Cox-2 Inhibitors: Popular Yet Controversial Drugs

An article for patients

If you are among the estimated 50 million Americans living with chronic pain, then you are probably familiar with coxibs. Coxibs is the abbreviation for cyclooxygenase inhibitors. They belong to the family of nonsteroidal anti-inflammatory drugs (NSAIDs) of which aspirin, ibuprofen (Advil, Motrin), and naproxen (Aleve) are the most well known. Coxibs were designed to provide aspirin’s benefits without its negative side effects on the gastrointestinal system.

History of COX-2 inhibitors vs traditional NSAIDs

Aspirin was discovered in 1897 by chemist Felix Hoffman and introduced by the Bayer Company two years later. Since then, it has been considered the gold standard oral pain reliever. However, continued use of aspirin can cause stomach upset among other more serious and potentially life threatening problems such as gastrointestinal bleeding. To understand why these undesirable reactions occur, researchers investigated how aspirin works in the body. In 1971, pharmacologist John Vane showed that aspirin stops the action of an enzyme called cyclooxygenase, or COX. COX plays a key role in the body’s experience of pain.

Vane’s Nobel prize-winning discovery fueled more studies. Two COX forms, COX-1 and COX-2, were uncovered. COX-1 enzymes are normally found in most tissues and protect the stomach lining. In contrast, COX-2 enzymes become active when the body senses pain and responds by promoting inflammation. Traditional NSAIDs, like aspirin, block both COX forms. This reduces pain but also makes the stomach vulnerable. These discoveries suggested the possibility of a drug that could relieve pain and inflammation without damaging the stomach lining. Thus was born a new line of pain management drugs called selective COX-2 inhibitors.

In the hope that selective coxibs could have the benefits of aspirin and NSAIDs but none of their drawbacks, they were dubbed “super aspirins”. They were expected to benefit people with intolerances to other NSAIDs. To date, the FDA has approved three COX-2 inhibitors: celecoxib (Celebrex, 1998), rofecoxib (Vioxx, 1999), and valdecoxib (Bextra, 2001). Lumiracoxib (Prexige) is currently being considered.

The controversy 

The early results of two large, drug industry-sponsored clinical trials, CLASS and VIGOR, showed Celebrex and Vioxx to produce fewer stomach problems than other NSAIDs. These favorable findings led to a dramatic rise in the prescribing rates of COX-2 inhibitors. However, enthusiasm waned as the research was scrutinized. When the final results of the CLASS study emerged, Celebrex was determined to not reduce stomach complications as effectively as initially reported. This finding raised concerns about the drug’s alleged safety advantage. In response, the FDA mandated Pharmacia Corp. (company later acquired by Pfizer,Inc.) Celebrex’s manufacturer, to include standard precautions about NSAID risks in the drug’s product label.

Controversy surrounding Cox-2 inhibitors continued to escalate. The VIGOR study revealed that patients taking Vioxx had a greater risk for heart attack than those taking a traditional NSAID. In 2004, Vioxx’s manufacturer, Merck and Co., announced a voluntary worldwide withdrawal of the drug. Merck’s landmark decision was based on data from the more recent APPROVe clinical trial. APPROVe had been prematurely stopped due to the appearance of cardiovascular problems. The study demonstrated that patients who used Vioxx for at least 18 months had an increased risk for heart attack, stroke, and blood clots compared to patients who were not given the drug. Then in 2005, Pfizer Inc. similarly withdrew Bextra. The FDA had determined that Bextra’s adverse effects, such as cardiac problems and skin reactions, outweighed its anti-inflammatory benefits. Celebrex remains on the market as Pfizer contemplates a large safety study to definitively examine the issue of overall safety and benefit of Celebrex.

COX-2 inhibitors vs traditional NSAIDs.

While the therapeutic strength of COX-2 inhibitors lies in their ability to reduce stomach complications, their adverse reactions cannot be overlooked. Compared to traditional NSAIDs, Vioxx and Bextra exhibit safety problems that were sufficiently serious to warrant complete and immediate recalls. Celebrex is presently on the market with a tougher label. Nevertheless, the FDA in March 2005 published a warning that new research results suggest that Celebrex users may be at increased risk for cardiovascular events.

It is easy to forget two important points about COX-2 inhibitors vs. traditional NSAIDs: they both have the same effectiveness, and they both can cause side effects related to blood pressure, liver, and kidney problems.

Unfortunately the patient often gets lost in the middle of these complex debates about drug safety. The bottom line about COX-2 inhibitors, as far as can be seen at the time of this writing, is that they are safer than traditional NSAIDs on the GI tract (stomach and intestines), but cause increased risk of cardiovascular problems (heart attacks and strokes) with prolonged use. COX-2 inhibitors have an additional, unique safety advantage, which is that they do not increase the risk of bleeding; increased bleeding risk is a safety issue with traditional NSAIDs. It appears that there are patients who would benefit more from COX-2 inhibitors, even the ones withdrawn from the market, than from traditional NSAIDs. Such patients could include those who need the medications short-term and would be at high risk for bleeding or GI problems (such as patients with pain after brain or spine surgery), or patients for whom the possibility of bleeding or cardiovascular side effects outweighs the risk of cardiovascular side effects (such as patients with high GI risk but low cardiovascular risk, who need long-term pain relief).

The bottom line for patients is to work with your doctor to find the treatment that makes most sense for you given your risk profile, and not to overreact to the latest news stories.

To date, COX-2 inhibitors remain controversial. Although problems exist with their use, these drugs may continue as a first line treatment for some patients. If your doctor has determined that selective coxibs are more harmful than beneficial for you, there are alternatives. These include aspirin, ibuprofen, naproxen, acetaminophen (Tylenol), and other non-selective NSAIDs. Natural treatments, like nutritional supplements, exercise, physical therapy, and acupuncture, are also available. In some inflammatory pain, where NSAIDS would most likely be a main-stay of treatment, exercise may need to be moderated so the condition does not worsen. It is hoped that the next generation of COX-2 inhibitors will be better drugs, but for now, these purported super aspirins are still being heavily studied.


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