Although overdoses of Tylenol can harm the liver, the study published in today's edition of the Journal of the American Medical Association is the first to note signs of trouble among healthy people taking the pain reliever as directed.

Rethink Maximum Dosage?

"This study shows that even taking the amount on the package can be a problem for some people," said Dr. William M. Lee of the University of Texas Southwestern Medical School. Lee was not involved in the research.

Tylenol is the No.1 brand of acetaminophen, the main ingredient in more than 200 types of pain relievers and cold remedies. As many as 100 million Americans take acetaminophen safely each year, according to estimates.

Still, the over-the-counter drug is the leading cause of acute liver failure in the US, and there have been calls for increased regulation to prevent overdoses. Concerns about suicide through acetaminophen overdose led to restrictions on how many pills could be sold at one time in England.

Lee said the latest study shows the maximum dose of Extra Strength Tylenol is set too high. The maximum dose is two 500-milligram pills every six hours or 4 grams daily.

Dr. Paul Watkins of the University of North Carolina, Chapel Hill, the lead author of the study, said acetaminophen generally is safe at the highest doses, but he acknowledged that the margin of safety is small.

"I think this study reminds us of what we already know: that you should stop at the 4-gram dose and not take more than you need," he said.

Above the Safety Threshold

The study of 145 healthy volunteers at two US medical centers compared a placebo, Extra Strength Tylenol and prescription painkillers that contain acetaminophen -- such as Percocet, which is a combination of acetaminophen and oxycodone, an opioid painkiller.

Patients took the medication or placebo every six hours for 14 days. Aminotransferase, a liver enzyme that can indicate possible liver damage when found at elevated levels, was measured daily for eight days and afterward at regular intervals.

All patients were on the same diet.

Out of 106 patients, 41, or 39 percent, who took acetaminophen alone or in combination with another drug saw their liver enzymes increase to more than three times the upper limit of normal, the researchers said. Twenty-seven patients had enzyme levels more than five times normal, and eight patients had eight times the normal amount of enzyme.

Three times the normal level of aminotransferase is considered the threshold at which doctors become concerned about possible liver damage.

Watkins attributed the sharply elevated enzymes to the Tylenol and not to the opioid medications.

Of the 39 patients on a placebo, only one had enzymes that exceeded twice the normal level.

Enzyme levels continued to increase in patients for up to four days after they stopped taking acetaminophen. It took as long as 11 days for their enzymes to return to normal, the scientists said.

Earlier Research Called into Question

The study was paid for by Purdue Pharma, which was developing a pill that combined acetaminophen and an opioid. Purdue suspended testing because of the drug's effects on liver enzymes, Watkins said.

"They did not see this as smooth sailing to get this approved" by the Food and Drug Administration," he noted.

A company representative could not be reached for comment.

McNeil Consumer Healthcare, the unit of Johnson & Johnson that markets Tylenol, said the latest study contradicted previous research sponsored by the company that showed no meaningful elevations in liver enzymes.

The company said that Tylenol was safe to use as directed and that high enzyme levels did not indicate liver damage in the absence of other symptoms.

Watkins plans other studies to see whether patients' livers become accustomed to acetaminophen over time. He noted that large numbers of elderly arthritis patients take high doses of Tylenol for long periods without liver injury.

(c) 2006 The Record; Bergen County, N.J.. All rights reserved.
(c) 2006 Daily News Central. All rights reserved.