Yellow light on pain relievers

American Heart Association guidelines recommend using caution for all medications that ease pain.

Like a boulder hurled into a quiet pond, the recall of the painkiller Vioxx sent shock waves through the medical community and the general public that are still rippling today. The abrupt announcement by drug maker Merck in the fall of 2004 that Vioxx was linked to an increase in heart attack risk triggered a closer look at all of the medications we reach for to ease pain, calm inflammation, and cool fevers.

Under the magnifying glass, every pain reliever — indeed, every drug — has its flaws. It's common knowledge that aspirin, ibuprofen, and other pain relievers can be hard on the stomach. What has come to light over the past couple of years is that some commonly used pain medications can, like Vioxx, raise the risk of having a heart attack or stroke. The possibility of this happening is highest in people with heart disease or at high risk of it. That's a big tent, covering those with angina or heart failure; those who have had bypass surgery or angioplasty; heart attack and stroke survivors; and those with peripheral vascular disease, diabetes, and the metabolic syndrome.

To help doctors and the rest of us make the safest painkiller choices, the American Heart Association (AHA) has come out with step-by-step recommendations. Aspirin and acetaminophen top the AHA's list of preferred options. The AHA experts list narcotic pain relievers next as a possibility for short-term problems. Then come naproxen and other anti-inflammatory drugs, followed — as a last resort — by the COX-2 inhibitors, of which Celebrex is the only member.

Why the ruckus?

Aspirin, ibuprofen, naproxen, Celebrex, and their relatives belong to the family of medicines known as nonsteroidal anti-inflammatory drugs (NSAIDs). These drugs work by interfering with a protein known as cyclooxygenase (COX). There are two types of this protein, COX-1 and COX-2.

Cells in the stomach and intestines constantly produce COX-1, which makes hormone-like compounds called prostaglandins that protect these tissues against stomach acids and digestive enzymes. Cells elsewhere in the body turn on COX-2 in response to inflammation. COX-2 stimulates the production of prostaglandins that cause swelling and pain.

Some NSAIDs inhibit the activity of both COX-1 and COX-2. That's why they ease pain but also upset the stomach or cause gastrointestinal bleeding. Drug companies designed Vioxx and Bextra (both now off the market) and Celebrex to disrupt COX-2 more tenaciously than COX-1. That selectivity let these so-called COX-2 inhibitors relieve pain without wreaking quite as much havoc in the digestive system. When the COX-2 inhibitors hit the market, they were hailed as a breakthrough. That's been tempered by new knowledge about their drawbacks.

COX-2 is involved in more than just inflammation. Cells lining arteries contain COX-2, especially when the arteries stiffen or are stressed. Inhibiting COX-2 production in a healthy artery doesn't matter, because it doesn't contain much of it. But in an artery stressed by atherosclerosis, turning off COX-2 changes the balance of blood clotting factors. This change makes small blood cell fragments known as platelets more "sticky." Their tendency to clump together promotes the development of small clots that can block an artery. In a coronary artery, such a blockage can cause a heart attack; in the brain, it can cause a stroke.

Careful study of older NSAIDs showed that they do the same thing as Vioxx and Celebrex, but probably to lesser degrees. The AHA dissects the differences and offers a pain relief strategy that starts with the least risky medications and works its way down to riskier ones if needed.

Safe start

The safest option for quelling muscle or joint pain is a nondrug approach. Try heating pads, ice, and physical therapy first. Even if they don't completely do the trick, they may at least let you cut back on how often you take a pain reliever or how much you take.

For most people, the first pain reliever to start with is aspirin or acetaminophen. Their advantages? Aspirin is good for the heart, and acetaminophen kills pain in a different way than NSAIDs, so it doesn't affect blood clotting like they do. Both drugs have side effects, of course. Aspirin can upset the stomach and cause bleeding in the digestive system. Acetaminophen can damage the liver, especially at high doses or when it is in the body along with alcohol. Four grams a day (12 regular-strength Tylenol tablets) is considered a safe upper limit, but that might be too much for people whose livers aren't in tip-top shape or who drink daily.

If aspirin or acetaminophen doesn't work for you, the AHA suggests a narcotic pain reliever as the next step. These include prescription drugs such as tramadol (Ultram), codeine, and fentanyl (Duragesic). While narcotics probably aren't the right choice for arthritis pain, they might be an option for short-term aches like a severe muscle strain.

Cousins to aspirin, called nonacetylated salicylates, may be alternatives to aspirin. These include salsalate (Disalcid) and choline magnesium trisalicylate (Trilisate). They are easier on the stomach but lack aspirin's protection against cardiovascular disease. To get that, you would also need to take a daily baby aspirin.

Climbing higher

If those options don't work, the next step is another NSAID. Try naproxen (Aleve) first, suggests Dr. Elliot Antman, lead author of the AHA recommendations. "On the basis of what we know now, it appears that naproxen is neutral in regards to cardiac risk," says Dr. Antman, who directs the coronary care unit at Harvard-affiliated Brigham and Women's Hospital. After that comes ibuprofen (Advil); next is diclofenac, but more caution is needed with it since it blocks COX-2 more than COX-1.

Caution with COX-2 inhibitors

Celebrex, the only remaining COX-2 inhibitor on the market, should be the last resort for managing pain. (Other COX-2 inhibitors are under development, but it isn't clear whether the FDA will approve them.) These drugs ease pain and inflammation and may be a bit easier on the stomach than other NSAIDs. But in addition to their side effect of increasing the risk of clots in the bloodstream, COX-2 inhibitors can also reduce blood flow through the kidneys, cause them to hang onto sodium, and increase blood pressure.

If Celebrex is the only painkiller that lets you get through the day, then use it. But do so with your eyes wide open to the possible hazards. Make sure you know the warning signs of a heart attack or stroke, and have your blood pressure and kidney function checked every six months or so.

Protecting the stomach

The majority of people who take aspirin or another NSAID don't develop ulcers or gastrointestinal bleeding. If you have, or might, there are several ways to reduce the chances of this happening. Taking the drug with food and drinking a full glass of water with it can help. Medications that slow acid production are another option. There are three types: proton-pump inhibitors such as esomeprazole (Nexium), lansoprazole (Prevacid), omeprazole (Prilosec), pantoprazole (Protonix), and rabeprazole (Aciphex); Hâ‚‚ blockers such as cimetidine (Tagamet), famotidine (Pepcid), nizatidine (Axid), and ranitidine (Zantac); and misoprostol (Cytotec), a synthetic prostaglandin analogue.

Don't block aspirin

Aspirin helps prevent heart attacks and strokes by altering the action of COX-1 inside platelets. This makes platelets become less "sticky" and thus less likely to clump and form artery-blocking blood clots. Ibuprofen blocks this heart-protecting action of aspirin. The interaction isn't a problem if you take ibuprofen once in a while. But if you take it a few times a week or more often, try this: Take your aspirin in the morning, and wait at least 30 minutes before taking ibuprofen. If that isn't feasible, try to delay taking aspirin for at least eight hours after taking ibuprofen.

Using common sense

Recommendations like these can sometimes seem like overkill. Don't be afraid to take aspirin, Tylenol, Advil, or Aleve for a headache or other occasional aches and pains. If you need one several times a week, that's when you need to pay more careful attention. Stay in touch with your doctor, and remember to mention any over-the-counter medications, especially pain relievers, that you are taking.