Insufficient Progress Against Liver Disease From Acetaminophen/Opioid Combination Products

Acetaminophen (TYLENOL) is the most widely used pain reliever in the world. It is approved in the United States both as a prescription drug and for over-the-counter use. The safe dose varies between individuals because of factors such as age, nutrition and the amount of alcohol consumed. Acetaminophen, however, can cause liver damage due to the narrow safety range between the therapeutic effect of acetaminophen and its toxicity. Each year, acetaminophen is responsible for 2,600 hospitalizations and 500 deaths in the United States; half of these are unintentional overdoses. It is the most common cause of liver transplantation.[1]

For years, combination prescription pain-relief products containing both acetaminophen and opioids have been of particular concern. In January 2011, after years of considering regulatory actions, the U.S. Food and Drug Administration (FDA) limited the amount of acetaminophen in prescription drug products, including opioid combination products, to 325 mg per tablet; manufacturers were required to comply by March 2014.[2] The agency also required labeling changes, including a black-box warning about the potential for severe liver injury in the prescribing information for prescription drug products containing acetaminophen.[3]

A 2023 study in the Journal of the American Medical Association assessed the effects of the FDA mandate.[4] The study compared odds of hospitalization involving acetaminophen and opioid toxicity and the percentage of cases of acute liver failure from acetaminophen-and-opioid combination products before and after the agency’s announcement. The study found that limiting the amount of acetaminophen in the combination products to 325 mg per tablet and adding the black-box warning were associated with significant and persistent decreases in both the annual rate of hospitalizations involving acetaminophen and opioid toxicity and the proportion per year of acute liver failure cases related to acetaminophen and opioid toxicity.[5] The decreases, however, were less than might have been hoped for. The study was unable to determine whether the declines were due to limiting the dose, the boxed warnings or both.

Moreover, the mandate did not cover acetaminophen when used alone. Prior to the mandate, the odds of hospitalization involving toxicity from acetaminophen alone had been decreasing, but disturbingly, the mandate was associated with the odds of hospitalization from liver toxicity increasing.[6]

Every week, tens of millions of Americans consume products containing acetaminophen. Although the FDA’s actions have helped to reduce the frequency of liver damage from acetaminophen-and-opioid combination products, there is more work to be done.[7] The safety of acetaminophen can be improved by reducing the amount consumed. However, alternative pain relievers also pose risks, such as gastrointestinal bleeding and kidney damage from nonsteroidal anti-inflammatory drugs and aspirin. Developing safer and more effective alternatives may be the best path forward.[8]
 

References

[1] Agrawal S, Khazaeni B. Acetaminophen toxicity. February 12, 2023. https://www.ncbi.nlm.nih.gov/books/NBK441917/. Accessed May 8, 2023.

[2] Prescription drug products containing acetaminophen: actions to reduce liver injury from unintentional overdose. Fed Regist. 2011;76:2691-2697. https://www.govinfo.gov/content/pkg/FR-2011-01-14/html/2011-709.htm. Accessed May 8, 2023.

[3] Ibid.

[4] Orandi BJ, McLeod C, MacLennan PA, et al. Association of FDA mandate limiting acetaminophen (paracetamol) in prescription combination opioid products and subsequent hospitalizations and acute liver failure. JAMA. 2023;239(9):735-744. doi:10.1001/jama.2023.1080.

[5] Ibid.

[6] Ibid.

[7] Ghany MG, Watkins PB. Moving the needle to reduce acetaminophen (paracetamol) hepatotoxicity. JAMA. 2023;239(9):713-715. doi:10.1001/jama.2023.1002.

[8] Ibid.