Drug Safety

, Volume 35, Issue 2, pp 149–157 | Cite as

Trends in Hepatic Injury Associated with Unintentional Overdose of Paracetamol (Acetaminophen) in Products with and without Opioid

An Analysis Using the National Poison Data System of the American Association of Poison Control Centers, 2000–7
Original Research Article


Background: Unintended hepatic injury associated with the use of paracetamol (acetaminophen)-containing products has been growing.

Objective: The aim of the study was to seek a better understanding of the causes of this observation in order to evaluate the potential impact of proposed preventive measures.

Study Design: Retrospective analysis of a large database containing prospectively collected patient exposure data, clinical symptomatology and outcome.

Setting: The National Poison Data System database for 2000–7 involving exposures to paracetamol and an opioid was obtained and analysed. This dataset was limited to non-suicidal cases in patients 13 years of age and older. For comparison, the parallel, mutually exclusive dataset involving exposures to one or more non-opioid containing paracetamol products was analysed.

Outcome Measure: Trends in the numbers of patients exposed, treated, and mildly and severely injured were obtained and compared with each other and with trends calculated from publicly available data on sales and population. The association of injury with the number of paracetamol-containing products and the reason for taking them were also assessed.

Results:Comparators: During the study period, the US population of those 15 years of age and over rose 8.5%; all pharmaceutical-related calls to all US poison centres rose 25%. For the 8-year period from 2001 to 2008, sales of over-the-counter paracetamol products rose 5% (single-ingredient products fell 3%; paracetamol-containing combination cough and cold products rose 11%) and prescription paracetamol combination products rose 67%.

Opioids with paracetamol: A total of 119 731 cases were identified, increasing 70% over the period. The exposure merited acetylcysteine treatment in 8995 cases (252% increase). In total, 2729 patients (2.3%) experienced some hepatic injury (500% increase). Minor injuries rose faster than severe injuries (833% vs 280%) and most injuries (73.0%) were from overuse of a single combination product only, but the injury rate increased with use of more than one paracetamol-containing product. Abuse and misuse accounted for 34% of cases but 58% of the severe injuries.

Paracetamol without opioid: A total of 126 830 cases were identified, increasing 44%, and 15 706 cases merited acetylcysteine (70% increase). A total of 4674 patients (3.7%) experienced some hepatic injury (134% increase). Use of more than one non-opioid paracetamol product occurred in 7.3% of patients and was associated with a lower injury rate.

Conclusions: Hepatic injury associated with paracetamol use is increasing significantly faster than population, paracetamol product sales and poison centre use. This suggests a growing portion of consumers is self-dosing paracetamol beyond the toxic threshold. This is true for paracetamol with and without opioids, but the increase in hepatic injury is greater when paracetamol is taken with an opioid. This disproportionate rise is greatest with misuse and abuse of paracetamol products in combination with opioids. Increasing self-dosage of the opioid combination products for the opioid effect is likely to result in more cases of toxic exposure to paracetamol. In contrast, cases of exposure to paracetamol-containing cough and cold products are underrepresented among those injured. In the absence of opioid-containing products, consumption of more than one paracetamol-containing product did not contribute to injury. Efforts to modulate unintentional paracetamol-related hepatic injury should consider these associations.


  1. 1.
    Woodcock J. A difficult balance: pain management, drug safety, and the FDA. N Engl J Med 2009; 261: 2105–7CrossRefGoogle Scholar
  2. 2.
    Manthripragada A, Zhou E, Budnitz D, et al. Characterization of acetaminophen overdose-related emergency department visits and hospitalizations in the United States. Pharmacoepidemiol Drug Saf 2011; 20: 819–26PubMedCrossRefGoogle Scholar
  3. 3.
    Schiødt FV, Rochling FA, Casey DA, et al. Acetaminophen toxicity at an urban county hospital. N Engl J Med 1997; 337: 1112–7PubMedCrossRefGoogle Scholar
  4. 4.
    Bond GR, Hite LK. Population based incidence and outcome of acetaminophen poisoning by type of ingestion. Acad Emerg Med 1999; 6: 1115–20PubMedCrossRefGoogle Scholar
  5. 5.
    Myers RP, Shaheen AA, Li B, et al. Impact of liver disease, alcohol abuse, and unintentional ingestions on the outcomes of acetaminophen overdose. Clin Gastroenterol Hepatol 2008; 6: 918–25PubMedCrossRefGoogle Scholar
  6. 6.
    Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-induced acute liver failure: results of a United States multi-center, prospective study. Hepatology 2005; 42: 1364–72PubMedCrossRefGoogle Scholar
  7. 7.
    Lee WM. Acetaminophen toxicity: changing perceptions on a social/medical issue. Hepatology 2007; 46: 966–70PubMedCrossRefGoogle Scholar
  8. 8.
    Joint Meeting of the Drug Safety and Risk Management Advisory Committee with the Anesthetic and Life Support Drugs Advisory Committee and the Nonprescription Drugs Advisory Committee: meeting announcement [online]. Available from URL: http://www.fda.gov/advisorycommittees/calendar/ucm143083.htm [Accessed 2010 Dec 11]
  9. 9.
    Krenzelok EP. The FDA Acetaminophen Advisory Committee Meeting: what is the future of acetaminophen in the United States? The perspective of a committee member. Clin Toxicol (Phila) 2009; 47: 784–9CrossRefGoogle Scholar
  10. 10.
    American Pain Foundation’s position statement regarding the FDA Advisory Committee’s recommendations concerning acetaminophen. Release date: September 14, 2009 [online]. Available from URL: http://www.painfoundation.org/about/position-statements/fda-acetaminophen-recommendations.html [Accessed 2011 Jul 6]
  11. 11.
    Kuehn BM. Prescription drug abuse rises globally. JAMA 2007; 29: 1306Google Scholar
  12. 12.
    United Nations. International Narcotics Control Board 2010 report [online]. Available from URL: http://www.incb.org/incb/en/annual-report-2010.html [Accessed 2011 Jul 2]
  13. 13.
    National Center for Injury Prevention and Control, Centers for Disease Control and Prevention. WISQARS nonfatal injury reports [online]. Available from URL: http://webappa.cdc.gov/sasweb/ncipc/nfirates2001.html [Accessed 2010 Oct 18]
  14. 14.
    National Poison Data System. Annual reports of the American Association of Poison Control Centers 2000–2007 [online]. Available from URL: http://www.aapcc.org/dnn/NPDSPoisonData/NPDSAnnualReports.aspx [Accessed 2010 May 24]
  15. 15.
    Food and Drug Administration, Center for Drug Evaluation and Research. Joint Nonprescription Drugs Advisory Committee and Pediatric Advisory Committee Meeting. Over-the-counter acetaminophen-containing drug products in children: background package. May 17–18th, 2011 [online]. Available from URL: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/NonprescriptionDrugsAdvisoryCommittee/UCM255306.pdf [Accessed on 2011 Jul 6]
  16. 16.
    Stockler M, Vardy J, Pillai A, et al. Acetaminophen (paracetamol) improves pain and well-being in people with advanced cancer already receiving a strong opioid regimen: a randomized, double-blind, placebo controlled cross-over trial. J Clin Oncol 2004; 22: 3389–94PubMedCrossRefGoogle Scholar
  17. 17.
    Neirenburg DW, Melmon KL. Introduction to clinical pharmacology and rational therapeutics. In: Melmon KL, Carruthers SG, editors. Melmon and Morrelli’s clinical pharmacology: basic principles in therapeutics. 4th ed. New York, NY: McGraw-Hill Professional, 2000: 3–62Google Scholar
  18. 18.
    Bower WA, Johns M, Margolis HS, et al. Population-based surveillance for acute liver failure. Am J Gastroenterol 2007; 102: 2459–63PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2012

Authors and Affiliations

  • G. Randall Bond
    • 1
    • 2
  • Mona Ho
    • 1
  • Randall W. Woodward
    • 1
  1. 1.Division of Emergency Medicine, Cincinnati Children’s Hospital Medical Center and Department of PediatricsUniversity of CincinnatiCincinnatiUSA
  2. 2.Cincinnati Drug and Poison Information Center, Cincinnati Children’s Hospital Medical CenterCincinnatiUSA

Personalised recommendations