Limits to acetaminophen in prescription painkillers linked to drop in hospitalizations

Limits to acetaminophen in prescription painkillers linked to drop in hospitalizations

Since the FDA announced limits on acetaminophen packaged in any prescription pain reliever from up to 750 milligrams (mg) to 325 mg, there has been an 11% to 16% annual decrease in the number of hospitalizations and cases of acute liver failure involving combined sedative. Photo by jorono/Pixabay

Acetaminophen, a popular over-the-counter drug for millions of people struggling with pain and fever, can also be found in prescription pain relievers that combine acetaminophen and an opioid in one pill.

The problem? The US Food and Drug Administration has long known that high doses of acetaminophen (Tylenol) can damage the liver. So in 2011 the FDA set new safety limits on the exact amount of acetaminophen that can be packed into each prescription pain reliever.


Now, a new study shows that exercise is likely to save lives.

Since the FDA announced the regulatory change, which lowered acetaminophen limits from up to 750 milligrams (mg) to up to 325 mg, there has been an 11% to 16% annual decline in the number of hospitalizations and acute failure cases of the liver. which includes the combination pain reliever. One such combination is Vicodin, which contains hydrocodone and acetaminophen.

“This suggests that the mandate is likely to be the biggest driver in reducing the incidence of acute liver failure and hospitalizations in combination acetaminophen-opioid products,” said study author Dr. Jayme Locke, director of the University of Alabama at Birmingham Comprehensive Transplant Institute.

The report was published in Tuesday’s issue of the Journal of the American Medical Association. Locke and her colleagues stressed that their investigation does not conclusively prove that the FDA mandate directly caused the drop in acetaminophen-opioid drug complications.

“Of course, other factors may have played a role,” Locke noted. “For example, the mandate may have brought the issue of acetaminophen toxicity to the fore for both providers and patients,” apparently leading some to reduce acetaminophen doses themselves.

At the same time, she noted that the FDA’s mandate did not place any new restrictions on over-the-counter acetaminophen dosage. Not surprisingly, “similar [downward risk] the trends were not just observed in acetaminophen,” Locke said.

According to the study authors, the intended purpose of combining acetaminophen with an opioid was to allow doctors to expose patients to lower doses of each of the two drugs. Given the growing crisis of opioid addiction, this approach made sense.

But researchers began to warn that at such high doses acetaminophen was proving toxic to the liver.

In fact, the new report points to a 2005 study that found that more than 4 in 10 of all cases of acute liver failure linked to acetaminophen use ended up being traced to acetaminophen-opioid pain relievers.

In 2009, such red flags prompted an FDA advisory panel to recommend an outright ban on such combination drugs. In the end, the FDA chose the dose limit route.

To see if the new limit had a protective impact, Locke’s team analyzed figures compiled by the National Inpatient Sample (NIS) and the Acute Liver Failure Study Group (ALFSG).

The NIS data provided details of approximately 473 million hospital admissions between 2007 and 2019. The ALFSG data focused on adult patients who were treated for acute liver failure between 1998 and 2019.

The investigators then ranked the risk of liver failure and hospitalization before the FDA mandate versus the risk after the mandate. And what they saw was a dramatic drop in risk, coinciding with the FDA’s 2011 mandate.

For example, NIS data found that while roughly 12 out of 100,000 hospitalizations involved combined drug toxicity just before the FDA’s move, that figure dropped to just over 4 out of 100,000 by 2019. And while the risk to be hospitalized with combined drug toxicity was increased. 11% per year up until the time of the FDA’s new limit, this figure actually turned into an 11% decline per year after the limit was announced.

The ALFSG figures revealed a similar dynamic: 27% of acute liver failure cases were attributed to the drug combination at the time of the FDA’s move, but that figure fell to 5% by 2019.

Locke said the study did not identify what percentage of combination drug users struggled with a substance use disorder before or after the FDA’s move. Nor did the team assess whether the new acetaminophen limit in any way reduced the potency of acetaminophen-opioid combinations.

But based on the evidence, Locke said her team is “satisfied with the mandate’s effectiveness in reducing the incidence of acute liver failure.”

Dr. Marc Ghany, chief of the hepatology clinical research section in the liver disease branch at the US National Institute of Diabetes and Digestive and Kidney Diseases, co-authored an editorial accompanying the study.

Ghany suggested that the FDA’s mandate can only go so far, given that combination acetaminophen-opioid formulations account for only about 20% of total acetaminophen use in the United States.

He noted that the study found that “hospitalization rates for individuals using over-the-counter and over-the-counter acetaminophen-only products actually increased over the same period.”

The challenge now, Ghany said, is what to do about the risk of toxicity among the vast majority of patients using over-the-counter acetaminophen.

“Efforts to improve consumer education on the harm risks of acetaminophen and to provide simple and clear information on the risks of liver damage on the product label continue. But this alone may not be enough, given the trust of general perception among consumers that over-the-counter medications are safe,” he noted.

“The only way to protect against acetaminophen-related liver damage and death,” Ghany said, “would be to develop safer and more effective pain relievers.”

More information

There’s more about acetaminophen at the US National Institutes of Health.

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