Acetaminophen Opioid Combinations and Liver Toxicity: Updated Data 2023

Hospitalizations for acute liver failure involving acetaminophen and opioid toxicity decreased significantly after the FDA mandated limiting acetaminophen to 325 mg in combination acetaminophen and opioid products over a decade ago.

Comparing Hospitalization Data for Liver Failure

In their study, published in JAMA, Dr. Orandi and colleagues reviewed hospitalization data for acetaminophen and opioid toxicity from the National Inpatient Sample (NIS) from 2007 to 2019 and cases of acute liver failure (ALF) from the US Acute Liver Failure Study Group (ALFSG), a prospective cohort of adults with ALF, from 1998 to 2019.¹

The primary outcomes were the odds of hospitalization for acetaminophen and opioid toxicity and the proportion of ALF cases involving combined acetaminophen and opioid toxicity before and after the FDA mandate.

A total of 2,631 ALF cases were identified in the ALFSG from the first quarter of 1998 through the third quarter of 2019; 465 of these involved acetaminophen and opioid toxicity. The median age of the ALF patients was 39.0 years; 85.4% were women.

Decrease in Hospitalizations since the FDA Mandate

Orandi et al compared hospitalizations before and after the announcement of the FDA mandate in January 2011 (2007 to 2010 and 2011 to 2019) using NIS data. Hospitalizations with acetaminophen and opioid toxicity increased by 11% per year before the announcement (odds ratio [OR] 1.11) and decreased by 11% per year after the announcement (OR 0.89).

Similarly, the proportion of ALF cases from ALFSG increased by 7% per year prior to the FDA announcement, and decreased by 16% per year during the period after the announcement (OR 1.07 and 0.84, respectively). However, the annual hospitalization rate and proportion of ALF cases involving acetaminophen alone increased during the period after the mandate. Results were similar across subgroup analyses.

However, the results were strengthened by the consistency of the data from two separate sources, and by the completeness of the data. Despite limitations, the current study shows an association between limits on acetaminophen dosage and a significant decrease in the yearly hospitalization rate and the yearly proportion of ALF cases involving acetaminophen and opioid toxicity, the researchers said.

Practical Takeaways: Remain Cognizant of Acetaminophen Opioid Toxicity

“The decline in the odds of hospitalization with acetaminophen and opioid toxicity that began after the announcement could be attributed to increased awareness and product labeling changes that were part of the mandate, rather than the actual 325 mg limit,” the researchers wrote in their discussion.¹ By contrast, data from Canada² showed that updated labeling requirements for acetaminophen and acetaminophen-containing products “were not associated with a decline in hospitalizations for accidental acetaminophen overdose or accidental combination acetaminophen and opioid product overdose, suggesting that publicity and labeling changes alone may be insufficient to achieve measurable change.”¹

“Acetaminophen overdose is a leading cause of acute liver failure in several countries,” said Tony Antoniou, PhD, pharmacist, clinical epidemiologist, and associate professor in the department of family and community medicine at the University of Toronto, Canada. “Because acetaminophen overdose is a potentially fatal, yet avoidable, form of drug-related harm, it is important to identify risk minimization initiatives that can reduce the incidence of these events” and reduce the burden of such events on individuals and healthcare systems.

Dr. Antoniou noted that he “was pleasantly surprised to see that the FDA mandate was associated with a reduction in hospitalizations involving the products covered by the mandate. It speaks to the potential effectiveness of more direct measures beyond patient education and changes to product labels.”

“Clinicians should continue to advise their patients of the risks of taking too much acetaminophen, considering that it is available in hundreds of over-the-counter products,” Dr. Antoniou said. Also, advise pain patients to speak with a physician or pharmacist when selecting such products to avoid inadvertent overdoses, he added.

Ideally, the FDA will be encouraged by the current study findings, Dr. Antoniou said, and the results “will spur additional measures targeting other over-the-counter acetaminophen preparations that can then be subject to similar evaluation.”