Amid the noise about Tylenol, there’s a real risk: an overdose

While news feeds and social media are abuzz with unproven claims about links between acetaminophen and autism in children, there are well-established concerns about the harmful effects of an overdose of the over-the-counter pain and fever medication.

In fact, acetaminophen poisoning is among the most common causes of non-prescription medication-related hospitalization and death in the United States, says Kennon Heard, MD, PhD, a professor in the CU Anschutz Department of Emergency Medicine and the department’s section chief of medical toxicology.

By one estimate, acetaminophen poisoning accounts for 56,000 emergency department visits and 2,600 hospitalizations annually in the U.S. It’s also responsible for nearly half of acute liver failures and about 20% of liver transplant cases in the U.S.

Heard has been researching and publishing on acetaminophen poisoning for more than 25 years. He’s currently helping to lead a multiyear clinical trial investigating a new treatment that potentially could ward off liver damage in severe cases of acetaminophen overdose – a treatment involving a drug used to treat antifreeze poisoning.

Heard notes that CU and Denver Health, home of the Rocky Mountain Poison & Drug Safety center, “have been the center of the acetaminophen research universe for the past 40 years. There’s been a long history of this type of work being done here, and it’s great to be a part of it.”

Many reasons for overdoses

Acetaminophen is the active ingredient in Tylenol and similar store-brand products used to treat moderate pain and low-grade fever. Also, it is combined with other ingredients in many over-the-counter remedies for colds, flu, menstrual relief, and sinus problems.

Acetaminophen has been in use for decades and has been established as safe and effective when taken as directed. But exceeding recommended doses – either all at once or repeatedly – can lead to serious medical problems.

“There are cases where people accidentally take too much acetaminophen,” Heard says. “Or maybe they have a really bad toothache, and they think if two is good, four is better, eight is even better, and so on. Or it’s someone who’s taking multiple repeated overdoses. Those are the people who get into trouble.”

It’s not uncommon for acetaminophen overdoses to be associated with suicide and self-harm, he added. “The No. 1 rule at the Poison Center is that if it’s available, people will take it, and a lot of people have Tylenol in their medicine chest.”

A drug called acetylcysteine has been established for decades as a highly effective antidote to acetaminophen overdose, but it becomes less effective if administered later than eight hours after ingesting the acetaminophen.

“The problem is that many patients don’t present with acetaminophen poisoning until after they have liver injury, at which point the acetylcysteine is less effective, and in some cases doesn’t really work at all,” Heard says.

Focus on fomepizole

In their current clinical trial, Heard and his colleagues are focusing on fomepizole, a drug approved for use as an antidote for poisoning by ethylene glycol and methanol, ingredients found in many types of antifreeze. Sometimes people drink antifreeze by mistake, while others with alcohol use disorder might consume antifreeze as a substitute for alcohol.

Fomepizole works by inhibiting a family of enzymes called alcohol dehydrogenase, preventing them from breaking down ethylene glycol and methanol into toxic metabolites.

Since as far back as the 1990s, when he was a medical toxicology fellow, Heard has encountered mounting indications that fomepizole might also be valuable as a treatment in acetaminophen overdoses, especially in cases of severe toxicity. Those indications came in the form of scattered case reports about individual patients and in animal studies.

A recent study reported that doctors have significantly increased their off-label use of fomepizole for acetaminophen poisoning, especially in cases of severe toxicity.

Ultimately, Richard Dart, MD, PhD, a professor of emergency medicine and Heard’s longtime mentor on acetaminophen research projects, suggested a trial to assess fomepizole to better establish its benefits. Dart has been the director of Rocky Mountain Poison & Drug Safety since 1992.

Proof of concept

The current phase II clinical trial seeks to determine if fomepizole, when added to the standard treatment of acetylcysteine, can reduce liver injury in high-risk acetaminophen poisoning patients. It’s a “proof of concept” study that aims to find out whether the combination therapy is promising enough to warrant further, larger-scale trials.

In the trial, one group of patients is given the fomepizole-acetylcysteine combination, and the other group gets acetylcysteine alone. It’s a double-blind trial, meaning neither the researchers nor the participants know who is receiving which therapy until the study is complete.

“We’ll compare the amount of liver damage, as measured by their liver enzymes, to see whether the fomepizole provides an added protective benefit beyond the standard treatment,” Heard says.

Patients are now being enrolled at Denver Health, UCHealth University of Colorado Hospital, Children’s Hospital Colorado, and a few other sites. Enrollment is going slowly because of the difficulty in finding patients who fit the trial criteria, Heard said, but investigators hope to have about 40 patients enrolled in a year to 18 months.

If results are encouraging, Heard foresees advancing to a larger trial with more patients – a trial that looks at longer-range outcomes, such as survival rates and whether patients ultimately need a liver transplant.

“The message that I would want to get out,” Heard adds, is that people using acetaminophen products should read the label and be careful not to exceed recommended doses, and also to be aware that acetaminophen might be in multiple products in a typical medicine chest.

“We’ve started to recognize that the number of people who die from an accidental overdose is pretty close to the number of people who deliberately take an overdose,” he says.
Heard’s collaborators in the trial include Dart and Andrew Monte, MD, PhD, also an emergency medicine professor.