A dozen take-home messages about the pills that take the hurt away.

Remember when it was so simple? Take two aspirin, call the doctor in the morning. Now we’ve got a staggering number of pain relievers to choose from. Picking the right one is enough to give you a headache! And whatever you might think about the Vioxx debacle, it certainly made us aware that these medications — even the ones sold over the counter — are serious drugs, capable of doing great harm as well as rescuing us from some awful pain. So here are a few pointers to help you navigate the pain reliever aisle.

1. Tylenol can cause liver damage. The active ingredient in Tylenol is acetaminophen. Acetaminophen overdoses, half of them unintentional, are now the leading cause of acute liver failure in the United States. Four grams per day (about 12 regular-strength Tylenol tablets) is considered the safe upper limit, but that might be too much for some. Large doses are the main risk, but there are reports of people developing liver problems after taking small to moderate amounts of acetaminophen for long periods of time.

Warning: People who drink alcohol regularly or have a less than healthy liver are more vulnerable to acetaminophen’s toxic effects, so the safety threshold for them is lower. Exactly how much lower is difficult to say, but some experts say that to be on the safe side, heavy drinkers shouldn’t take more than 2 grams daily.

Acetaminophen is an ingredient in many over-the-counter cold and headache medications; for example, Extra Strength Excedrin contains 250 mg. Prescription pain relievers like Percocet and Vicodin also contain acetaminophen. Some people may be taking more of the drug than they realize because of these “hidden sources.”

The danger here needs to be kept in perspective. Millions of Americans take acetaminophen every year, yet the cases of overdoses causing acute liver failure number in the hundreds, and a large percentage of those are suicide attempts. Over all, it’s a remarkably safe drug.

2. If it’s about NSAIDs, it doesn’t apply to acetaminophen. Most of the pain relievers that we’re familiar with, like ibuprofen, naproxen, and some that aren’t so familiar, like diclofenac (Cataflam, Voltaren), are nonsteroidal anti-inflammatory drugs (NSAIDs). As the name implies, they quell pain by quieting inflammation. Acetaminophen, however, is not an NSAID. It is not anti-inflammatory and relieves pain in other ways.

3. All the NSAIDs may increase heart attack risk. NSAIDs revolutionized the treatment of pain but have the drawback of being hard on the stomach; in extreme cases, they cause gastrointestinal bleeding, a serious — sometimes deadly — side effect.

The COX-2 inhibitors — celecoxib (Celebrex), rofecoxib (Vioxx), valdecoxib (Bextra) — were supposed to be the better NSAIDs: a new generation of medications that would relieve pain just as well as, if not better than, the old NSAIDs, but spare the gut.

Of course, it hasn’t worked out that way — to put it mildly. Vioxx was yanked from the market in 2004 after it was linked to an increased risk for heart attacks. Lawsuits, court cases (the verdicts have gone both ways), and a bitter controversy about incomplete reporting of research results ensued. Bextra came off the market a few months after Vioxx because of possible cardiovascular effects and a link to a potentially fatal skin disease.  The COX-2 inhibitor Celebrex remains on the market. Celebrex and some of the other COX-2 drugs (such as meloxicam, sold as Mobic) may be safer than Vioxx and Bextra because they inhibit not just the COX-2 enzyme but also the COX-1 to some degree, which is closer to the way the traditional NSAIDs work.

Soon all the NSAIDs fell under a cloud of suspicion — and it’s still there. Finnish researchers reported in 2006 that use of all NSAIDs increased the user’s risk of having a heart attack. An earlier Danish study came to a similar conclusion. And Harvard researchers, analyzing data from the Nurses’ Health Study, have found that heavy users (at least 22 days per month) of the traditional NSAIDs are twice as likely to have a heart attack or stroke as those who took fewer of the pills. But in the nurses’ study, it was only smokers who had increased heart disease risk from NSAIDs.

When a pair of Australian researchers combined the results from 23 studies, diclofenac, indomethacin (Indocin), and Vioxx stood out as the NSAIDs most likely to have cardiovascular side effects. Ibuprofen and piroxicam (Feldene) increased risk only slightly, and naproxen, not at all.

4. Naproxen may be the safest one for the heart. Other studies besides the Australians’ have concluded that naproxen doesn’t increase heart attack risk. Although the Finnish study didn’t give it a clean bill of health, of all the NSAIDs, naproxen increased heart attack risk the least. Whether naproxen, like aspirin, might actually protect people from heart attacks remains unclear. The Australians found no evidence of a protective effect, but a Harvard study in 2006 did, as have some others.

5. Low doses of Celebrex seem to be safe. After the bad news about Vioxx and Bextra, the future of all the COX-2 drugs was in doubt. But Celebrex has stayed on the market, and at doses of 200 mg per day or less, doesn’t seem to make a heart attack any more likely. (We’re hedging our bets a little because study results haven’t been uniformly positive.)

6. You can take something to help with the stomach woes. If NSAIDs bother your stomach or you’re at high risk for gastrointestinal complications, taking a proton pump inhibitor like omeprazole (Prilosec) or lansoprazole (Prevacid) can help. Taking one of these offsets the side effect.

7. Take your daily aspirin before ibuprofen or naproxen. If you’re worried about possible heart-related complications from taking NSAIDs, consider taking a low dose of aspirin. Small daily doses of aspirin (the standard amount is 81 mg) make platelets less “sticky,” which reduces the chances of the formation of a blood clot in an artery that supplies the heart or brain. Aspirin has this anti-adhesive effect because it gloms on to an enzyme called cyclooxygenase, which indirectly controls the levels of the substance (thromboxane A2) that gives platelets their stick. Ibuprofen and naproxen also seek out cyclooxygenase. If they get there first, there’s no room for aspirin.

The FDA recommends that when you take aspirin for cardiovascular protection, you should wait at least 30 minutes before taking ibuprofen. Alternatively, you can take an aspirin eight hours after taking ibuprofen. The FDA recommendation doesn’t include naproxen, but studies have shown that naproxen can also prevent aspirin from attaching to the the cyclooxygenase enzyme.

8. Beware of blood pressure increases. The NSAIDs, including the COX-2 drugs, tend to boost blood pressure. The effect is strongest and happens more consistently in people who have high blood pressure already and are taking medication to control it, but there’s evidence that people with normal blood pressure are also affected. Acetaminophen, in high doses and among women, has also been shown to cause small hikes in blood pressure. Low-dose aspirin doesn’t increase blood pressure and may, in fact, work to lower it if you take it at night.

9. Don’t go cold turkey. If you take an NSAID regularly, don’t stop suddenly. Sudden withdrawal makes blood clots more likely to form. Talk to your doctor about lowering your dose gradually and possibly taking a low-dose aspirin if you aren’t taking one already.

10. Beware of kidney woes. NSAIDs, including the COX-2 drugs, can be hard on the kidneys and, in extreme cases, cause kidney failure. Aspirin, ibuprofen, and perhaps sulindac (Clinoril) are less risky in this regard.

11. The dose matters. Many of the risks associated with pain relievers emerge only after long-term or heavy use. You shouldn’t be scared about taking the occasional Advil or Aleve for a headache or aches and pains. The risk is negligible.

12. Your genes matter. There is a lot of individual variation in how people react to pain relievers. For some, Celebrex may be the only pill that works. For others, acetaminophen does the trick. It may take some trial and error to find the pill that works best for you.

For more information on pain, order our Special Health Report, Low-Back Pain: Healing your aching back, at www.health.harvard.edu/LBP.