Frequent users of phenacetin, a drug closely related to the popular painkiller acetaminophen (sold as Tylenol and other brands), face a 16 times greater risk of death from kidney disease than non-users, according to a 20-year study of Swiss women published today.
Previous studies had identified phenacetin's link with kidney disease and prompted the Food and Drug Administration to order the drug off the U.S. market in 1982.
But an editorial published with the new study suggests that the magnitude of the kidney disease risk, as well as an additional finding of higher death rates in phenacetin users from heart disease and cancer, raises questions about acetaminophen. That drug accounts for about $300 million of the $1.2 billion spent annually on pain relievers.
Because of the close chemical relationship between the two drugs, "it becomes fairly urgent to learn more about acetaminophen" and its possible effects on the kidneys and blood vessels, wrote Paul D. Stolley, a professor of medicine at the University of Pennsylvania. He wrote the editorial accompanying the study in today's issue of the New England Journal of Medicine.
The body chemically converts phenacetin into acetaminophen. Both drugs then undergo further transformation, and some of the chemical end products that are eventually excreted by the kidney are the same after taking either drug, Stolley said in an interview.
"I think we have a lot of unanswered questions about acetaminophen," he said. "I'm not saying it's dangerous. I'm saying we'd better take a look at it."
Anthony Temple, director of regulatory and medical affairs for McNeil Consumer Products, the maker of Tylenol, said it was "inappropriate" to infer that acetaminophen might produce the same kind of kidney damage as phenacetin.
"It's simply not the same drug as phenacetin," he said. "It is metabolized differently."
Only one study so far has linked acetaminophen with kidney damage. That report, published by a U.S. government researcher in 1989, found that adults who took regular, daily doses of the drug had a risk of serious kidney disease that was three times higher than normal. But the study was small and the findings were regarded as tentative.
For phenacetin, in contrast, the evidence is clear. The new report, by Ulrich C. Dubach and Til Sturmer of Basel, Switzerland, and Bernard Rosner of Harvard Medical School, presents data on disease and death rates in 623 women who were regular phenacetin users. They were studied from 1968 to 1988.
When compared to a "control" group of 621 women who did not regularly take phenacetin, those taking the drug had twice as high an overall death rate, three times as high a death rate from heart disease, twice as high a death rate from cancer, and 16 times as high a death rate from kidney disease. There were 74 deaths among the phenacetin users and 27 deaths in the control group.
Phenacetin was introduced as a painkiller in 1887, and was used for decades, both alone and in combination with other drugs, as a pain and fever remedy before it was banned.
In the new study, phenacetin users whose urine tests suggested that they had taken five or more 250-milligram tablets in the previous 12 hours were considered to be in a "high-dose" group. Women whose urine tests suggested that they had taken between one and four tablets were considered to be in a "low-dose" group.
The risk of dying from kidney disease was dose-related, with "low-dose" users having five times the risk of non-users and "high-dose" users having 23 times the risk of non-users.
Stolley said experimental studies in animals suggest that either phenacetin or one of its byproducts produced by the body is toxic to the kidneys, but that toxin has not been identified.
Temple, the spokesman for the maker of Tylenol, said that phenacetin is metabolized by the body to produce both acetaminophen and another chemical, para-phenetidin. The latter substance, "in our view, is the metabolite responsible for the majority of phenacetin-associated toxicity."
Acetaminophen, by contrast, is not broken down into para-phenetidin, he added.
Stolley said that because acetaminophen is chemically similar and shares phenacetin's properties as a pain and fever reliever, it also may share its potential for damaging the kidneys. "Is it a probability? A possibility? Nobody knows."
He said further studies are especially needed because acetaminophen is being promoted for adults and children as an alternative to aspirin. Aspirin can cause stomach ulcers and gastrointestinal bleeding, and has been linked to Reye's syndrome, a serious liver disorder, when taken by children who have chickenpox, influenza or other viruses.