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In September 2004, rofecoxib (Vioxx) was voluntarily withdrawn from the market after studies found that the drug was linked to an increased risk of heart attack and stroke.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.