stuff of ligaments, tendons, and cartilage. If a patient has a long history of NSAIDs this should be addressed prior to stem cell therapy and a treatment plan discussed.

Research: Stopping NSAIDs usage is seen as a way to help patients avoid joint replacement surgery and worsening pain

Researchers at the University of New England and the Center for Molecular Medicine at the Maine Medical Center Research Institute published a report in the journal Arthritis and Rheumatology. (11) In this report they wanted to examine evidence that exercise, commonly recommended for patients with osteoarthritis pain is beneficial. Especially, they wanted to know, if exercise is beneficial in situations where the pain is chronic and persistent, resistant to non-steroidal anti-inflammatory drugs, and associated with advanced osteoarthritis.

So they looked at laboratory rats and put them through a series of tests including a vigorous treadmill exercise program for 4 weeks. What they found was exercise induces pain relief in advanced, NSAID-resistant osteoarthritis, likely through increased endogenous opioid signaling. Endogenous opioids are the natural brain chemicals our bodies make to fight pain. Endogenous means from within. The most famous of these brain chemicals are endorphins. Not only do endorphins help alleviate pain but they also reduce anxiety and enhance mood. People who run long distances are familiar with the term “runner’s high.” That is what you can get while exercising, an “exercise high.”

One more thing, not only did the exercise release these natural painkillers we have inside us, but the treadmill exercise also secreted chemicals that blocked certain bone loss and helped with a potential bone-stabilizing effect on the osteoarthritis joint. In other words, the exercise helped block part of the joint bone erosion seen in advanced osteoarthritis.

When some patients stopped using NSAIDs and started exercising as best they could, these patients were much better.

So bringing this forward, and this is something we have seen many times in the many years we have seen patients, here we have someone in pain, they are taking anti-inflammatories because they and their health care providers believe inflammation is at the core of the problem. The pain persists, the NSAIDs are replaced by exercise felt much better.

Stopping NSAID usage is seen as a way to help patients avoid joint replacement surgery and worsening pain

At the Veteran’s Affairs of the Connecticut Healthcare System and Yale School of Medicine, a study is underway. The study is titled:

Discontinuing a non-steroidal anti-inflammatory drug (NSAID) in patients with knee osteoarthritis: Design and protocol of a placebo-controlled, noninferiority, randomized withdrawal trial. (12)

The hypothesis of this study, that is what the researchers are confident they will find is that a placebo will be just as effective as meloxicam, a commonly prescribed anti-inflammatory medication.

If the researchers can show this, then they can show, NSAIDs do not offer benefits and the need and way to get patients to stop using NSAIDs must be explored.

This is from the study:

“Knee osteoarthritis is the most common cause of knee pain in older adults. Despite the limited data supporting their use, non-steroidal anti-inflammatory drugs (NSAID) are among the most commonly prescribed medications for knee osteoarthritis.”
The use of NSAIDs for knee pain warrants careful examination because of toxicity associated with this class of medications. . .This study is the first clinical trial to date examining the effects of withdrawing an NSAID for osteoarthritis knee pain. If successful, this trial will provide evidence against the continued use of NSAIDs in patients with osteoarthritis knee pain.”

Research: The reason a joint replacement is recommended is that NSAIDs do not work. In fact, NSAIDs usage accelerated the pain that led to joint replacement recommendation.

Below is a quote from research in the medical journal Pain. (13) In this statement, doctors suggest that the reason a joint replacement is recommended and performed is that NSAIDs do not work and, in fact, cause the pain that leads to joint replacement recommendations.

“Difficulty in managing advanced osteoarthritis pain often results in joint replacement therapy. Improved understanding of mechanisms driving NSAID-resistant ongoing osteoarthritis pain might facilitate the development of alternatives to joint replacement therapy. Our findings suggest that central sensitization (a heightened sense of pain) and neuropathic features contribute to NSAID-resistant ongoing osteoarthritis joint pain.”

In our practice, we see patients of all ages. We see the high school athlete, we see the great-grandparent. If both have knee problems – from sports-related injury or age deterioration, both prior to their visit with us, they will likely be prescribed an NSAID. Why? Because doctors believe that NSAIDs still offer the best of both worlds – an anti-inflammatory medication and a pain reliever.

As such, NSAIDs are still considered the first-line treatment for osteoarthritis-related pain despite significant side effects including PREVENTING HEALING and ACCELERATE osteoarthritis and joint deterioration.

NSAIDs give a false sense of healing make things worse. Now research suggests that NSAIDs can be addictive

From the above studies, it is clear that NSAIDs inhibit the individual’s chance of healing. NSAIDs are used because they decrease pain, but they do so at the expense of hurting the healing of the injured soft tissue. A good example of this is a study on the use of Piroxicam in the treatment of acute ankle sprains in the Australian military. (14)

Compared with the placebo group, the subjects treated with Piroxicam had less pain, were able to resume training more rapidly, were treated at a lower cost, and were found to have increased exercise endurance upon resumption of activity. At first glance in reviewing this study, NSAIDs appear to be great, but the real question is…did they help the ligament injury heal?

To test ligament healing, the ankles were tested via the anterior drawer test. During this test, the ankle was moved forward to determine the laxity of the ligaments. In this study, at every date of testing after the initial injury, days three, seven, and fourteen, the Piroxicam-treated group demonstrated greater ligament instability.

At the time of the initial injury, the ligament instability in the Piroxicam group and the control group were exactly the same. This study showed that the NSAID stopped ligament healing, yet the person felt better. The authors noted, “This result is of concern in that it may reflect a paradoxically adverse effect of the NSAID-derived analgesia in allowing subjects to resume activity prematurely.”

The controversy surrounding NSAIDs in people over 75

Recently researchers from the University of Leeds, University of Southampton, and the University of Oxford in the United Kingdom questioned the safety of Tylenol for treating pain related to chronic inflammation, especially in patients over 65. Publishing in the journal Drugs and Aging (15) the researchers offered this suggestion: “Given that the analgesic benefit of paracetamol (Tylenol) in osteoarthritis joint pain is uncertain and potential safety issues have been raised, more careful consideration of its use is required.”

In the March 2019 issue of the medical journal Addictive Behavior, (16) German researchers gave evidence of patient dependence on non-opioid analgesics (NOAs) including NSAIDs.

The researchers looked at 400 patients on average 75 years old.

They found that twenty-eight (28) seniors (7%) were NOA-dependent.
- Of whom, twenty-four were currently dependent and four patients were currently in remission
They found twenty-one (75%) patients were mild, five patients (17.9%) moderately, and two (7.1%) patients severely dependent on NOAs.
All patients showed at least one sign of physical dependence (tolerance and/or withdrawal symptoms) and most of them reported additional behavioral dependence symptoms.

This cross-sectional study provides further evidence of the existence of a physical and behavioral dependence on NOAs including NSAIDs.

When the older patient need NSAIDs

Authors of a paper in the journal Therapeutic Advances in Musculoskeletal Disease, June 2021 (17) wrote: “We believe there is room for NSAIDs in the treatment of osteoarthritis in the very old. The disease is painful, disabling, and severe enough to justify, in some cases, the risks. A small percentage of very old osteoarthritis patients will respond to NSAIDs and experience a clinically significant improvement.”

However the researchers do point out the specific NSAID-related risks, writing:

“The side effects of NSAIDs are numerous and can be serious: hypersensitivity, dizziness and falls, headaches, rare hepatotoxicity, drug interactions, possible chondrotoxicity, etc. The major side effects of NSAIDs are gastrointestinal GI complications, renal disturbances, and cardiovascular events. These side effects are related to the inhibition of cyclo-oxygenase (COX) enzyme activity and prostaglandin synthesis (these are disruptions of the normal maintaining of the gastric mucosa and regulating renal blood flow. Additionally this can cause problems with water and salt retention). They can be severe, leading to death, especially in frail patients. They may occur early in the course of treatment, although in most studies the risks appear to increase with longer use or higher doses.”

We hope you found this article informative and it helped answer many of the questions you may have surrounding NSAIDs. If you would like to get more information specific to your challenges please email us: Get help and information from our Caring Medical staff

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References

1 Hauser RA. The acceleration of articular cartilage degeneration in osteoarthritis by nonsteroidal anti-inflammatory drugs. Journal of Prolotherapy. 2010;2(1):305-22. [Google Scholar]
2 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. [Google Scholar]
3 Katsuno T, Togo K, Ebata N, Fujii K, Yonemoto N, Abraham L, Kikuchi S. Burden of Renal Events Associated with Nonsteroidal Anti-inflammatory Drugs in Patients with Osteoarthritis and Chronic Low Back Pain: A Retrospective Database Study. Pain and Therapy. 2021 Jan 13:1-3. [Google Scholar]
4 Miura T, Kijima H, Konishi N, Kubota H, Yamada S, Tazawa H, Tani T, Suzuki N, Kamo K, Fujii M, Sasaki K. Preoperative medications is one of the factor affecting patient-reported outcomes after total hip arthroplasty. Journal of Orthopaedics. 2020 Dec 30. [Google Scholar]
5 Bernthal NM, Hart CM, Sheth KR, Bergese SD, Ho HS, Apfel CC, Stoicea N, Rojhani A, Jahr JS. Local and Intra-articular Administration of Nonsteroidal Anti-inflammatory Drugs for Pain Management in Orthopedic Surgery. American Journal of Therapeutics. 2020 Dec 10. [Google Scholar]
6 Almekinders, L. An in vitro investigation into the effects of repetitive motion and nonsteroidal anti-inflammatory medication on human tendon fibroblasts. American Journal of Sports Medicine. 1995; 23:119-123. [Google Scholar]
7 Salem O, Wang HT, Alaseem AM, Ciobanu O, Hadjab I, Gawri R, Antoniou J, Mwale F. Naproxen affects osteogenesis of human mesenchymal stem cells via regulation of Indian hedgehog signaling molecules. Arthritis Research & Therapy. 2014 Aug;16(4):1-9. [Google Scholar]
8. Caron MM, Emans PJ, Sanen K, Surtel DA, Cremers A, Ophelders D, van Rhijn LW, Welting TJ. The role of prostaglandins and COX-enzymes in chondrogenic differentiation of ATDC5 progenitor cells. PloS one. 2016 Apr 6;11(4):e0153162.[Google Scholar]
9 Foulke BA, Kendal AR, Murray DW, Pandit H. Fracture healing in the elderly: A review. Maturitas. 2016 Oct 31;92:49-55.[Google Scholar]
10 Kono Y, Kawano S, Takaki A, Shimomura Y, Onji M, Ishikawa H, Takahashi S, Horii J, Kobayashi S, Kawai D, Yamamoto K. Oxidative stress controlling agents are effective for small intestinal injuries induced by non‐steroidal anti‐inflammatory drugs. Journal of gastroenterology and hepatology. 2017 Jan 1;32(1):136-45. [Google Scholar]
11 Allen J, Imbert I, Havelin J, Henderson T, Stevenson G, Liaw L, King T. Effects of treadmill exercise on advanced osteoarthritis pain in rats. Arthritis & Rheumatology. 2017 Jul;69(7):1407-17. [Google Scholar]
12 Goulet JL, Buta E, Brennan M, Heapy A, Fraenkel L. Discontinuing a non-steroidal anti-inflammatory drug (NSAID) in patients with knee osteoarthritis: Design and protocol of a placebo-controlled, noninferiority, randomized withdrawal trial. Contemporary clinical trials. 2018 Feb 28;65:1-7. [Google Scholar]
13 Havelin J, Imbert I, Cormier J, Allen J, Porreca F, King T. Central Sensitization and Neuropathic Features of Ongoing Pain in a Rat Model of Advanced Osteoarthritis. J Pain. 2016 Mar;17(3):374-82. [Google Scholar]
14 Slatyer, M. A randomized controlled trial of Piroxicam in the management of acute ankle sprain in Australian regular army recruits. American Journal of Sports Medicine. 1997; 25:544-553. [Google Scholar]
15 Conaghan PG, Arden N, Avouac B, Migliore A, Rizzoli R. Safety of paracetamol in osteoarthritis: what does the literature say?. Drugs & aging. 2019 Apr 1;36(1):7-14. [Google Scholar]
16 Bonnet U, Strasser JC, Scherbaum N. Screening for physical and behavioral dependence on non-opioid analgesics in a German elderly hospital population. Addictive behaviors. 2019 Mar 1;90:265-71. [Google Scholar]
17 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. [Google Scholar]
18 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. [Google Scholar]

This page was updated September 6, 2021