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Over the past year there has been controversy concerning the safety of what used to be a commonly prescribed class of anti-inflammatory medications. This group of drugs, called COX-2 inhibitors, includes Vioxx, Bextra, and Celebrex. The increasing media coverage of the dangers of these medications has raised patients' concern. We would like to answer some common questions and provide you with a brief overview of the rise and fall of the Cox-2 inhibitors.

What is a COX-2 inhibitor?

Cox-2 inhibitors are a subgroup of non-steroidal anti-inflammatory (NSAID) medications that are used to relieve pain and inflammation. Celebrex, Vioxx and Bextra are Cox-2 inhibitor medications. "Cox -2" is an enzyme that produces inflammation in the joints. The "Cox -1" enzyme is involved with producing a protective lining on the stomach. The Cox -2 inhibitor drugs were designed to reduce the Cox-2 enzyme activity only. The older NSAIDs inhibit both the Cox-2 enzyme and the Cox -1 enzyme, thereby decreasing production of the stomach's protective lining and producing stomach upset. Therefore, the Cox - 2 medications, Vioxx, Bextra, and Celebrex, were originally marketed as having fewer side effects than the older anti-inflammatory analgesics such as aspirin, acetominophen (Tylenol) and ibuprofen (Motrin).

How new are these Cox-2 medications?

Celebrex FDA approved in December of 1998

Vioxx FDA approved in May of 1999

Bextra FDA approved in November of 2001

These drugs were well received initially. In addition to successfully treating many patients' pain and inflammation, researchers found that Celebrex and Vioxx have some beneficial effects in prevention of colon polyps and colorectal cancer.

The popularity of these medications was reflected in their financial success. By December 1999, Celebrex had generated $1.4 billion in annual sales, a record for a drug in its first year on the market. Combined annual sales for the three drugs reached $5.3 billion in December of 2003.

So what went wrong?

These drugs not only treated pain effectively but they also showed promise in treating other conditions. In fact, a study published in the New England Journal of Medicine found that six months of twice-daily treatment with 400 mg of Celebrex led to a significant reduction in the number of colorectal polyps in patients with familial adenomatous polyposis, a condition that has nearly 100 percent risk of developing into colorectal cancer. More and more research was done until adverse side effects were discovered.

Here's a quick review of the major studies:

September 2000 - A Journal of the American Medical Association article examined whether Celebrex produces less stomach upset than the older NSAIDs. They concluded that Celebrex had a lower incidence of gastrointestinal toxic effects than ibuprofen or diclofenac, even when Celebrex was given at twice and four times the normal dosage. No difference in adverse cardiovascular effect was reported between the Celebrex and the NSAID (ibuprofen/diclofenac) group.

November 2000 - The New England Journal of Medicine published a study concluding that Vioxx is associated with significantly less gastrointestinal problems than naproxen (Alleve). However, a higher incidence of myocardial infarction was found among the group of patients taking Vioxx. Heart attacks occurred 0.1% of the patients taking Naproxen, and 0.4 % of the patients taking Vioxx. The overall mortality rate and the rate of death from cardiovascular causes were similar in the two groups.

September 2004 - A three year clinical trial evaluating the efficacy of VIOXX in preventing recurrence of colorectal polyps was stopped as an increased risk for heart attack and stroke was seen in the patients taking VIOXX compared to those taking placebo. This increase in cardiovascular problems was seen after patients had been taking Vioxx for 18 months. The results for the first 18 months of the this study did not show any increased risk of confirmed cardiovascular events with Vioxx compared to placebo.
Following these results, Merck & Co., Inc. voluntarily withdrew Vioxx from the market on Sept. 30, 2004. Over the next few months, several studies found that Bextra has not only an increased risk of cardiovascular problems, but is also associated with an increased risk of a rare but life-threatening skin reaction called Stevens Johnson Syndrome.

Bextra was pulled from the market on April 7, 2005 after the FDA determined that Bextra posed too high a risk of adverse cardiovascular events, as well as Stevens Johnson Syndrome.

Celebrex remains the only Cox-2 inhibitor still on the market.

So, is Celebrex safe?

Evidence of increased risk of cardiovascular events with the use of Celebrex exists. However, the risk of heart attack and stroke appears to be greatest when Cox-2 inhibitors are used long-term and in patients who are at cardiovascular risk.

Many health care professionals feel that the Cox-2 medications are effective and safe when used properly in the right patient. Many other NSAIDs including naproxen have also been shown to carry an increased cardiovascular risk. The FDA has requested that ALL NSAIDs include a boxed warning on their package insert to highlight the potential increased risk of cardiovascular events.

Why/How do the cox-2 drugs cause heart attacks and stroke?

A physician from the University of Pennsylvania who has been studying the cardiovascular effects of the Cox-2 inhibitors for 6 years has said that these drugs decrease blood levels of a cardioprotective fat called prostacyclin. When prostacyclin levels fall, the arteries are more vulnerable to clotting, high blood pressure, heart attack, and stroke.

What can we learn from the ups and downs in the chronicle of the Cox-2 inhibitors?

All medications have side effects. A risk-benefit assessment must be done for each individual patient for each drug. For example, when compared to other NSAIDs, the Cox-2 inhibitors are equally effective at relieving pain, less likely to upset the stomach, but more frequently associated with heart attack and stroke when used for over a year. For a person without heart disease who has stomach upset with traditional NSAIDs, Celebrex may be a good option. On the other hand, a person who has heart disease would be better off using another pain medication and avoiding Celebrex.

We hope everyone has a great beginning to their fall and you will hear from us again soon!

The Doctors and Staff of South Florida Institute of Sports Medicine