A Food and Drug Administration (FDA) mandate limiting the amount of acetaminophen in prescription combination opioid products resulted in a significant decrease in hospitalizations and severe hepatotoxicity, according to findings published in JAMA.

In 2011, following reports of serious livery injury, the FDA had required manufacturers of prescription acetaminophen combination products to limit the amount of acetaminophen to 32 5mg per tablet or capsule. To assess the impact of this federal mandate, researchers from the University of Alabama and Weill Cornell Medicine, reviewed yearly rates of hospitalization and acute liver failure cases from the National Inpatient Sample (NIS; from 2007 to 2019), a large US hospitalization database, and the Acute Liver Failure Study Group (ALFSG; from 1998 to 2019), a cohort of 32 US medical centers.

In the NIS, there were 39,606 cases of hospitalizations involving acetaminophen-opioid toxicity; in the ALFSG database, 465 of the 2631 cases of acute liver failure were reported to be acetaminophen-opioid related.

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Findings showed that the predicted incidence of hospitalizations associated with acetaminophen-opioid toxicity 1 day before the FDA announcement was 12.2 cases per 100,000 hospitalizations (95% CI, 11.0-13.4). By the fourth quarter of 2019, it was reported to be 4.4 cases per 100, 000 hospitalizations (95% CI, 4.1-4.7) (absolute difference, 7.8 cases per 100,000 [95% CI, 6.6-9.0]; P < .001).

Prior to the FDA announcement, the odds of hospitalization due to acetaminophen-opioid toxicity increased 11% per year (odds ratio [OR], 1.11 [95% CI, 1.06-1.15]); after the announcement, it decreased 11% per year (OR, 0.89 [95% CI, 0.88-0.90]).

With regard to acute liver failure, the predicted percentage of cases associated with acetaminophen-opioid toxicity 1 day prior to the FDA announcement was found to be 27.4% (95% CI, 23.3-31.9). This decreased to 5.3% (95% CI, 3.1-8.8) by the third quarter of 2019 (absolute difference, 21.8% [95% CI, 15.5-32.4]; P < .001).

Prior to the FDA announcement, the percentage of acute liver cases related to acetaminophen-opioid toxicity increased 7% per year (OR, 1.07 [95% CI, 1.03-1.1]; P < .001); after the announcement, it decreased 16% per year (OR, 0.84 [95% CI, 0.77-0.92]; P < .001).

While the authors conclude that the study does show a link between the FDA mandate and subsequent reductions in hospitalization and serious liver injury with acetaminophen-opioid medications, they caution that it does not prove causality.

“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; however, in Canada, successive updated labeling requirements for acetaminophen and acetaminophen-containing products requiring more explicit emphasis on the medications’ contents and risks of misuse 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,” the authors note.


  1. Orandi BJ, McLeod MC, MacLennan PA, et al. Association of FDA mandate limiting acetaminophen (paracetamol) in prescription combination opioid products and subsequent hospitalizations and acute liver failure. Published online March 7, 2023. JAMA. doi:10.1001/jama.2023.1080
  2. FDA rule lowering drug dose is associated with less liver injury. News release. March 7, 2023. https://www.eurekalert.org/news-releases/981660.

This article originally appeared on MPR