• Posted March 8, 2023

FDA-Mandated Tweak to Common Rx Painkillers May Have Saved Lives

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

The problem? The U.S. Food and Drug Administration has long known that high dosages of acetaminophen (Tylenol) can harm the liver. So, in 2011 the FDA set new safety limits on exactly how much acetaminophen could be packed into any prescription painkiller.

Now, a new study shows the move likely saved lives.

Ever since the FDA announced the regulatory change, which slashed the limits on acetaminophen from up to 750 milligrams (mg) to up to 325 mg, there has been an 11% to 16% annual drop in the number of hospitalizations and acute liver failure cases involving the combo painkiller. One such combo is Vicodin, which contains hydrocodone and acetaminophen.

"This suggests that the mandate was likely the largest driver in the decreases in acute liver failure cases and hospitalizations in combination acetaminophen-opioid products,"said study author Dr. Jayme Locke, director of the University of Alabama at Birmingham's Comprehensive Transplant Institute.

The report was published in the March 7 issue of the Journal of the American Medical Association. Locke and her colleagues stressed that their investigation does not definitively prove that the FDA mandate directly caused acetaminophen-opioid drug complications to plummet.

"Certainly, other factors could have played a role,"Locke noted. "For example, the mandate may have brought the issue of acetaminophen toxicity to the forefront for both providers and patients,"presumably leading some to cut down on acetaminophen dosages on their own.

At the same time, she pointed out that the FDA mandate did not place any new limits on over-the-counter acetaminophen dosing. Not surprisingly, "similar [downward risk] trends were not observed in acetaminophen alone,"Locke said.

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

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

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

In 2009, such red flags prompted an FDA advisory panel to recommend an outright ban on such combo drugs. In the end, the FDA chose the dosage 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).

NIS data provided details on roughly 473 million hospitalizations between 2007 and 2019. ALFSG data focused on adult patients who were treated for acute liver failure between 1998 and 2019.

The investigators then stacked pre-FDA mandate liver failure and hospitalization risk up against post-mandate risk. And what they saw was a dramatic drop in risk, coinciding with the FDA's 2011 mandate.

For example, NIS data revealed that while roughly 12 out of 100,000 hospitalizations involved combo drug toxicity just before the FDA move, that figure dropped to just above 4 in 100,000 by 2019. And while the risk for being hospitalized with combo drug toxicity had been increasing 11% a year up to the time of the FDA's new limit, that figure actually flipped to an 11% drop per year after the limit was announced.

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

Locke said the study did not identify what percentage of combo drug users struggled with a substance use disorder before or after the FDA 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 "pleased with the effectiveness of the mandate at decreasing acute liver failure cases."

Dr. Marc Ghany, section chief of clinical hepatology research at the liver diseases branch at the U.S. 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 only account for about 20% of total acetaminophen use in the United States.

He pointed out that the study found "the rate of hospitalizations for individuals using non-prescription, over-the-counter acetaminophen-only products actually increased over the same period."

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

"Efforts to improve consumer education on the risks of acetaminophen injury, and to provide simple and clear information of the risks of liver injury on the product label continue. But this alone may be insufficient, given the general belief among consumers that over-the-counter medications are safe,"he noted.

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

More information

There's more on acetaminophen at the U.S. National Institutes of Health.

SOURCES: Jayme Locke, MD, MPH, director, UAB Comprehensive Transplant Institute, chief, division of transplantation, and professor of surgery, University of Alabama at Birmingham; Marc Ghany, MD, MHSc, section chief, clinical hepatology research section, liver diseases branch, U.S. National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Md.; Journal of the American Medical Association, March 7, 2023