Around 25 billion doses of acetaminophen, or paracetamol, are sold globally every year. Worldwide, acetaminophen overdose is among the leading causes of acute liver failure, and the leading cause in many countries. Acetaminophen is most often purchased as an over-the-counter medication. Prescribed pain relievers often combine acetaminophen with other medications. In 2011 the US FDA issued a mandate limiting the maximum acetaminophen dose in prescribed products that include opioids and required boxed warning labels. Watch this video to find out whether the mandate worked to decrease hospitalizations for acute liver failure resulting from acetaminophen and opioid toxicity.
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Around 25 billion doses of acetaminophen, or paracetamol, as it’s known outside North America, are sold globally every year. This includes acetaminophen by itself, as well as in combination with other drugs. The vast majority of acetaminophen is sold over the counter. In the US, acetaminophen is the number 1 over the counter drug. But acetaminophen is also among the leading causes of acute liver failure worldwide, and in many countries the leading cause.
Lewis Nelson: What's interesting is if we brought acetaminophen to the FDA today as the first, for the first time, knowing what we know about it, whether it would have gotten through.
That's Dr Lewis Nelson, Chair of the Department of Emergency Medicine and Chief of the Division of Medical Toxicology at Rutgers New Jersey Medical School.
Lewis Nelson: In toxicology, you know, we have a mantra that basically says, "dose makes the poison." For the most part, you could take a, a recommended dose of acetaminophen for years, daily, and not have liver toxicity.
But liver toxicity can occur quickly once you go above the recommended dose, or if you have certain conditions that put you at higher risk. And, for the record, the maximum recommended daily dose of acetaminophen for most adults is 4 grams or 4000 mg.
In 2009, Dr Nelson chaired an FDA advisory panel on liver injury related to acetaminophen use. One of the issues it focused on was reducing unintentional acetaminophen overdose, which is a significant problem. If you look at the patients who overdose on acetaminophen and progress to acute liver failure, potentially more than half of those cases might be unintentional.
Jayme Locke: One week you are walking, talking, living your life, going to your job or recovering from something. And then next thing you know, you're presenting to the E.R. in extremis, admitted to the hospital and told that you have acute liver failure and the only way to save your life is a liver transplant.
That's Dr Jayme Locke, Chief of the Division of Transplantation and Director of the Comprehensive Transplant Institute at the University of Alabama at Birmingham.
A few years ago, she and her colleagues treated yet another patient with acute liver failure who accidentally overdosed after using acetaminophen by itself as well as a prescription combination product that contained acetaminophen and opioids.
This is one of the situations that was explicitly addressed in the FDA advisory committee chaired by Dr Nelson about a decade earlier.
Acting upon the advice of that committee, the FDA issued a mandate in 2011 limiting the maximum dose of acetaminophen in prescription combination products with opioids and requiring a boxed warning about the risks of liver failure that could lead to liver transplant or death.
Dr Locke and her colleagues wanted to know if that mandate had done what it meant to: had it decreased the odds of getting hospitalized with acetaminophen and opioid toxicity?
They conducted an interrupted time series analysis of US hospitalizations. Dr Babak Orandi was the lead author of the study. He’s an assistant professor of surgery at the University of Alabama at Birmingham and an Obesity Medicine fellow at Weill Cornell Medicine.
Babak Orandi: Leading up until the announcement that the FDA made, there was an increase in the odds of hospitalization for acetaminophen and opioid toxicity by, an increase by about 11% per year leading up to that announcement. And right after the announcement, it dropped by 11% per year on average. Real world data tends to be messy, and our findings were pretty consistent no matter how we looked at the data.
The comparator group that the researchers used was hospitalizations for acute liver failure with acetaminophen toxicity but without opioid toxicity.
Babak Orandi: And we found that in general, the odds of having a hospitalization with just acetaminophen alone either remained stagnant leading up to the up to the time cutoff or was increasing. And then after the policy was announced and or implemented, we saw that those numbers continued to increase.
So it appears that when it comes to prescription combination products that contain acetaminophen and opioids, the 2011 FDA mandate did work. But if you look more broadly at acute liver failure resulting from acetaminophen use, aside from combination opioid drugs, the rate of hospitalizations continues unabated. More effort will be needed to address this problem. So what could that look like?
According to Dr Orandi and Dr Locke, a similar intervention—that is reducing the dose of acetaminophen—could be considered for over-the-counter combination products, like cough and cold medicines. Better measures to increase patient awareness are also needed.
Ultimately, the best solution might be the development of safer, more effective pain medications. But that's a long way off. In the meantime, acetaminophen is likely to remain the most common drug worldwide.
Jayme Locke: Acetaminophen is actually a good product. It does work. And I think it is something that we need to maintain in our armamentarium in terms of pain relief, fever control, things like that. But I think we can maybe do it a little smarter.
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