Acetaminophen, a popular over-the-counter medication 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 United States Food and Drug Administration has long known that high doses of acetaminophen (Tylenol) can damage the liver. So in 2011, the FDA set new safe limits on the exact amount of acetaminophen that can be contained in any prescription pain reliever.
Now, a new study shows that decision likely saved lives.
Since the FDA announced the regulatory change, which lowered the limits for acetaminophen from 750 milligrams (mg) to 325 mg, there has been an 11% to 16% annual drop in the number of hospitalizations and cases. acute liver failure. involving the painkiller combo. One such combo is Vicodin, which contains hydrocodone and acetaminophen.
“This suggests that mandate was likely the primary driver of the decrease in acute liver failure cases and hospitalizations in acetaminophen-opioid combination products,” said study author Dr. Jayme Locke, director of the University of Alabama at the Comprehensive Transplant Institute in Birmingham.
The report was published in Tuesday’s issue of the Journal of the American Medical Association. Locke and his colleagues stressed that their investigation does not definitively prove that the FDA mandate directly caused complications from acetaminophen-opioid drugs to drop.
“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 providers and patients alike,” presumably leading some to lower acetaminophen doses themselves.
At the same time, she pointed out that the FDA’s mandate does not impose any new limits on the dosage of over-the-counter acetaminophen. Unsurprisingly, “similar trends (down in risk) were not seen in acetaminophen alone,” Locke said.
According to the study authors, the intended purpose of combining acetaminophen with an opioid was to allow physicians 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 found to be toxic to the liver.
In fact, the new report highlights a 2005 study that found that more than 4 in 10 cases of acute liver failure related to acetaminophen use ended up being attributed to acetaminophen-based opioid painkillers.
In 2009, such red flags prompted an FDA advisory committee to recommend an outright ban on these combination drugs. Ultimately, the FDA went the dosage limit route.
To see if the new limit had a protective impact, Locke’s team analyzed numbers compiled by the National Inpatient Sample (NIS) and the Acute Liver Failure Study Group (ALFSG).
The NIS data provided details of approximately 473 million hospitalizations 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 stacked the risk of liver failure and hospitalization before the FDA mandate against the post-mandate risk. And what they saw was a dramatic drop in risk, coinciding with the FDA’s 2011 mandate.
For example, NIS data found that while about 12 in 100,000 hospitalizations involved combined drug toxicity just before the FDA move, that number dropped to just over 4 in 100,000 in 2019. And while the risk of being hospitalized for combined drug toxicity had increased. 11% per year until the time of the new FDA limit, this figure actually dropped to 11% per year after the limit was announced.
The ALFSG numbers 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 number dropped to 5% in 2019.
Locke said the study did not identify the percentage of combination drug users with a substance use disorder before or after the FDA move. The team also did not assess whether the new acetaminophen limit in any way reduced the potency of acetaminophen-opioid combinations.
But based on the evidence, Locke said his team was “satisfied with the effectiveness of the mandate in reducing cases of acute liver failure.”
Dr. Marc Ghany, section chief of clinical research in hepatology at the liver disease branch of the US National Institute of Diabetes and Digestive and Kidney Diseases, co-authored an editorial accompanying the study.
Ghany suggested that the FDA mandate can only go so far, given that combination formulations of acetaminophen and opioids only account for about 20% of total acetaminophen use in the United States.
He pointed out that the study found that “the rate of hospitalizations for people using over-the-counter acetaminophen products actually increased over the same time period.”
The challenge now, Ghany said, is what to do about the risk of toxicity in the vast majority of patients who use over-the-counter acetaminophen.
“Efforts to improve consumer education about the risks of harm from acetaminophen and to provide simple, clear information about the risks of liver damage on the product label continue. But this alone may not be enough. , given the general belief 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 painkillers.”
There is more on acetaminophen at the US National Institutes of Health.
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