The science behind the pain medication scandal

In the last several months, drugs once recognized as safe have been linked with health risks leading to heart attacks and strokes. Drug manufacturer Merck has recalled its arthritis and acute pain medicine, Vioxx, Pfizer has issued warnings for Celebrex and Bextra, also used for arthritis pain, and most recently, the Food and Drug Administration issued a cautionary statement for the over-the-counter painkiller Aleve.

Accompanying the news reports on the harmful nature of these drugs are the buzzwords COX-2 inhibition. What they mean and how pain medications can affect the heart, however, are often left unexplained.

Mark Fendrick, a doctor of internal medicine at the University Hospital who has studied the safety of arthritis medication, says the issue is prostaglandins. Found nearly everywhere in the body, they are the chemicals that produce the signals that cause pain — most common pain medications work by inhibiting prostaglandin formation.

Aside from inducing pain, prostaglandins also play an important role in the cardiovascular system. One type, prostacyclin, causes the relaxation of blood vessels and slows the formation of blood clots. A relaxed blood vessel is wider, so unclotted blood cells flow more easily. Another type, thromboxane, does the very opposite. Clotted cells can have difficulty flowing through a vessel narrowed by thromboxane.

“They make the blood vessels smooth or sticky,” Fendrick said.

The major enzyme responsible for the formation of these molecules is cyclooxygenase, or COX. It creates the starting molecule from which the prostaglandins are formed.

For years, scientists believed it was a single enzyme, but recent research suggests they were wrong.

In 1989, researchers at Washington University stumbled upon a possible new COX that was activated by specific stimuli that would lead to inflammation. Previously, scientists were only aware of one type of enzyme, now called COX-1, which was thought to always be active, perpetually producing prostaglandins. Fendrick calls it a “housekeeping enzyme.”

A year after the study was published in the Journal of Biological Chemistry, four separate labs — three reported in the Journal and one in Proceedings of the National Academy of Sciences — confirmed the existence of the new enzyme. Its DNA sequence was 60 percent similar to COX-1, making it sort of a fraternal twin.

This new form, called COX-2, was thought to be inducible, meaning it would lie dormant until inflammation turned it on. If COX-1 was like a student during finals, tirelessly working day and night, then COX-2 was like procrastinating student during the semester, doing nothing until a deadline spurred him into action.

Since traditional painkillers that target both forms of COX were found to cause adverse side effects, such as bleeding in the stomach and intestines, scientists looked for alternative options. They thought they had found one in COX-2.

“What makes COX-2 inhibitors ‘cool,’ ” Fendrick said, “is not that they block COX-2 but that they don’t block COX-1.”

Scientists thought not blocking COX-1 was safer, as COX-1 helped protect the lining of the stomach and intestines. Blocking only COX-2 seemed logical because it was turned on only in inflamed tissue, causing pain. Scientists believed that unlike COX-1, it had no function in healthy tissue. They were wrong about that, too.

In 1999, the year Vioxx hit the market, the FitzGerald lab at the University of Pennsylvania found that COX-2 is in fact responsible for producing prostacyclin, the hormone with blood-thinning properties, all the time, not merely under inflammatory conditions. While this study, published in Proceedings, suggested possible cardiovascular risks, early clinical trials of COX-2 inhibitors were not designed to look at these risks, and thus the drugs appeared to be safe.

Other labs continued to focus on the inducible properties of COX-2. In 2001, a study in the Journal of Immunology reported strong evidence that COX-1 seems to favor the production of thromboxane, which encourages blood clotting, whereas COX-2 seems to favor the production of prostacyclin. The balance of power comes into play again, and each enzyme plays a role in maintaining its own side.

For most nonsteroidal anti-inflammatory drugs, or NSAIDs, like aspirin, ibuprofen or naproxen — the generic name for Aleve — this is not a problem. NSAIDs are nonselective, meaning they block the action of both COX-1 and COX-2. At recommended doses, they have a stronger effect on COX-1. At higher doses, however, increased COX-2 inhibition becomes an issue, which prompted the recent statement about high doses and long-term use of Aleve.

However, COX-2 inhibition is the only factor when it comes to COX-2 inhibitors like Vioxx, Celebrex and Bextra. While selective COX-2 inhibition alleviates pain, it also ends up reducing the body’s normal supply of prostacyclin, which helps prevent blood clots. It removes an important protective mechanism, leaving patients already at risk for heart problems more vulnerable.

Fendrick thinks this explanation is a “leap of faith,” though, as evidence for it has not been found in the autopsies of patients. But he added that COX-2 inhibitors are no better at relieving pain than the NSAIDs — that they have never been proven to be more effective: “This is a myth that needs to be broken.”

The Canadian pharmaceutical company Dimethaid is trying to take advantage of recent events by increasing the marketing for its topical cream Pennsaid, which is already being distributed in some European countries. Pennsaid is an NSAID like aspirin, but because it is a cream and not a pill, it does not have the harmful gastrointestinal side effects.

There is a simpler alternative, what Fendrick calls a “back to the future” approach: using two old drugs to achieve a new benefit. Taking a traditional NSAID along with a drug to protect the stomach will provide equal pain relief with similar protection compared to the COX-2 inhibitors.

“I find it ironic that a drug that was developed to enhance safety,” Fendrick said, “may meet its demise due to safety concerns.”