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.
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.
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.
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.
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.
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.
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.