However, Schiff said, "This paper is important, because they're showing that what we thought was the upper limit of safety in people who are not regular drinkers or fasting -- that it's too high. To me, the critical factor is, 'What is the upper limit that's safe?' "
Millions of people take acetaminophen for pain relief. Some of these people can't take aspirin because of its gastrointestinal effects, or can't take nonsteroidal anti-inflammatory drugs (NSAIDs) such as naproxen (Aleve). Use of Celebrex, one of a newer class of NSAIDs called cox-2 inhibitors, is also controversial because of cardiovascular problems linked to two recalled cox-2s, Vioxx and Bextra.
The current findings came about by accident. In the process of conducting a trial on a combination acetaminophen/narcotic drug, Purdue Pharma discovered that a number of healthy volunteers had a high incidence of abnormalities in blood aminotransferase (ALT and AST) tests used to measure levels of specific liver enzymes. Those results "would normally be considered very alarming," Watkins said.
The initial concern was that it was the narcotic, hydrocodone, that was responsible for the increase.
That trial was halted, and the company called in Watkins and another expert to design the current study, published in the July 5 issue of the Journal of the American Medical Association.
Watkins and two other authors reported having served as paid consultants to Purdue during the planning and execution of the study but not during preparation of the article.
For this study, 145 healthy adults each received either a placebo, one of three acetaminophen/opioid combinations, or acetaminophen alone for 14 days. Each active treatment included 4 grams of acetaminophen daily, the maximum recommended daily dosage.
None of the patients in the placebo group had a maximum ALT measurement of more than 3 times the upper limit of normal.
However, in the four treatment groups, 31 percent to 44 percent of patients had a maximum ALT of more than three times the upper limits of normal. Those in the acetaminophen-alone group had a similar elevation, suggesting that the opioid had nothing to do with the effect.
"It was so unbelievable that I am conducting an ongoing study with 50 people," Watkins added. "That's not in the JAMA paper, but we're finding that it verifies the findings."
The authors suspect, however, that ALT elevations should go down, even after continued use of acetaminophen. "I'm quite convinced that if we continue to treat people, they would come back to normal, so that about after a month, I believe liver chemistries would be normal, even continuing," Watkins said.
One question raised by the paper is whether aminotransferase elevations are even accurate in predicting the potential for liver damage.
"In the past, when we've seen liver enzyme abnormalities to this extent, it has indicated to us physicians that there is significant liver injury or damage occurring," Watkins said. "Since we have decades of experience and know the safety of acetaminophen, are the tests as good as we thought they were? Maybe they're not good predictors as to which drugs are going to have liver problems," he added.
It's also possible that a number of past tests have been misread, incorrectly attributing elevations to a drug other than acetaminophen.
"Because recommended doses of acetaminophen have not been previously recognized to cause liver enzyme elevations, physicians may have embarked on costly liver evaluations unnecessarily," Watkins said. "Also, treatment with other drugs suspected to cause liver problems, such as lipid-lowering medicines, may have been stopped unnecessarily."
The message to consumers is to pay attention to dosing and duration of use when taking acetaminophen (and other drugs). In particular, pay attention to "hidden" acetaminophen in other drug products.
"There are a lot of combination drugs that include acetaminophen that people aren't aware," Schiff said. "That's been a problem."
More information
For more on acetaminophen, head to the National Library of Medicine. |
