Coxibs: A Failure on the Path to Success?

Coxibs include the drugs celecoxib (Celebrex), rofecoxib (Vioxx), and valdecoxib (Bextra). They are a sub-category of non-steroidal anti-inflammatory drugs (NSAIDs) that have been developed over the past couple of decades. Their original purpose was to prevent some of the digestive problems associated with NSAIDs use, but they have been shown to cause more heart problems.

NSAIDs are an extremely common type of medication.  They include aspirin, ibuprofen and naproxen as over-the-counter medications. NSAIDs that might require a prescription include indomethacin (or indometacin), etodolac and nabumetone. And there are others.

These medicines are used mainly to treat pain, inflammation, and sometimes fever.  The over-the-counter versions are often marketed as medicines for headaches, general discomfort, and menstrual pain. Doctors also prescribe these medications for painful chronic conditions such as rheumatoid arthritis, osteoarthritis, and gout.

So if these drugs already exist, why develop new versions? In high doses, NSAIDs commonly cause severe side effects. The most common side effects of NSAIDs are to the digestive system.  They might include nausea, diarrhea, and indigestion. In some cases there is bleeding of the stomach or intestines, which can lead to serious complications or even death.

It’s going to get technical for a little bit here. Coxibs were NSAIDs developed to provide the same benefits to patients suffering from pain and inflammation, but without the stomach problems. All NSAIDs affect the hormones called prostaglandins. These naturally occurring chemicals trigger pain, swelling and fever.

Unfortunately, prostaglandins also help regulate the normal function of the stomach and intestines.  Without them, the digestive system doesn’t produce its natural protective lining and a hole (otherwise known as an ulcer) can develop.

So coxibs were developed to more specifically target different chemical pathways. Most NSAIDs interrupt prostaglandins by binding to the enzymes cyclooxygenase 1 and 2 (COX-1 and COX-2). Without these enzymes, prostaglandin cannot function, and the pain and swelling are reduced. Coxibs target only the COX-2 enzyme.  The word “coxib” is actually short for “COX-2 inhibitor.” And the drugs were successful in that task. Partly.

In short-term studies, the use of coxibs has shown to have fewer side effects in the stomach and intestines. Long-term studies, however, don’t show a significant improvement. More problematic, however, is that the COX-2 inhibitors have an increased risk of causing heart disease among long-term users.

All NSAIDs (except low-dose aspirin) carry some heart risk. This is especially true for people taking high doses or using NSAIDs regularly for an extended period of time. Coxibs have a much higher than normal risk of causing heart attack and stroke even than other NSAIDs. For this reason, coxibs have been largely pulled from the market and aren’t available in many countries.

Currently, the only COX-2 inhibitor available in the USA is celecoxib. It’s marketed under the brand name Celebrex. Previously, rofecoxib and valdecoxib (Vioxx and Bextra respectively) were available, but the were pulled in 2004 and 2005. Rofecoxib is still used as a painkiller for animals, however, and certain countries around the world still make these drugs available despite the risk.

The rise and fall of coxibs are a step on the path to better medications.  This particular group of drugs wasn’t successful, but the idea was a good one. Due to the complexity of the human body, it’s almost impossible to affect only a single process such as pain or swelling. So medications cause side effects. The increasingly targeted medications, though, are making strides towards more specific action. Maybe the next group will do better than the COX-2 inhibitors.

Graphic courtesy of FreeDigitalPhotos.Net.

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