NSAID Hysteria -- Chicken Little Revisited

John A. Goldman, MD, FACP, FACR, FASLMS, CCD; Sanford S. Hartman, MD, MBA


Chicken Little felt a drop of rain and thought that the sky was falling![1]

As practicing rheumatologists with over 65 (35 + 30) years in rheumatology, we are disturbed by the data "sensationalizing" the adverse gastrointestinal, renal, and cardiovascular outcomes associated with nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase (COX)-2 NSAIDs (COX-1 sparing).[2,3,4,5,6,7,8,9,10,11,12] This is not completely new information (ie, some data are newer than others), and if one reviews all of these drugs, many other adverse outcomes can be readily noted.[2,3,8,9,10,11] There are no side-effect-free medications, and the physician tries the best that he or she can to minimize the risk-benefit ratio of any therapeutic regimen. There are far more dangerous drugs with potentially worse outcomes, and we use them all of the time. (Would someone like to profile the potential toxicities of corticosteroids, preparations that seem to be used far more glibly than the COX-2 inhibitors?) If aspirin were first coming on the market now as a medication for pain, arthritis therapy, headache therapy, and fever control, would anyone feel any safer taking a medication with life-threatening side effects, such as gastrointestinal bleeding and other types of hemorrhage, potentially fatal allergic-like reactions (including anaphylaxis), or less risky side effects (such as skin purpura)? If accepted now, it would be required to have a "black box" warning.

So, Chicken Little told Henny Penny . . .

We support all of these medications being available. Many of our previous rofecoxib ( Vioxx ) patients are now without a suitable alternative (translation -- miserable). They have tried other anti-inflammatory agents without success or with side effects and/or risks worse than the presumed risks of the COX-2s.[4,5,6,7,8,9,10,11,12] The COX-2s have multiple benefits, including reduced adverse gastrointestinal outcomes; a lack of antiplatelet activity; decreased rectal polyp proliferation; preoperative pain relief with less need for narcotics and less risk of bleeding; no interference with aspirin cardioprophylaxis; control of pain; migraine therapy (available as a liquid for children); and improvement in fever, headaches, arthritis, and inflammation. We use them in different patients for different reasons.

Then, Chicken Little and Henny Penny told Ducky Lucky . . .

Patients make choices all of the time. They are willing to take medication risks when they believe that it is worth the possibilities of escaping the misery of their diseases and leading more productive and functional lives. We call this quality of life. Our patients have many needs: work, child care, shopping, taking their children to the circus, treating their migraines, cooking their food, and other activities of daily living. As rheumatologists, like all physicians, with patient guidance and consent, we have used medications with varying levels of risk. Patients are much more aware of the risks of medications than at any time in the past. They hear statements or misstatements from a growing cadre of "experts" -- all the way from the not-so-saintly press, to the opportunistic legal community, to the bandwagon-jumping politicians. They also hear this information from their local pharmacists (if they're allowed to have one in lieu of some mail-off "bargain"), their personal physicians (who one hopes are properly informed), and the overzealous public media advertising that is so near and dear to the hearts of the pharmaceutical industry. They hear comments that they can use other NSAIDs because they are all the same in studies. From criteria that are measured in studies, this may appear to be so, but with individual patients these others may not work. They are on rofecoxib after having tried all of the other "pain relievers." All this is confounded by the fact that the peer-reviewed literature on the increased cardiovascular risk profiles of rofecoxib, celecoxib ( Celebrex ), and valdecoxib ( Bextra )* have not been completely published and are still under investigation. We are getting "pundate data" from the press, and decisions are being made on a lack of data. We, as physicians, have to treat patients with the "best data we have available" (à la Donald Rumsfeld), and we decry decreasing our choices when we can risk-stratify and treat accordingly. In some, we may have to add a baby aspirin a day even though we do not have randomized, double-blind, controlled, 3-year studies to tell us that this is the best choice to make. And there may be differences between men and women.[13,14] In fact, we do not have randomized, controlled, double-blind, 3-year cardiovascular studies on any of the other NSAIDs or COX-2s beyond rofecoxib.[10] We suspect that we would see problems with some or all of them, NSAIDs and COX-2s, in such a designed study. The "best data we have available" are so far not good enough. We have observational trial "signals," which used to be called "trends" in our literature.

Then, Chicken Little and Henny Penny and Ducky Lucky told Goosey Lucy . . .

The decision to remove rofecoxib from the market was a corporate decision. Some agree with that decision, but we do not. We are from Atlanta, Georgia, and remember another misguided corporate decision -- that of Coca Cola removing Classic Coke from the market for New Coke . At least they were wise enough to eventually bring back Classic Coke . We hope that Merck may see the wisdom of bringing rofecoxib back with whatever warnings are necessary -- and maybe a little less (or preferably no) TV, radio, and print media carrots of unreasonable expectation. Instead of pharmaceutical companies "trash marketing" their products to physicians and the public by denigrating the competition, maybe a little honesty and full disclosure of "the good, the bad, and the ugly" by the pharmaceutical industry will go a long way. (Have we all sunk to the level of those running for office in this country?) Good science would go a long way here. In one of our offices, we have a sign on the drug closet -- the "Rheumatology No-Spin Zone."

Then, Chicken Little and Henny Penny and Ducky Lucky and Goosey Lucy all told Turkey Lurkey . . .

We have seen other public outcries over the years bring medical data to the physician and public (daily aspirin, thalidomide, estrogens, cholesterol, calcium, and L-tryptophan -- to name a few). In rheumatology we are having a problem helping our patients with the shortage or presumed shortage of injectable methotrexate. Other drugs have recently been removed from the market, including cervastatin ( Baycol ), alosetron ( Lotronex ), cisapride ( Propulsid ), and troglitazone ( Rezulin ). The controversy over hormone therapy after the Woman's Health Initiative (WHI) and even now over whether children or the elderly should get flu vaccines keeps this discussion timely. Sometimes the fanfare outweighs the information; sometimes the information is extremely helpful; and sometimes the conclusions of the prematurely released information change when more information becomes available. Interpretations and misinterpretations of data are rampant, and, unfortunately, some of our own professional organizations are too timid to enter the fray. Statistics -- even correct ones -- are open to such disparate interpretations that Mark Twain probably stated it best with his comment: "There are lies, damn lies and statistics.[15]" Scientific data need rigorous evaluation and reevaluation. We encourage adequately powered, controlled, head-to-head trials to ably tell the differences between the products. These latter type of data should be required by the US Food and Drug Administration (FDA) and by other regulatory agencies in other countries. Now we have only placebo or nonplacebo, controlled trials that may or may not compare "similar" drugs.

Finally, Chicken Little, Henny Penny, Ducky Lucky, Goosey Lucy, and Turkey Lurkey all looked up in the sky themselves . . .

We believe that the scientific community must take control. Allowing the trial lawyers to run the show is akin to crying "fire" in a crowded theater. ("Have you been harmed by rofecoxib, celecoxib, or valdecoxib?" " Or "...over 100,000 people have died from rofecoxib....") Even worse, one critical pundant was on the board of a hedge fund, Great Point Partners, whose investment successes are potentially directly affected by his publicly expressing his "medical opinion.[16]" Although he defended himself by saying that he never discussed Merck and resigned as a $12,000/year advisor, this still implies a serious conflict of interest.[17] Allow the scientific community to see the data, and if that is really what it says, then let the chips fall where they may. But let's get rid of the emotional and outrageous attacks, and let's not allow our scientific peers to be silent on a matter of such importance to our patients.

We had written this essay before the FDA hearings of February 16-18, 2005, and having only seen the press releases and reviews, we believe that their critique is consistent with what we have written here.[18,19]

And, what did they find? It was only sprinkling.

*The removal of valdecoxib (Bextra) from the market on April 8, 2005 continues to confound this issue for our patients and confuses the medical and patient community. As rheumatologists, we completely disagree with this removal but would agree to "black box" warnings for all of these medications. While patients in studies develop problems, the quality-of-life issues for our patients are not completely covered in studies, because studies are in groups and our patients are individuals, whom we treat as individuals. Their specific problems include their medical comorbidities, work status, family needs, and psychological issues, which cannot be individualized in a study of large populations. Every physician needs to approach a therapeutic decision with all of this information. We need to access both the risks and benefits with all medications, including these. See: FDA Public Health Advisory. FDA announces important changes and additional warnings for COX-2 selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs). Available at: https://www.fda.gov/cder/drug/advisory/COX2.htm. Accessed April 8, 2005.


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