Overdoing acetaminophen

Many overdoses are accidental, so the FDA may require new warnings on the popular pain reliever and lower the daily limit.

For a long time, acetaminophen, the active ingredient in Tylenol, has seemed to be the safe bet among the commonly available pain relievers.

Aspirin can be hard on the stomach and is out of the question for young children because of its link to Reye's syndrome, a rare but potentially fatal condition that affects the brain and liver. Ibuprofen, naproxen, the other nonsteroidal anti-inflammatory drugs (NSAIDs) — they're also hard on the gut. And if you take them regularly, there's a risk of an increase in blood pressure.

The COX-2 inhibitors were supposed to be the next big thing in pain relief, sparing the gut while vanquishing the pain. But they fell into disrepute several years ago after studies connected them to heart attacks. Celecoxib (Celebrex) has managed to stay on the market, but the lofty expectations for the COX-2 inhibitors haven't been met.

Now even safe-and-steady acetaminophen is looking less so.

It's been known for some time that large doses of acetaminophen can cause liver failure, but study results and tallies kept by the nation's poison control centers have shown that this is more than just a theoretical concern. By some counts, tens of thousands of Americans are hospitalized each year for liver problems caused by acetaminophen, and several hundred die. Many of the overdoses are suicide attempts, but one important study found that nearly half were accidental.

And clear-cut overdoses may not be the only problem. Even supposedly safe amounts of acetaminophen — doses close to 4,000 milligrams (mg) per day, the current daily limit — may be quite toxic to the liver in a small number of people.

To add insult to injury, acetaminophen may have deleterious effects beyond the liver. Harvard researchers have linked the drug to high blood pressure. Other researchers have identified a possible connection to asthma. These are preliminary, hypothesis-generating findings, not proof of cause and effect. Still, they're another reason the perception of acetaminophen as a harmless drug is changing.

In 2009, a group of experts called the Acetaminophen Hepatotoxicity Working Group (hepatotoxicity means liver poisoning) made several recommendations to the FDA that would tighten up the rules for acetaminophen. As of July 2009, the FDA hadn't decided which, if any, of the recommendations to implement, but some changes are likely.

Regardless of what the FDA decides to do, a more judicious approach to acetaminophen is warranted — but an overreaction is not. Millions of people take acetaminophen every day with no untoward effects — and are in less pain because they do. Just because acetaminophen isn't completely safe — no drug is — doesn't mean it's dangerous.

Hard to pin down

Acetaminophen, which in other countries is called paracetamol (pronounced par-ah-SET-ah-mol), was first synthesized and used in patients in the late 19th century. But it was dropped in favor of a related drug, phenacetin, and fell into obscurity until it was rediscovered in the 1950s after phenacetin proved to have too many side effects. Acetaminophen didn't catch on until the early 1980s, when it filled the void left by aspirin as the safe pain reliever and fever reducer for children after aspirin was linked to Reye's syndrome.

Acetaminophen is usually put in its own category, separate from the NSAIDs, because it doesn't have their anti-inflammatory effects. Some research shows that it does interfere with prostaglandin synthesis, like NSAIDs, but in a way that doesn't produce a widespread effect on inflammation. Some research suggests that the fever-reducing effects of acetaminophen come from inhibition of COX enzymes in the brain. Other research has shown that large doses may activate some of the same systems in the brain as morphine and the other opioid pain relievers. A relatively new theory is that acetaminophen has effects similar to cannabinoids, a group of compounds that includes some of the psychoactive substances in marijuana. This could explain the relaxed, drowsy, and euphoric feelings some people have after taking acetaminophen.

Metabolized in the liver

Acetaminophen may be enigmatic in some respects, but there's no doubt that it provides the kind of "fast relief" so often promised in commercials. It leaves the gastrointestinal tract quickly. Blood concentrations peak within an hour after taking an oral dose.

Like many drugs, acetaminophen is metabolized in the liver. Most of it gets broken down and altered into substances that are uneventfully excreted in the urine. But a small percentage is rendered into a compound that's extremely harmful to liver cells. The full name is so unwieldy that it's almost always referred to by its initials, NAPQI (also a mouthful but an improvement).

Usually, NAPQI is rendered harmless because it combines with glutathione, another compound in the liver. But if there's too much NAPQI, which can happen with an acetaminophen overdose, or not enough glutathione to sop up NAPQI, which happens if you haven't eaten well or are malnourished, then liver damage can occur.

Dangerous for chronic drinkers

If you drink a lot of alcohol in one session and take a normal dose of acetaminophen, you probably are not going to have liver problems. In the short term, alcohol and acetaminophen are metabolic competitors, so lots of alcohol can alter acetaminophen metabolism, producing less NAPQI.

It also seems that heavy drinkers aren't any more likely than nondrinkers to suffer liver damage from a single large dose of acetaminophen.

The trouble starts when heavy drinkers take a lot of acetaminophen over a period of time — several days, at least, and maybe longer. (In this context, heavy drinkers are defined as people who have three or more drinks a day.) A drinking habit and a poor diet often go hand in hand. Multiple high doses of acetaminophen are more dangerous for drinkers partly because their glutathione levels tend to be low because they don't eat well. Drinking also tends to shunt acetaminophen down a metabolic pathway that results in more NAPQI.

One of the recommendations from the FDA's working group is to set a lower daily limit for acetaminophen for people who routinely have three or more alcoholic drinks a day. How much lower was not specified.

"Hidden" sources

Part of the problem with acetaminophen dosing is that we're often taking the drug without realizing it, because acetaminophen is an ingredient in so many medicines. The powerful prescription painkillers Darvocet, Percocet, and Vicodin contain anywhere from 350 to 650 mg in each pill. And it's an ingredient in many over-the-counter medications: the cold and flu products like NyQuil and TheraFlu, Excedrin's migraine headache products, and even some varieties of Alka-Seltzer. Acetaminophen from these sources can start to add up. Moreover, the initial symptoms of liver toxicity from acetaminophen are often vague — fatigue, some nausea — and easily confused with the symptoms of the illness people are attempting to treat with the drug.

When researchers have compared accidental overdoses of acetaminophen with intentional ones, they've found something surprising: accidental overdoses tend to result in more serious liver damage than the intentional ones, even though the intentional overdoses were much larger. The explanation: people who take too much acetaminophen by mistake delay getting medical care because the early symptoms are nondescript and, of course, they don't know they're doing anything that might cause them harm. So by the time the accidental overdose patient gets medical attention, the acetaminophen levels are high and the damage to the liver more extensive.

How much is too much?

It's difficult to pinpoint the amount of acetaminophen that will result in a liver-damaging overdose. People's reactions vary, depending on the health of their livers, their glutathione levels, and maybe some as-yet-unidentified genetic factors. Some sources say 12,000 mg over a 24-hour period will have toxic effects on the liver. To put that in perspective: you'd have to take 37 regular-strength pills (at 325 mg each) to hit the 12,000-mg mark.

But there's evidence that much lower amounts will harm the liver. According to the FDA working group, the median daily dose associated with the liver injuries recorded in the agency's adverse event database and in a large liver failure study was 5,000 mg to 7,500 mg. That's uncomfortably close to 4,000 mg, the current daily limit for safe intake, so the working group recommended lowering it to 3,250 mg, which works out to 10 regular-strength pills a day.

The antidote

Acetaminophen overdosing is treatable with a drug called acetylcysteine, but it's important that it be caught early. Serious liver damage is unlikely and death extremely rare if acetylcysteine is given within eight to 10 hours after the overdose, regardless of the amount of acetaminophen in the bloodstream at that time. But after that, the higher the acetaminophen level in the blood, the less effective acetylcysteine becomes.

Acetylcysteine is a hard drug to take. The full course starts with one large "loading" dose and then 17 smaller ones that need to be taken every four hours. Delivered as a liquid, the drug has a terrible rotten-egg taste that often makes people vomit. Doctors worry about patients not finishing the full course, so they often keep them hospitalized to make sure they do. There is an intravenous version, but it's reserved for people who simply can't tolerate the foul taste, pregnant women, and those whose livers are already beginning to fail, so they need a large dose in a hurry.

What you should do

For starters, what you should not do is throw out your acetaminophen. It's an excellent drug with a good safety record. But you should view acetaminophen as a serious drug — not something you can pop like candy. Here are a few pointers:

  • Keep tabs on the amount of acetaminophen you are taking. Remember to include in your totals the amounts in over-the-counter medications.

  • Be especially careful if you are taking a heavy-duty prescription painkiller like Percocet or Vicodin. Each pill may contain as much as 650 mg of acetaminophen.

  • If you're sick and not eating well, limit your daily intake of acetaminophen to about 3,000 mg. Fasting or malnourishment lowers the glutathione levels in your liver, which makes it more vulnerable to the toxic byproduct of acetaminophen metabolism.

  • If you regularly drink three or more servings of alcohol a day, you must limit your intake of acetaminophen if you're taking the drug over several days. Steady drinkers are vulnerable to acetaminophen poisoning.

  • If you have hepatitis or another liver disease, ask your doctor about whether it's safe for you to take acetaminophen and, if so, how much.