Trying times for painkiller choices

Content provided by the Faculty of the Harvard Medical School

Trying times for painkiller choices

Vioxx, Bextra, and Celebrex can increase the risk for heart attack and other cardiovascular problems. So can the old standbys, like ibuprofen and acetaminophen.

The ruckus over the safety of three blockbuster painkillers — Vioxx, Celebrex, and Bextra — is shining the spotlight on how drugs are tested and marketed. Just as important, it is exposing our all-too-comfortable relationship with painkillers.

The sudden removal of Vioxx from the market in 2004 because of possible cardiovascular side effects — after an estimated 20 million Americans had taken the drug — sparked calls for drug approval reform, not to mention thousands of lawsuits. A few months later, Bextra was yanked due to life-threatening skin reactions and possible cardiovascular effects. But the problems aren’t limited to the new kids on the block. We’re learning that the old standbys, like ibuprofen (Advil, Motrin, others) and acetaminophen (Tylenol), aren’t entirely blameless when it comes to heart trouble.

It isn’t exactly news that painkillers have potentially dangerous side effects. We’ve known for decades that aspirin, ibuprofen, and other nonsteroidal anti-inflammatory drugs (NSAIDs) can upset the stomach and cause serious, even deadly, gastrointestinal bleeding. That hasn’t stopped us from using the drugs. More than 30 million American adults take over-the-counter painkillers daily.

Vioxx, Celebrex, and Bextra were developed as gentler-on-the-stomach alternatives. They aren’t any stronger than traditional NSAIDs, and they cost a lot more, so their use should have been limited to people in whom the older NSAIDs caused gastrointestinal problems or who didn’t get relief from the older drugs. But thanks to aggressive direct-to-consumer marketing campaigns, millions of people who ended up taking Vioxx, Celebrex, and Bextra could have used a traditional NSAID instead.

What NSAIDs do

From aspirin to Vioxx, all NSAIDs work by blocking cyclooxygenase, a pair of enzymes dubbed COX-1 and COX-2 that have different jobs around the body. Cells throughout the body turn on COX-2 in response to inflammation. It oversees the production of prostaglandins, hormone-like compounds that cause swelling and pain. Cells in the stomach and the intestines constantly make COX-1, where it helps produce other prostaglandins that protect against stomach acids and digestive enzymes.

Nonselective NSAIDs like aspirin, ibuprofen, and naproxen (Aleve, others) block both COX-2 and COX-1. By shutting off COX-2, they ease pain; by shutting off COX-1, they remove a shield against corrosive stomach acids. Vioxx, Bextra, and Celebrex were designed as selective COX-2 blockers, meaning they blocked COX-2 but not COX-1. In theory, that would let them kill pain without posing problems for the stomach.

Too bad it isn’t that simple. These enzymes are also at work in the heart, lungs, and blood vessels, as well as the nervous, immune, and reproductive systems. We’ll focus on the cardiovascular effects here (see “How NSAIDs affect the body”).

COX-1 stimulates platelets in the blood to churn out thromboxane A2. This substance makes platelets “sticky.” Clumps of sticky platelets create a nucleus around which blood clots form. When a clot blocks an artery in the heart, it causes a heart attack; in the brain, it causes a stroke. Aspirin knocks out COX-1 in platelets, making them less sticky. This is how it protects against heart attacks and strokes.

COX-2 helps produce prostacyclin inside blood vessels. Prostacyclin is good for circulation in three ways. It prevents platelets from clumping. It relaxes blood vessels, allowing for smoother blood flow. And it stalls the growth of smooth muscle cells in the endothelium (the lining of blood vessels), which helps prevent artery-clogging atherosclerosis. Blocking COX-2 shuts off these sources of artery protection.

Other influences

The term “selective COX-2 blocker” is a bit misleading. All NSAIDs block both COX-1 and COX-2. At one end of the spectrum is Prexige, which is available in other countries but not here. Like Vioxx, it blocks COX-2 far more powerfully than it does COX-1 (see “COX blocking power”). At the other end are naproxen and ketorolac (Toradol), which are better at blocking COX-1 than COX-2.

COX blocking power

Genes matter, too. People respond differently to the good and bad effects of NSAIDs. Some people find greater pain relief with COX-2 blockers, even though these drugs generally aren’t any more powerful at killing pain than traditional NSAIDs. Some people, particularly those with existing heart disease or at high risk for it, are more susceptible than others to the harmful side effects of COX-2 blockers. And some people develop serious stomach upset or bleeding after taking ibuprofen or naproxen, while others never have a moment of stomach trouble.

There’s also the issue of other medications. Taking low-dose aspirin in addition to a traditional NSAID increases the chances of gastrointestinal trouble. Taking low-dose aspirin with a COX-2 blocker wipes out any stomach protection from the drug. The commonly used antidepressants known as selective serotonin reuptake inhibitors, such as Prozac and Zoloft, also increase the chances of stomach bleeding, especially when they are taken with NSAIDs. Other drugs could similarly influence the risk of NSAID-related harms.

Defining benefits, risks

The benefits of NSAIDs are indisputable. They soothe pain, from the temporary irritation of a stress headache to the constant ache of arthritis. They ease inflammation and lower fever. Aspirin helps prevent heart attacks. And the COX-2 inhibitors were showing promise as a way to prevent precancerous polyps from growing into full-blown colon cancer.

What about their risks?

Stomach trouble. In the United States alone, traditional NSAIDs account for as many as 100,000 hospitalizations and 16,000 deaths a year due to stomach bleeding and other gastrointestinal damage. COX-2 blockers reduce but don’t eliminate this side effect. In an early Vioxx study, 21 in 1,000 volunteers taking the drug developed a stomach problem, compared with 45 in 1,000 volunteers taking naproxen. Celebrex may cause even less stomach trouble.

Blood pressure. NSAIDs and COX-2 blockers boost blood pressure and can counteract the effect of some blood pressure–lowering drugs. Some people don’t experience any rise in blood pressure; others have substantial elevations.

Heart attack. In June 2006, British and Italian researchers gathered data from 138 NSAID trials that included 145,000 participants. They found that use of a COX-2 blocker was linked with a moderate increase in the chances of having a heart attack. The increase amounted to an extra three to five heart attacks for every 1,000 people taking the drugs for a year. High-dose regimens of ibuprofen or diclofenac (Cataflam, Voltaren) had similar effects. Reports in the summer of 2006 in the New England Journal of Medicine suggest that even short-term use of Vioxx may be linked with heart attacks, and that the risk may linger for a year or more after stopping the drug. In a study in the spring of 2006 from the Harvard-based Nurses’ Health Study, women who used a traditional NSAID at least 22 days per month were twice as likely to have had a heart attack or stroke or to have died of cardiovascular disease over a 12-year period as those who used less or none at all. (The absolute increase was from 2.5 events per 1,000 women to 4.3 per 1,000.)

Heart failure. The use of traditional NSAIDs or Vioxx may lead to or worsen heart failure, while Celebrex has less of an effect.

In general, cardiovascular side effects were most likely to happen in people with existing heart disease or those at high risk for it.

What about acetaminophen?

Doctors often recommend acetaminophen (Tylenol) as an alternative to NSAIDs. It doesn’t ease inflammation or affect the stomach. But acetaminophen does have side effects of its own.

At high doses, or when taken with alcohol, acetaminophen can damage the liver. And like NSAIDs it, too, has cardiovascular effects. In the Nurses’ Health Study, women who took acetaminophen more than 21 days a month were more likely to have heart attacks or strokes or to die of cardiovascular disease than those who used it less often.

Juggling benefits, risks

NSAIDs aren’t magic bullets. When you take one, it doesn’t head straight for your aching knees, sore back, or throbbing temples. Instead, it produces a body-wide chemical reaction that eases your pain and, with luck, does little else.

Most of us overlook or outright ignore the risks of taking an NSAID — or any other drug, for that matter — especially old familiars we can buy without a prescription. Given what we’re learning about NSAIDs, it’s time to pay closer attention.

The best way to minimize side effects is to take the lowest dose that works for you, and to take it only when needed. Finding the dose that’s right for you takes some experimentation. Your doctor may also be able to suggest non-drug alternatives, like exercise or acupuncture, that may reduce your pain.

Which painkiller to choose depends on you (see “Which painkiller is right for you?”). Traditional NSAIDs and acetaminophen remain the mainstays for quelling pain, though only NSAIDs ease inflammation. They’re all you need if they work for you and your stomach doesn’t mind them. If NSAIDs upset your stomach or cause gastrointestinal bleeding, taking an acid blocker can help. (Your doctor may also want to test you for Helicobacter pylori, the bacterium that causes ulcers.) Acid blockers include omeprazole (Prilosec), lansoprazole (Prevacid, Prevpac), esomeprazole (Nexium), pantoprazole (Protonix), and rabeprazole (Aciphex).

If you are in the small minority who don’t get relief from a traditional NSAID or acetaminophen, and you don’t have heart disease or risk factors for it, don’t rule out a COX-2 blocker like Celebrex. It may be a good option, as long as you are aware of the risks and alert for possible side effects.

Our understanding of the cardiovascular consequences of COX-2 blockers and traditional NSAIDs is still quite crude, based on limited long-term evidence. We will keep you posted on important developments, such as results from the ongoing PRECISION trial, which is testing Celebrex against ibuprofen and naproxen in 20,000 people with arthritis who also have heart disease or are at high risk for it.

What we know now is that NSAIDs and COX-2 are generally safe, but can pose problems for the heart. The risk is low, but given how often we take these drugs, it is worth being aware of.

And the COX-2-NSAID saga has already taught us two lessons we seem doomed to learn over and over again:

• Newer doesn’t necessarily mean better.

• And over-the-counter doesn’t necessarily mean risk-free.

E-mail This | Print This

Last updated:	September 27, 2006