The annual rate of hospitalizations and proportion per year of acute liver failure (ALF) cases involving acetaminophen (paracetamol) and opioids fell in the years after FDA limited the amount of acetaminophen in combination products to 325 mg, a study shows. “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 authors write. “However, in [a study from] 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 analysis relied on 2007–19 hospitalization data with ICD-9/ICD-10 codes consistent with both acetaminophen and opioid toxicity from the National Inpatient Sample (NIS), a large U.S. hospitalization database, and ALF cases from 1998 to 2019 involving acetaminophen and opioid products from the Acute Liver Failure Study Group (ALFSG) of 32 U.S. medical centers. The odds of opioid- and acetaminophen-related hospitalizations before and after the 2011 mandate showed the following: “In the NIS, among 474,047,585 hospitalizations from Q1 2007 through Q4 2019, there were 39,606 hospitalizations involving acetaminophen and opioid toxicity; 66.8% of cases were among women; median age, 42.2 (IQR, 28.4-54.1). In the ALFSG, from Q1 1998 through Q3 2019, there were a total of 2,631 ALF cases, of which 465 involved acetaminophen and opioid toxicity; 85.4% women; median age, 39.0 (IQR, 32.0-47.0). The predicted incidence of hospitalizations 1 day prior to the FDA announcement was 12.2 cases/100,000 hospitalizations (95% CI, 11.0-13.4); by Q4 2019, it was 4.4/100,000 hospitalizations (95% CI, 4.1-4.7) (absolute difference, 7.8/100,000 [95% CI, 6.6-9.0]; P < .001). The odds of hospitalizations with acetaminophen and opioid toxicity increased 11%/y prior to the announcement (odds ratio [OR], 1.11 [95% CI, 1.06-1.15]) and decreased 11%/y after the announcement (OR, 0.89 [95% CI, 0.88-0.90]). The predicted percentage of ALF cases involving acetaminophen and opioid toxicity 1 day prior to the FDA announcement was 27.4% (95% CI, 23.3%-31.9%); by Q3 2019, it was 5.3% (95% CI, 3.1%-8.8%) (absolute difference, 21.8% [95% CI, 15.5%-32.4%]; P < .001). The percentage of ALF cases involving acetaminophen and opioid toxicity increased 7% per year prior to the announcement (OR, 1.07 [95% CI, 1.03-1.1]; P < .001) and decreased 16% per year after the announcement (OR, 0.84 [95% CI, 0.77-0.92]; P < .001). Sensitivity analyses confirmed these findings.”
Editorial: “Switching to other pain relievers such as nonsteroidal anti-inflammatory drugs and aspirin poses risks of gastrointestinal bleeding and kidney toxicity,” editorialists write. “Other proposed solutions include copackaging acetaminophen with its antidote, removing acetaminophen-containing pediatric products from the market, and even withdrawal of acetaminophen from the market. None of these have gained traction or are likely to occur.
“The FDA should be heartened by the data reported [in this study] and should continue efforts to improve the safety of acetaminophen through public health policies. The best solution would be the development of safer, more effective analgesics.”