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Hepatotoxicity of non-narcotic analgesics

  • Keith G. Tolman
    Correspondence
    Requests for reprints should be addressed to K.G. Tolman, MD, University Medical Center, 50 North Medical Drive, Salt Lake City, Utah 84132
    Affiliations
    Division of Gastroenterology, Section of Hepatology, University of Utah School of Medicine, Salt Lake City, Utah, USA
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      Abstract

      The central role of the liver in drug metabolism sets the stage for drug-related hepatotoxicity. The incidence of hepatotoxicity associated with non-narcotic analgesics is low, but their widespread use—both prescription and over-the-counter—makes analgesic-associated hepatotoxicity a clinically and economically important problem. Hepatotoxicity is considered a class characteristic of nonsteroidal anti-inflammatory drugs (NSAIDs), despite the fact that they are a widely diverse group of chemicals. In fact, there are many differences in the incidence, histologic pattern, and mechanisms of hepatotoxicity between, as well as within, chemical classes. Most NSAID reactions are hepatocellular and occur because of individual patient susceptibility (idiosyncrasy). Aspirin, however, is a dose-related intrinsic hepatotoxin. Acetaminophen is also an intrinsic hepatotoxin but rarely demonstrates hepatotoxicity at therapeutic doses. It does cause hepatotoxicity with massive overdoses and with therapeutic doses in susceptible patients such as chronic users of alcohol. No hepatotoxicity has been reported to date with tramadol, another non-narcotic analgesic.
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      References

        • Weinblatt M.E.
        • Tesser J.R.P.
        • Gilliam III, J.H.
        The liver in rheumatic diseases (Abstr.).
        Semin Arthritis Rheum. 1982; 11: 399
        • Runyon B.A.
        • LaBrecque D.R.
        • Anuras S.
        The spectrum of liver diseases in systemic lupus erythematosus.
        Am J Med. 1980; 69: 187-194
        • Lee W.M.
        Drug-induced hepatotoxicity.
        N Engl J Med. 1995; 333: 1118-1127
        • Watkins P.B.
        Drug metabolism by cytochromes P-450 in the liver and small bowel.
        Gastroenterol Clin North Am. 1992; 21: 511-526
      1. Samarasinghe DA, George J, Farrell GC. Drug-induced liver disease. In: Gitnick G, ed. Current Hepatology 1994;14:117–167.

        • Dreifuss F.E.
        • Langer D.H.
        • Moline K.A.
        • et al.
        Valproic acid hepatic fatalities. II US experience since 1984.
        Neurology. 1989; 39: 201-207
        • Kenna J.G.
        • Knight T.L.
        • Van Pelt F.N.A.M.
        Immunity of halothane metabolite-modified proteins in halothane hepatitis.
        Ann NY Acad Sci. 1993; 685: 646-661
        • Locoeur S.
        • Andre C.
        • Beanne P.H.
        Tienilic acid-induced autoimmune hepatitis.
        Mol Pharmacol. 1996; 50: 326-333
        • Bourdi M.
        • Chen W.
        • Peter R.M.
        • et al.
        Cytochrome P4502E1 is a major autoantigen associated with halothane hepatitis.
        Chem Res Toxicol. 1997; 9: 1159-1166
        • Berson A.
        • Freneaux D.
        • Larrey D.
        • et al.
        Possible role of HLA in hepatotoxicity. An exploratory study on 71 patients with drug-induced idiosyncratic hepatitis.
        J Hepatol. 1994; 20: 338-342
        • Zimmerman H.J.
        Effects of aspirin and acetaminophen on the liver.
        Arch Intern Med. 1981; 141: 333-342
        • Gonzalez F.J.
        Human cytochromes P450.
        Trends Pharmacol Sci. 1992; 13: 346-352
        • Wrighton S.A.
        • Steven J.C.
        The human hepatic cytochrome P450 involved in drug metabolism.
        Crit Rev Toxicol. 1992; 22: 1-21
        • Fry S.W.
        • Seeff L.
        Hepatotoxicity of analgesics and anti-inflammatory agents.
        Gastroenterol Clin North Am. 1995; 24: 875-905
        • Carson J.L.
        • Strom B.L.
        • Duff A.
        • Gupta A.
        • Das K.
        Safety of nonsteroidal anti-inflammatory drugs with respect to acute liver disease.
        Arch Intern Med. 1993; 153: 1331-1336
        • Lewis J.H.
        Hepatic toxicity of non-steroidal anti-inflammatory drugs.
        Clin Pharm. 1984; 3: 128-138
        • Paulus H.E.
        FDA Advisory Committee meeting.
        Arthritis Rheum. 1982; 25: 1124-1125
      2. Zimmerman HJ. Acetaminophen poisoning and NSAID toxicity. Presented at the American Association for the Study of Liver Diseases Postgraduate Course, November 7, 1997, Chicago, Illinois.

        • Tolman K.G.
        Hepatotoxicity of antirheumatic drugs.
        J Rheum. 1990; 17: 6-11
        • Prescott L.E.
        Effects of non-narcotic analgesics on the liver.
        Drugs. 1986; 32: 129-147
        • Kretz-Rommel A.
        • Boelsteri U.A.
        Diclofenac covalent protein binding is dependent on acyl glucuronide formation and is inversely related to P450-mediated acute cell injury in cultured rat hepatocytes.
        Toxicol Appl Pharmacol. 1993; 120: 155-161
        • Hargus S.J.
        • Amouzedeh H.R.
        • Pumford N.R.
        • et al.
        Metabolic activation and immunochemical localization of liver protein adducts of the nonsteroidal anti-inflammatory drug diclofenac.
        Chem Res Toxicol. 1994; 7: 575-582
        • Garcia Rodriguez L.A.
        • Perez Gutthann S.
        • Walker A.M.
        • et al.
        The role of nonsteroidal anti-inflammatory drugs in acute liver injury.
        BMJ. 1992; 305: 865-868
        • Tarazi E.M.
        • Harter J.G.
        • Zimmerman H.J.
        • et al.
        Sulindac-associated hepatic injury.
        Gastroenterology. 1993; 104: 569-574
        • Janota J.
        • Wincey C.W.
        • Sandiford M.
        • et al.
        Effect of salicylate on the activity of plasma enzymes in the rabbit.
        Nature. 1960; 185: 935-936
        • Tolman K.G.
        • Peterson P.
        • Gray P.
        • et al.
        Hepatotoxicity of salicylates in monolayer cell cultures.
        Gastroenterology. 1978; 74: 205-208
        • Zimmerman H.J.
        • Maddray W.C.
        Toxic and drug-induced hepatitis.
        in: Schiff L. Schiff E.R. Diseases of the Liver. 7th ed. JB Lippincott, Philadelphia1993: 707-783
        • Raucy J.L.
        • Lasker J.M.
        • Lieber C.S.
        • Black M.
        Acetaminophen activation by human liver cytochromes P450IIE1 and P4501A2.
        Arch Biochem Biophys. 1989; 271: 270-283
        • Zimmerman H.J.
        • Maddray W.C.
        Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol.
        Hepatology. 1995; 22: 767-773
        • Nelson S.D.
        Molecular mechanisms of the hepatotoxicity caused by acetaminophen.
        Semin Liver Dis. 1990; 10: 267-278
        • Lauterburg B.H.
        • Velez M.E.
        Glutathione deficiency in alcoholics.
        Gut. 1988; 29: 1153-1157
        • Rumack B.H.
        • Peterson R.C.
        • Koch G.G.
        • et al.
        662 cases with evaluation of oral acetylcysteine treatment.
        Arch Intern Med. 1981; 141: 380-385
        • Epstein M.
        Renal prostaglandins and the control of renal function in liver diseases.
        Am J Med. 1986; 80: 46-55
        • Daskalopoulos G.
        • Kronborg I.
        • Katlov W.
        • et al.
        Sulindac and indomethacin suppress the diuretic action of furosemide in patients with cirrhosis and ascites.
        Am J Kid Dis. 1985; VI: 217-221