The Cox-2 Inhibitors Controversy

From Our Archives
Question and Answer with Dr. William Shiel and Dr. Michael Smith

Dr. Shiel is a a practicing rheumatologist, and Chief Medical Editor of, and Dr. Smith is Senior Medical Editor, WebMD, Inc.

  1. Question: Dr. Smith
    Are Cox-2 inhibitors less likely to irritate the stomach than older antiinflammatory drugs?

    Answer: Dr. Shiel
    Selective Cox-2 inhibitors (such as Celebrex and Bextra) NOTE: April 7, 2005, Pfizer has agreed to suspend sales and marketing of Bextra in the U.S., pending further discussions with the with the FDA. For more information, please read the FDA press release. , do not inhibit the Cox-1 enzyme in the stomach and are thus felt to be less toxic to the stomach than traditional antiinflammatory drugs (such as aspirin, ibuprofen, or naproxen). These traditional anti-inflammatory drugs, called nonselective Cox-1/Cox-2 inhibitors, inhibit both Cox-1 and Cox-2 enzymes. While inflammation is reduced by blocking Cox-2, the protective mucus lining of the stomach is also reduced when Cox-1 is blocked, which can cause stomach upset, ulcers, and bleeding.

Current evidence suggests that the selective Cox-2 inhibitors are less toxic to the stomach than traditional antiinflammatory drugs. This effect is especially significant in persons who are at risk of stomach bleeding, such as those with a history of prior stomach bleeding or patients on blood thinning medications.

  1. Question: Dr. Smith
    There are studies on Cox-2 inhibitors showing heart risks for elderly people. Is the concern only in elderly people?

    Answer: Dr. Shiel
    Actually, while there have been studies demonstrating a heart risk in persons in the Medicare age group, the issues raised pertain to any patient with underlying risk factors for heart disease or stroke. This means not only the elderly may be at risk, but also those who have underlying known heart disease (either coronary artery disease or congestive heart failure) or known blood vessel disease (atherosclerosis or calcification of blood vessels).

Caution might be also be used for those with high blood pressure and a tendency toward fluid retention (edema). It has been shown that ALL antiinflammatory drugs (traditional and Cox-2 inhibitors) can worsen blood pressure or cause fluid retention and patients should be monitored for such side effects. Similarly, in the elderly who are at risk for kidney impairment, or in any patient with known kidney disease, antiinflammatory drugs should be used cautiously with close monitoring of kidney function.

  1. Question: Dr. Smith
    Do the new Cox-2 inhibitors relieve pain better than older traditional anti-inflammatory drugs, like ibuprofen and naproxen?

    Answer: Dr. Shiel
    No. As a group, the benefit of these drugs lies in their lower incidence of gastrointestinal side effects not in their effectiveness. Clinical research has shown that the Cox-2 inhibitors are essentially equivalent to traditional antiinflammatory drugs in effectiveness. Improved effectiveness has never been the point of these medications, nor have their respective manufacturers marketed them for that purpose.

Having said that, doctors are well aware that determining which patient is going to respond to which antiinflammatory drug to a certain degree involves some trial and error. Therefore, it is convenient to have options when treating chronic pain or inflammation.

  1. Question: Dr. Smith
    Do older anti-inflammatory drugs, like ibuprofen and naproxen (Aleve), have the same heart risks as the Cox-2 inhibitors?

    Answer: Dr. Shiel
    We don't know. Recently, the National Institutes of Health (NIH) was conducting a study for Alzheimer's disease prevention and was comparing naproxen (Aleve) in low doses (220 mg twice daily) to celecoxib (Celebrex) and a placebo. The trial was stopped as a precaution because of an "apparent" increase in heart attack and stroke in participants taking naproxen as compared to the placebo. This report, in my opinion, is completely inconclusive.
In order to determine if there are heart attack and stroke risks associated with naproxen and ibuprofen, much larger and longer term studies that are geared (preprogrammed) to look specifically at this issue will be necessary. Moreover, the doses evaluated will need to be in line with the doses commonly prescribed by doctors (375-500 mg twice daily) in order to provide adequate guidance information.
  1. Question: Dr. Smith
    Are Celebrex and Bextra likely to be removed from the market like Vioxx?

    Answer: Dr. Shiel
    I have absolutely no idea. And, this is after reviewing most major research reports about these drugs as well as attending a major symposium on them at the 2004 national arthritis meeting (American College of Rheumatology). The results of current studies are conflicting and incomplete. As a practicing clinician, it is my hope that as a result of an upcoming FDA review of research data, doctors will have clearer guidelines as to the use of all antiinflammatory drugs (both traditional and Cox-2 inhibitors).
I can say that if Celebrex and Bextra are removed from the market, there is some good news for those patients requiring antiinflammatory drugs who have underlying gastrointestinal risks. There is significant data that demonstrates a decreased risk of stomach bleeding in persons taking traditional antiinflammatory drugs who simultaneously take stomach protection drugs, called proton pump inhibitors. Examples of proton pump inhibitors include omeprazole (Prilosec), lansoprazole (Prevacid), esomeprazole (Nexium), pantoprazole (Protonix), and rabeprazole (Aciphex).

I might add that if these drugs are removed from the market, it will undoubtedly have serious consequences in patient care. A recent MedicineNet survey found that over half of former Vioxx users took matters into their own hands, stopping their drug and either taking no drug or substituting over-the-counter pain medications without contacting their doctor's office!

  1. Question: Dr. Smith
    Some studies have shown that Cox-2 inhibitors have been over-prescribed. To whom should these drugs be prescribed?

    Answer: Dr. Shiel
    In particular, a recent study published in Archives of Internal Medicine (January, 2005), showed that doctors were using Cox-2 drugs in a wide variety of patients instead of specifically selecting patients at risk for stomach bleeding as the ideal candidates. It was suggested that marketing and promotion of the drugs lead to their use in an unnecessarily large group of patients. Moreover, patients may have requested them because of perceived benefits.
Drug treatment is always based on a risk vs. benefit analysis. In clinical practice, Cox-2 inhibitors are considered after weighing the benefits vs. the risks. As more research clarifies the risks and the groups of patients who are more prone to these risks, it will become easier for patients and doctors to choose medications optimally.

Currently, Cox-2 drugs are most suited for patients who have a history of gastrointestinal bleeding or who are at risk for bleeding. Persons who are taking the blood thinning medication warfarin (Coumadin) cannot take traditional antiinflammatory drugs because of high bleeding risks. When an antiinflammatory drug is necessary, Cox-2 inhibitors are permissible for this group of patients.

The risks and benefits of taking a medication must be evaluated in an individualized fashion for each patient. The decision to take a medication requires knowledge of the severity of the condition treated, risks of alternatives, underlying medical conditions, past medication experiences, affordability of the drug, and the patient's age to adequately appreciate the risks.
  1. Question: Dr. Smith
    Is a lower dose of Celebrex or Bextra safer?

    Answer: Dr. Shiel
    In general, in order to minimize side effects, ALL medications should be used in the lowest dose and for the least amount of time as is reasonable for the particular condition being treated. But, is using a lower dose of Celebrex or Bextra safer than using a higher dose?
The answer is: We don't yet know.

For example, the studies that have demonstrated an increased risk of heart attack and stroke in patients taking Celebrex were in patients taking high doses (400-800 mg per day). This does not mean that taking 200 mg is free from risk or poses less risk. While many side effects can relate directly to the amount of the daily dose, some simply are associated with taking ANY of the medication. We need to have more research to clarify these issues.
  1. Question: Dr. Smith
    If a Cox-2 drug is discontinued, is the adverse risk of heart attack or stroke permanent?

    Answer: Dr. Shiel
    No. There is no evidence of a sustained adverse effect. The risk would only be expected to be present while taking the drug, not after it has been discontinued.
It is interesting to note that the heart attack and stroke risk detected in the Vioxx study (which led to its manufacturer to pull it from the market) did not present in study participants until the drug was taken for at least 18 months. There was no increased risk of heart attack or stroke detected in study participants who took Vioxx for less than 18 months. This suggests the possibility of some metabolism or enzyme change that takes time to occur in the body.
For more, please read Dr. Shiel's recent article, "Cox-2 Inhibitors Dilemma, What Patients Should Do."



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Reviewed on 6/13/2018