Medications called COX-2 inhibitors were designed to relieve pain as effectively as other common painkillers (e.g., ibuprofen) but without the risk of upset stomach. After their introduction, these drugs became enormously popular, especially for the treatment of inflammatory conditions such as arthritis. However, several research studies have raised concerns about their safety, particularly for heart patients. This caused the voluntary removal of two COX-2 inhibitors from the market and the addition of a strong "black box" warning to a third. Currently, only one prescription COX-2 inhibitor is available in the United States. In general, patients with cardiovascular disease are not prescribed COX-2 inhibitors if other pain–relieving options exist.

In September 2004, rofecoxib (Vioxx) was voluntarily withdrawn from the market after studies found that the drug was linked to an increased risk of heart attack and stroke. These side effects were noticed 18 months after patients began using the drug.  

In April 2005, the FDA also requested that the manufacturer of valdecoxib (Bextra) voluntarily remove the drug from the market in the United States pending further evaluation of the drug. This was due to the drug's potential risk for serious cardiovascular adverse events.

Currently, celecoxib (Celebrex) is the only COX-2 inhibitor that can be prescribed in the United States. However, manufacturers have agreed to place a strong “black box” warning on the packaging of this drug indicating its association with heart attacks and stroke.

The FDA continues to monitor this class of drugs through research studies for adverse side effects and changes in its recommendations.

Cyclo-oxygenase–2 (COX-2) inhibitors are special types of nonsteroidal anti-inflammatory drugs (NSAIDs). Like all NSAIDs, COX-2 inhibitors work by blocking the production of prostaglandins. Prostaglandins are hormone-like substances in the body that are quickly released at the site of an injury. The presence of these chemicals registers in the brain as “pain.” Prostaglandins also “protect” damaged tissues by bathing them in fluids, causing the tissue to swell or “inflame.” By blocking the production of prostaglandins, NSAIDs can reduce both the amount of fluid released after an injury and the number of pain “alerters” traveling through the nerves to the brain.

Unlike other NSAIDs,  COX-2 inhibitors are designed to  target only the pain-signaling prostaglandins (by inhibiting cyclo–oxygenase–2 or COX-2). Thus, the are often called selective COX-2 inhibitors. Most other NSAIDs affect COX-2 and the closely related cyclo-oxygenase-1, or COX-1. Among other things, COX-1 is known to protect the lining of the stomach. As a result, non-selective NSAIDs frequently cause some form of gastrointestinal upset and cannot be taken by patients with ulcers or other stomach ailments. When they were originally introduced, selective COX-2 inhibitors represented a major improvement in the management of inflammatory pain, and they quickly became among the most popularly prescribed drugs in America.

However, in late 2004, a number of questions were raised about long-term cardiovascular side effects associated with rofecoxib, or Vioxx. Studies had shown that patients who took Vioxx were slightly more likely to suffer from heart attack and stroke. Some estimates guessed that up to 100,000 heart attacks had been caused Vioxx. As a result of the controversy, Vioxx was voluntarily withdrawn from the market by its manufacturer and remains the subject of ongoing lawsuits.

Shortly afterward, in April 2005, another COX-2 inhibitor, valdecoxib (Bextra), was also voluntarily removed from the market because of concerns over raised risk of heart attack and stroke.

As a result, the only selective COX-2 inhibitor left on the market in the United States is celecoxib, or Celebrex. Extensive studies have not shown the same cardiovascular risk associated with Celebrex as other drugs in its class. As a precaution, however, the Food and Drug Administration (FDA) mandated that a strong "black box" warning be added to the packaging to warn consumers that use of Celebrex may be associated with increased risk of heart attack and stroke.

Despite their controversial history, manufacturers are working toward developing COX-2 inhibitors that do not have increased cardiovascular risk because these drugs worked very well to control pain without stomach upset. A number of other selective COX-2 inhibitors are sold around the world, including etoricoxib and lumiracoxib, but neither is approved for sale in the United States. In early 2007, the FDA denied etoricoxib's approval for the U.S. market until the manufacturer could provide more safety information. Lumiracoxib is also not approved for sale in the United States.

In contrast with the benefits associated with taking a daily aspirin, taking COX-2 inhibitors might be harmful to cardiovascular health, both for heart patients and non-heart patients.

First, a number of research studies have suggested that COX-2 inhibitors might increase the risk of cardiovascular problems, including:

Research has also linked the use of COX-2 inhibitors to non-cardiovascular related health risks, including:

• Aseptic meningitis. In rare instances, rofecoxib can cause this non-bacterial form of meningitis that requires hospitalization, but is typically not life threatening in persons with normal immune systems. Individuals with autoimmune diseases, such as lupus, are at higher risk of aseptic meningitis when taking rofecoxib. Rofecoxib was withdrawn from the market due to increased risks to cardiovascular health.
  
  
• Stevens-Johnson syndrome. Valdecoxib (Bextra) has been associated with this rare complication that can cause hypersensitivity reactions (lesions, rashes) on the skin, mucous membranes and gastrointestinal tract. It has also been associated with other life-threatening skin reactions, including toxic epidermal necrolysis and erythema multiforme. Valdecoxib was voluntarily removed from the US market in 2005.
  
  
• Pancreatic cancer. Researchers found that the use of COX-2 inhibitors caused an increase in the growth of existing pancreatic tumors in mice.

Ongoing research is seeking to confirm or rule out potential adverse cardiovascular effects of COX-2 inhibitors. There are also other factors to consider when deciding whether treatment with COX-2 inhibitors is appropriate. For instance, since COX-2 inhibitors could negate any heart-protecting effects of daily aspirin therapy, the greater expense of COX-2 inhibitors might not be justified. Cheaper nonsteroidal anti-inflammatory drugs (NSAIDs) offer the same painkilling benefits and the same stomach-related risks for patients taking aspirin every day.

It should be noted that the labels of all NSAIDs, including COX-2 inhibitors, as per the FDA, include the risk for stomach-related side effects (e.g., gastrointestinal bleeding, obstruction, perforation, stenosis).

Preparing questions in advance can help patients to have more meaningful discussions with their physicians regarding their conditions. Patients may wish to ask their doctor the following questions about cyclo-oxygenase 2 (COX-2) inhibitors:

1. Can I  safely use a COX-2 inhibitor?
   
   
2. What are the greatest risks for me using these drugs?
   
   
3. Under what circumstances would you prescribe COX-2 inhibitors for me?
   
   
4. How will the drug affect other medications I am taking for my heart condition?
   
   
5. How likely am I to develop serious side effects from the use of COX-2 inhibitors?
   
   
6. What alternative drugs can I use for my condition besides COX-2 inhibitors?
   
   
7. How do COX-2 inhibitors differ from over-the-counter pain relievers?
   
   
8. Are there any new COX-2 inhibitors coming on the market that may work better for me?
   
   
9. What are the warning signs of problems associated with COX-2 inhibitors?
   
   
10. How long can I stay on this drug?
    
    
11. Should I stop using COX-2 inhibitors if I think I’m pregnant?