The Little-Known Dangers of AcetaminophenDecember 2007
By Jay S. Cohen, MD,
The FDA Fails to Act
Despite calls for better warnings, nothing has changed. Over the years, the FDA has intermittently voiced a desire to reduce the number of cases of acetaminophen toxicity. In 2004, the agency launched an educational campaign on the safe use of over-the-counter medications.18 This initiative appears to have had no impact on acetaminophen statistics. Since then, a large study has been published demonstrating that therapeutic doses of acetaminophen cause liver injuries in a substantial number of users,19 and has raised serious questions about the safety of therapeutic doses of acetaminophen.
In 2007, an FDA medical officer revealed that the staff of the FDA’s Office of Surveillance and Epidemiology (formerly Office of Drug Safety) had recommended initiating measures similar to those adopted in Great Britain to reduce acetaminophen toxicity. These measures include limiting the number of acetaminophen pills in a package and packing the pills individually in foil packs. This recommendation never reached the FDA’s Nonprescription Drugs Advisory Committee, where it could have been considered and approved.20
Recently, in response to a scathing report by the Institute of Medicine, the FDA has made a lot of noise about enhancing its efforts to promote drug safety. Until proven otherwise, the FDA’s promises are hollow. The tilt of the FDA will continue to be in favor of the drug industry. For years, the FDA has understaffed and underfunded its safety divisions. It has not been unusual for high-ranking FDA officials to approve new drugs despite serious concerns of FDA medical officers about the drugs’ safety. Indeed, just recently another article critical of the FDA was published in the New England Journal of Medicine (September 6, 2007), in which Dr. Sheila Weiss Smith concluded that the FDA’s actions once again underscored “the low priority it assigns to its responsibility for arbitrating drug safety.”21
FDA Ignores Its Own Guidelines
With acetaminophen, FDA officials have long ignored their own regulations. FDA guidelines require drug companies to list adverse drug events if: 1) they are serious; 2) they occur in close proximity to using the drug; and 3) they are consistent with a drug’s known effects.22 Acetaminophen fits all of these requirements. In addition, animal studies provide ample evidence of a link between fasting, acetaminophen use, and liver failure.23
Moreover, a recent report demonstrated the link between acetaminophen, fasting, and liver toxicity. Doctors were at first puzzled why a nine-month-old child had developed liver toxicity after only two days of therapeutic doses of acetaminophen. Laboratory analysis revealed that the child had a genetically determined glutathione deficiency, causing her glutathione activity to be only 5% of normal. Without adequate glutathione, standard doses of acetaminophen were toxic in this child.24 The case provides human evidence that markedly decreased glutathione activity, which can also be caused by fasting, increases the risk of acetaminophen liver toxicity in humans.
FDA guidelines also state that rare, serious adverse events should be listed in product information “even if there are only one or two reported events.”22 The first cases linking acetaminophen, fasting, and liver toxicity were reported in the 1980s. More than 20 years have passed, during which time many more cases have been published. Where is the warning? Where are the meaningful measures to improve acetaminophen safety?
Perhaps the FDA’s inaction is related to resistance by the largest producer of acetaminophen products (McNeil Consumer Health, Tylenol® products) to implement a fasting warning and other safety measures. Acetaminophen is a widely used drug that generates more than two billion dollars per year in sales in the US. Additional warnings might undo acetaminophen’s reputation as the safest over-the-counter pain and fever remedy, and safety packaging might depress sales.
Some argue that it has not been fully proven that fasting increases the risk of liver toxicity from acetaminophen. This is a specious argument. Experts know that absolute proof will be difficult to obtain. Liver toxicity from acetaminophen and fasting is a rare event. If it occurs in one in 100,000 users, a study demonstrating this would require at least 300,000 patients, and it would take years to accomplish. This is why FDA guidelines do not require absolute proof of causality. The FDA simply requires a close, plausible association between a drug and an adverse event. This is certainly the case with acetaminophen and fasting.
Over the years, more and more physicians have accepted fasting as a legitimate risk factor for acetaminophen toxicity. In 2001, the Harvard Health Letter stated flatly: “It is dangerous to take acetaminophen after you’ve been fasting.”25 Three years later, in response to articles debating fasting and other risk factors with acetaminophen, Dr. Timothy Davern noted that in the gastroenterology division at the University of California, San Francisco, “fasting due to intercurrent illness [e.g. flu] appears to be a common predisposing factor” for acetaminophen toxicity.26
Things You Can Do
Given the potential risks of overusing acetaminophen, it is wise to use it sparingly, if at all. Those who have to take acetaminophen need to be aware of the factors that can increase the risks. These include taking acetaminophen while having three or more alcohol drinks a day, using multiple acetaminophen-containing products, or taking acetaminophen when you are unable to eat because of nausea, vomiting, loss of appetite, anorexia, malnutrition, or other causes of reduced nutrition. If your doctor prescribes a medication for pain, headache, or muscle tension, be sure to ask whether the drug contains acetaminophen. If you forget to ask your doctor, ask your pharmacist.
Be sure to read the label of any over-the-counter medication. If you are taking more than one medication, make sure that only one contains acetaminophen. Read the warnings. Stay within the recommended doses of acetaminophen. Overmedicating by even small amounts raises acetaminophen’s risks.
It should also be remembered that alternative medications such as ibuprofen, naproxen, or other anti-inflammatory drugs have their own risks (e.g. stomach ulceration and cardiovascular complications).27,28
For those who need to take these over-the-counter medications, consider taking antioxidants and other supplements at the same time to mitigate any adverse effects on the liver, kidney, and stomach.29 These nutrients provide antioxidant support to counteract the harmful build-up of oxidant by-products caused by taking acetaminophen. They also preserve the liver’s supply of glutathione, an antioxidant that is essential for the body’s detoxification of a number of drugs and toxins, and which is depleted by the metabolism of acetaminophen. Furthermore, glutathione levels fall with aging, thus increasing the risk of acetaminophen-induced liver damage, so it is even more important to maintain healthy liver function in the elderly.30
Nutritional supplements that may be used in conjunction with acetaminophen include N-acetylcysteine (NAC),31 vitamins C and E,32,33 S-adenosylmethionine (SAMe),34 whey protein,35-7 milk thistle extracts (silymarin and silibinin),38,39 and polyenylphosphatidylcholine.40
N-acetylcysteine is part of the body’s natural antioxidant system and helps maintain stores of glutathione in the liver.31 This nutrient is also used intravenously in conventional therapy as a primary treatment for liver toxicity triggered by acetaminophen overdose. Life Extension recommends taking 600 mg of N-acetylcysteine with at least 1 g of vitamin C per dose of acetaminophen, which will provide significant protection for the liver. Alternatively, whey protein, 20 g/day, mixed with cereal or a liquid, contains a high concentration of cysteine, which acts a key precursor to restoring glutathione levels in the liver.36,37
A lack of vitamin C or glutathione also causes vitamin E levels to fall. Supplementing with vitamin E, 400 IU per day (along with at least 200 mg of gamma tocopherol) can protect the liver while taking acetaminophen.33
For those who must take acetaminophen chronically, the herb milk thistle, which contains the active ingredients, silymarin and silibinin, restores the body’s supplies of glutathione, while reducing free radical production and lipid peroxidation in the liver.38,39 The recommended dose is 250 mg of milk thistle extract two or three times a day in patients taking long-term acetaminophen therapy.
In cases where liver function has already become compromised by analgesics or other toxins, S-adenosylmethionine (SAMe) may help repair the liver and prevent further damage.34
Polyenylphosphatidylcholine (PPC) is a soy extract that also protects the liver against injury from fibrosis, oxidative stress, and toxicity due to acetaminophen use.40 Life Extension recommends taking 1800 mg/day of PPC to protect the liver from noxious substances. Polyenylphosphatidyl-choline also offers powerful protection for the gastric mucosa, which is vulnerable to irritation and ulceration from high-dose analgesics such as aspirin, ibuprofen, or prescription anti-inflammatory drugs.41
It should be noted that any dietary supplementation regime should not be launched without the supervision of a physician or a qualified health care practitioner, who will be able to create a program that is appropriate for you.
Jay S. Cohen, MD, is an associate
professor of family and preventive medicine and psychiatry at the University of California, San Diego. Dr. Cohen is a nationally recognized expert on medications and their side effects. He has published books and medical journal articles and has spoken at major conferences and at the US Food and Drug Administration regarding the need for improved drug safety. Dr. Cohen also provides expert analyses and opinions in cases involving medication-induced injuries. His most recent book, What You Must Know About Statin Drugs and Their Natural Alternatives (Square One Publishers, 2006), explains who needs to reduce cholesterol or other risk factors for heart disease, and how they can do so safely. For more information, visit Dr. Cohen’s website at www.MedicationSense.com.
If you have any questions on the scientific content of this article, please call a Life Extension Health Advisor at 1-800-226-2370.
1. Eriksson LS, Broome U, Kalin M, Lindholm M. Hepatotoxicity due to repeated intake of low doses of paracetamol. J Intern Med. 1992 May;231(5):567-70.
2. Nourjah P, Ahmad SR, Karwoski C, Willy M. Estimates of acetaminophen (Paracetamol)-associated overdoses in the United States. Pharmacoepidemiol Drug Saf. 2006 Jun;15(6):398-405.
3. Ostapowicz G, Fontana RJ, Schiodt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med. 2002 Dec 17;137(12):947-54.
4. Lee WM. Acetaminophen and the US Acute Liver Failure Study Group: lowering the risks of hepatic failure. Hepatology. 2004 Jul;40(1):6-9.
5. Available at: http://www.emedicine.com/ped/topic7.htm. Accessed September 20, 2007.
6. Acetaminophen Alert. Consumer Reports. May, 2006:44.
7. MacDonald TM. Acetaminophen: risk-management urgently required. Pharmacoepidemiol Drug Saf. 2006 Jun;15(6):406-9.
8. Larson AM, Polson JS, Fontana RJ, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology. 2005;42(6):1364-72.
9. Osborne ZP, Bryant SM. Patients discharged with a prescription for acetaminophen-containing narcotic analgesics do not receive appropriate written instructions. Am J Emerg Med. 2003 Jan;21(1):48-50.
10. Gyamlani GG, Parikh CR. Acetaminophen toxicity: suicidal vs. accidental. Crit Care. 2002 Apr;6(2):155-9.
11. Tylenol® Extra Strength Acetaminophen. Warnings on package. McNeil Consumer Healthcare, 2006.
12. Moling O, Cairon E, Rimenti G, et al. Severe hepatotoxicity after therapeutic doses of acetaminophen. Clin Ther. 2006 May;28(5):755-60.
13. Lane JE, Belson MG, Brown DK, Scheetz A. Chronic acetaminophen toxicity: a case report and review of the literature. J Emerg Med. 2002 Oct;23(3):253-6.
14. Roberge R. Chronic acetaminophen toxicity. J Emerg Med. 2003 Nov;25(4):474.
15. Kadas I, Konczol F, Illes T. Fatal acute liver damage caused by a therapeutic dose of paracetamol. Orv Hetil. 1998 Jan 25;139(4):189-91.
16. Muniz AE, Rose SR, Liner SR, Foster RL. Unsuspected acetaminophen toxicity in a 58-day-old infant. Pediatr Emerg Care. 2004 Dec;20(12):824-8.
17. Shahroor S, Shvil Y, Ohali M, Granot E. Acetaminophen toxicity in children as a “therapeutic misadventure”. Harefuah. 2000 Apr 16;138(8):654-7, 710.
18. Available at: http://www.fda.gov/bbs/topics/NEWS/2004/NEW01008.html. Accessed September 20, 2007.
19. Watkins PB, Kaplowitz N, Slattery JT, et al. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA. 2006 Jul 5;296(1):87-93.
20. Ahmad SR. Safety of recommended doses of paracetamol. Lancet. 2007 Feb 10;369(9560):462-3.
21. Smith SW. Sidelining safety—the FDA’s inadequate response to the IOM. N Engl J Med. 2007 Sep 6;357(10):960-3.
22. Center for Drug Evaluation and Research. Guidance For Industry: Adverse Reactions Section of Labeling for Human Prescription Drug and Biological Product. US Food and Drug Administration, June 2006.
23. Price VF, Miller MG, Jollow DJ. Mechanisms of fasting-induced potentiation of acetaminophen hepatotoxicity in the rat. Biochem Pharmacol. 1987 Feb 15;36(4):427-33.
24. Tokatli A, Kalkanoglu-Sivri HS, Yuce A, Coskun T. Acetaminophen-induced hepatotoxicity in a glutathione synthetase-deficient patient. Turk J Pediatr. 2007 Jan;49(1):75-6.
25. The dangers of acetaminophen. Harvard Health Letter. July, 2001:6.
26. Davern TJ. Acetaminophen hepatotoxicity. Hepatology. 2004 Oct;40(4):1021-2.
27. Murphy CA, Dargie HJ. Drug-induced cardiovascular disorders. Drug Saf. 2007;30(9):783-804.
28. Sopena F, Lanas A. How to advise aspirin use in patients who need NSAIDs. Curr Pharm Des. 2007;13(22):2248-60.
29. Available at: www.lef.org/protocols/appendix/otc_toxicity_01.htm. Accessed September 10, 2007.
30. Chen TS, Richie JP Jr, Lang CA. Life span profiles of glutathione and acetaminophen detoxification. Drug Metab Dispos. 1990 Nov-Dec;18(6):882-7.
31. Atkuri KR, Mantovani JJ, Herzenberg LA, Herzenberg LA. N-Acetylcysteine-a safe antidote for cysteine/glutathione deficiency. Curr Opin Pharmacol. 2007 Aug;7(4):355-9.
32. Hill AS, Rogers QR, O’Neill SL, Christopher MM. Effects of dietary antioxidant supplementation before and after oral acetaminophen challenge in cats. Am J Vet Res. 2005 Feb;66(2):196-204.
33. Faintuch J, Aguilar PB, Nadalin W. Relevance of N-acetylcysteine in clinical practice: Fact, myth or consequence? Nutrition. 1999 Feb;15(2):177–9.
34. Lieber CS. S-Adenosyl-L-methionine and alcoholic liver disease in animal models: implications for early intervention in human beings. Alcohol. 2002 Jul;27(3):173-7. Review.
35. Tseng YM, Lin SK, Hsiao JK, et al. Whey protein concentrate promotes the production of glutathione (GSH) by GSH reductase in the PC12 cell line after acute ethanol exposure. Food Chem Toxicol. 2006 Apr;44(4):574-8.
36. Marshall K. Therapeutic applications of whey protein. Altern Med Rev. 2004 Jun;9(2):136-56
37. Lands LC, Grey VL, Smountas AA. Effect of supplementation with a cysteine donor on muscular performance. J Appl Physiol. 1999 Oct;87(4):1381-5.
38. Muriel P, Garciapiña T, Perez-Alvarez V, Mourelle M. Silymarin protects against paracetamol-induced lipid peroxidation and liver damage. J Appl Toxicol. 1992 Dec;12(6):439-42.
39. Basaga H, Poli G, Tekkaya C, Avas I. Free radical scavenging and antioxidative properties of ‘silibin’ complexes on microsomal lipid peroxidation. Cell Biochem Funct. 1997 Mar;15(1):27–33.
40. Lieber CS. The discovery of the microsomal ethanol oxidizing system and its physiologic and pathologic role. Drug Metab Rev. 2004 Oct;36(3-4):511-29. Review.
41. Anand BS, Romero JJ, Sanduja SK, Lichtenberger LM. Phospholipid association reduces the gastric mucosal toxicity of aspirin in human subjects. Am J Gastroenterol. 1999 Jul;94(7):1818-22.