NSAIDs have their limits in treating OA pain.

While nonsteroidal anti-inflammatory drugs (NSAIDs) may offer short-term relief from the pain and inflammation associated with many sports-related injuries, their long-term use appears to be an inadequate treatment for knee osteoarthritis (OA) pain, and is not always safe.

Serious Side Effects

Traditional NSAIDs, including the over-the-counter (o.t.c.) ibuprofen found in Advil[R] and Motrin[R], are cyclooxygenase (COX)-1 and COX-2 inhibitors. They control swelling, but by blocking the production of COX-1 enzymes, which are responsible for the regeneration of gastric mucousa, they can cause gastrointestinal (GI) problems. By some estimates, up to half of all endurance athletes suffer GI symptoms anyway. And even acetaminophen, which is not considered an NSAID because it lacks anti-inflammatory properties, when ingested in amounts greater than 2 g per day, can lead to bleeding and perforations. At 650 mg per capsule, two capsules twice daily of Tylenol Arthritis Pain Extended Relief[R] exceed this dose.

Selective nonsteroidals (coxibs) block only COX-2 enzymes, thereby alleviating the GI concern. However, we now recognize that COX-2 enzymes--prostaglandins (PGs) in particular--perform important regulatory functions as well. By inhibiting the production of PGs, which as vasodilators increase blood flow to the kidneys, all NSAIDs can exacerbate fluid imbalance, electrolyte disorders and kidney problems for long-distance runners. This is particularly true for runners in their 50s and 60s, for whom renal changes occur sooner just by virtue of their age.

In December, Pfizer found a 3.4 times greater risk of cardiovascular events in patients taking 800 mg of Celebrex[R] (celecoxib) daily, when compared to patients taking a placebo. And Bextra[R] (valdecoxib) now comes with a warning label since it may cause heart and blood-clotting problems in some patients who have recently had heart bypass surgery.

In September, Vioxx[R] (rofecoxib) was taken off the market when it was discovered that in 25-mg doses it creates twice the risk of myocardial infarction (MI) as compared to placebo. Though this coxib-specific "prothrombotic mechanism" is still being investigated, the theory goes that by inhibiting the COX-2 enzymes that dilate blood vessels, while allowing the production of the COX-1 enzymes that cause blood platelets to stick, coxibs can create a friendly environment for the formation of dangerous blood clots in some people.

Let's Not Panic

When co-morbidity factors are present, coxibs should be used only as needed, and in doses lower than previously thought. But a call for Celebrex's removal from the market might be premature. It's important to remember that at 33 months, the average duration of treatment in the now-suspended celecoxib trial was certainly long-term. And the doses in the study were two to four times the usual dose for OA patients, which is 200 mg. Additionally, in another cancer study involving the long-term use of Celebrex, there was no increased risk in patients taking a 400-mg daily dose. Nicholas Scarpa, MD, who serves as Medical Director of Rheumatology at the Arthritis Research Center of New Jersey, offers, "There were 20 cases out of 2,000 patients on the 800-mg dose. That means that 198 out of every 200 patients taking four times the recommended dose had no problems."

Another recently suspended NSAID study, a three-year exploration of potential Alzheimer's cures, serves to illustrate the complexity of present controversies. Researchers in that study, comparing 400 mg daily of Aleve[R] (naproxen) to Celebrex, had long observed a slightly elevated risk of heart problems and stroke with Aleve, but decided as late as December 10 that the phenomenon was probably not statistically significant, and was not troublesome enough to stop the study. Only after news broke about the suspended Celebrex study did the NIH halt the Alzheimer's trial--and according to University of Washington researcher John Breitner, MD, MPH, largely because too many patients dropped out of the study. The other point of interest here is that an o.t.c. nonsteroidal proved riskier--if marginally so--than the prescription-only Celebrex, which presented no increased cardio- or cerebrovascular risk in the trial.

Cost vs. Benefit

Still, a meta-analysis published recently in the British Medical Journal pooled data from trials over the past 19 years and found only a 9.2% average pain difference between knee OA patients treated with NSAIDs and those receiving a placebo. The researchers concluded that this meager benefit does not justify long-term use of these agents--non-selective or otherwise--to mitigate OA pain. The meta-analysis also found NSAIDs to be of limited use in attenuating acute pain in the short term.

Though there is evidence of an inflammation mechanism in OA, Scarpa notes that some cases seem to be induced by PGs and some by substances called cytokines. This may explain why some patients do well with PG-inhibitors and others don't: different enzymes appear to be responsible for the inflammation. NSAIDs, then, are in many ways less than ideal for treating OA.

Strategies with Promise

Given the potential minefield of non-steroidal side effects, regular load-bearing exercise and quadriceps strengthening look like far better solutions over the long term. In one recent study, two OA groups received the same NSAID, but one group fitness-walked while the other went about their normal routines. After six weeks of supervised fitness walking, the active group reported a 50% decrease in pain, and a third of them were even able to walk without taking their nonsteroidal medication.

In their ongoing Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT), the NIH is currently testing the conclusions of a meta-analysis that found glucosamine/chondroitin sulfate to be as effective as a nonsteroidal in attenuating stage-one OA over the long term; it even improved patients' x-ray scores. 1,500-mg doses of the nutraceutical improved cartilage function and strength in these people, regenerating destroyed cartilage as no NSAID could. As an unregulated nutraceutical, however, it's important to be sure you receive the right dose in o.t.c. products, the ingredients of which vary widely.

The controversy surrounding chronic NSAID use demonstrates that these drugs, while safe and effective for many people, can sometimes bring with them serious side effects. Where knee OA is concerned, fitness walking interventions and quadriceps exercises are preferable over the long term. And recent promising analyses of glucosamine studies suggest that the supplement is an effective nutraceutical therapy with far fewer side effects than NSAIDs. As always, you should scrupulously discuss with your physician what is best for you.

(BMJ, 2004, Vol. 329, No. 7478, pp. 1317-1320; Arch. Intern. Med., 2003, Vol. 163, No. 13, pp. 1514-1522; Curr. Sports Med. Rep., 2002, Vol. 1, No. 2, pp. 107-115)