Think Twice About NSAIDs

by Larry Creswell, M.D.

Non-steroidal anti-inflammatory drugs (NSAIDs) have been in the news recently and athletes should take notice. In a report in the British Medical Journal entitled, “Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis,” a group of Swiss investigators reviewed the use of NSAIDs in a large group of patients and concluded that there are important cardiovascular risks associated with the use of these medications.

The Basics of NSAIDs
We’ll return to the new report, but let’s begin by talking about NSAIDs in general. As their name suggests, these are medications (which are not steroids) that were designed and are prescribed for their anti-inflammatory effects. They also have anti-pyretic (fever-reducing) and analgesic (pain-reducing) effects, as well.

As a group, NSAIDs are very common drugs. The Swiss investigators noted that in the United States, as many as 5% of all doctor visits are associated with the prescription of an NSAID. Their collection of effects makes NSAIDs useful for the treatment of a wide range of acute and chronic conditions that produce pain or inflammation. The uses are nearly endless, but the NSAIDs are prescribed for the whole spectrum of arthritic conditions, postoperative pain, menstrual pain, migraine headache, and gout, among other conditions.

The primary adverse effects of these medications are the formation of stomach (gastric) ulcers or gastric bleeding and impairment of kidney function. Each of these adverse effects is dose-related, increasing in frequency with increased dosages of the NSAIDs.

The NSAID medications act by inhibiting the function of an enzyme called cyclooxygenase or COX. It turns out that there are two important forms of the COX enzyme -- COX1 and COX2. Most NSAIDs inhibit all of the COX enzymes, but newer, “selective” NSAIDs only inhibit the COX2 enzyme. These newer COX2-inhibitors were widely heralded and welcomed in the medical field because they were thought to be associated with less gastric bleeding. With further study, though, this benefit remains to be substantiated.

There are many medications in the NSAID family and the common agents with their trade names are summarized in the Table.

Generic Name - Brand Name(s)

Non-specific NSAIDs

• Aspirin
• Naproxen - Aleve, Anaprox, Midol Extended Relief
• Ibuprofen - Advil, Motrin, Nuprin
• Indomethacin - Indocin, Indocid
• Sulindac - Clinoril
• Ketorolac - Toradol
• Diclofenac - Voltaren
• Piroxicam - Feldene
• Meloxicam - Mobic

COX2 Inhibitors

• Celecoxib - Celebrex
• Rofecoxib - Vioxx
• Valdecoxib - Bextra

The First Indication Something was Wrong
Rofecoxib, one of the COX2-inhibitors developed by Merck, was approved by the U.S. FDA in May, 1999 for use in the treatment of arthritis, acute pain and menstrual pain. This was a wildly popular drug and eventually, as many as 80,000,000 patients worldwide were treated with Rofecoxib. Before approval of the drug by the FDA, studies of the drug suggested that Rofecoxib had a satisfactory safety profile.

Two post-market studies cast significant doubt on the safety of Rofecoxib, though. The first study was called VIGOR (Vioxx GI Outcomes Research) and was designed to study the possibility of reduced gastrointestinal adverse effects with the COX2-selective Vioxx compared to previously available nonselective NSAIDs. Specifically, this study compared the efficacy and adverse effects between Vioxx and naproxen and found that, over the 12-month span of the study, the rate of myocardial infarction (MI, or “heart attack”) was four times higher in the Vioxx than in the naproxen group. Importantly, this increased risk for MI was noted to occur within only twomonths of starting the Vioxx drug.

The second important study was called APPROVe (Adenomatous Polyp PRevention on Vioxx). This study was designed to evaluate the possibility that Vioxx could reduce the chance of developing colonic polyps (based on the observation that another COX2-inhibitor had already made this claim). The study was designed to last three years, but was terminated early when the investigators found that, compared to placebo, patients receiving Vioxx experienced a nearly 2-fold greater incidence of MI and stroke.

Based in large part on the findings of these two studies, Merck voluntarily withdrew Rofecoxib from the market in September, 2004.

The experience of Vioxx raised questions about the entire group of COX2-inhibitors, and for that matter, all NSAIDs, and any possible link to cardiovascular risk. Many studies designed to re-evaluate the safety of these medications have now been conducted, but there has remained some uncertainty about the degree of cardiac risk associated with the use of these drugs.

The New Study
In the current issue of the British Medical Journal, Sven Trelle and his colleagues at the Institute of Social and Preventive Medicine at the University of Bern report on a meta-analysis of previous studies of NSAIDs. This statistical undertaking combines the patient populations in 31 previous studies that included a total of 116,429 patients who received naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, rofecoxib, lumiracoxib, or placebo. The combined observations from the underlying studies amounted to more than 100,000 patient-years. The authors focused primarily on the development of MI, but also examined the effects of these drugs on the rates of stroke, death from cardiovascular disease, and death from any cause.

For three of the drugs (naproxen, diclofenac, and etoricoxib), there was no evidence of increased MI. For all of the other medications, though, there was an increase in the rate of MI during the study period: 1.3-fold for ibuprofen, 1.35-fold for celecoxib, and 2.12-fold for rofecoxib.

All drugs were associated with an increased rate of stroke: 1.3-fold for naproxen, 2.96-fold for diclofenac, 2.67-fold for etoricoxib, and 2.81-fold for lumiracoxib.

All drugs were associated with an increased rate of death from any cause, with risks ranging from 1.23-fold (for naproxen) to 2.31-fold (for diclofenac).

One important observation from this study is that both COX2-selective as well as non-selective NSAIDs were associated with increased cardiovascular risk. This refutes the previous claim from some authorities that the risk was inherent only in the COX2-inhibitors. Even ibuprofen and naproxen were associated with these risks.

The authors’ conclusion statement is quite stark: “Although uncertainty remains, little evidence exists to suggest that any of the investigated drugs are safe in cardiovascular terms.”

Implications for Athletes
Athletes use the NSAIDs when they’re injured. I’ve done it myself. We all have. Personally, I would rely on NSAIDs for their analgesic effects primarily, thinking that any anti-inflammatory effect would be a bonus. I’ve used NSAIDs for weeks in a row when I’ve been injured, primarily to allow me to continue to work (at my job). I’ll bet that many athletes rely on the use of NSAIDs to allow them to continue to train in spite of being injured as well. I’ve also seen athletes use NSAIDs prophylactically during competition to prevent any pain during an event.

As time goes by, and particularly with the information from the new Swiss report, evidence continues to accumulate that the NSAIDs -- all of them -- are probably associated with an increased risk of cardiovascular problems including MI, stroke and even death. And although the relative risk may seem small, even a 1.1- to 1.3-fold increased risk of these complications is meaningful. Athletes should keep these risks in mind when they choose to use NSAIDs.

Here are my suggestions for athletes regarding NSAIDs:

1. Never use NSAIDs prophylactically to prevent pain during training or racing.
2. As a first choice, use an alternative to NSAIDs when choosing an analgesic. Consider acetaminophen or a narcotic pain reliever.
3. If you choose to use an NSAID, use it for only a short period of time.
4. When injured, emphasize alternatives to medications such as rest, icing, compression, elevation, appropriate medical evaluation and appropriately supervised post-injury rehabilitation.

I wished to add a few more warnings on the potential downsides of NSAIDs as they pertain to training. NSAIDs work by interrupting the production and action of prostaglandins. Prostaglandins cause inflammation, pain and increased blood flow via dilation of blood vessels. These effects are “bad” in many circumstances but “good” in others. Nobody wants pain and swelling, and NSAIDs are very effective from this perspective. Many athletes have used these agents with impunity for years. But…

Our bodies need prostaglandins to overcome the vasoconstriction which accompanies stress to specific organ beds. Your kidneys will suffer decreased flow and may even fail when you add dehydration and low blood pressure to NSAID use.

NSAIDs will also lead to decreased blood flow to the stomach and bowel -- impairing digestion, and long-term, predispose you to gastric ulcers. This effect is due to reduced perfusion lowering the production of the protective mucous layer in the stomach. The often-described bloating experienced by most of us is exacerbated by these agents as well due to less blood flow available for digestion.

Dangerously high potassium levels (hyperkalemia), and dangerously low sodium levels (hyponatremia) are also often direct results of NSAID. This is due to the interruption of complex feedback loops, often with disastrous results.

Finally, NSAIDs have been shown to increase healing time, impair tendon healing, delay muscle rebuilding and may lead to bleeding tendencies. So, think about whether acetaminophen (Tylenol brand name) might be a better strategy when you are in pain.

Your non-beating organs thank you.

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