OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Ketorolac	74103-06-3	C15-H13-N-O3

ANNOTATED BIBLIOGRAPHY

References updated: 25 April 2018

• Zimmerman HJ. Drugs used to treat rheumatic and musculospastic disease. The NSAIDS. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 517-41.

  (Review of hepatotoxicity of NSAIDs published in 1999; ketorolac is not mentioned).
• Lewis JH, Stine JG. Nonsteroidal anti-inflammatory drugs and leukotriene receptor antagonists: pathology and clinical presentation of hepatotoxicity. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd Edition. Amsterdam: Elsevier, 2013. pp. 370-402.

  (Review of hepatotoxicity of NSAIDs mentions that ketorolac has not been implicated in cases of clinically apparent liver injury in the published literature).
• Grossner T, Smyth EM, Fitzgerald GA. Anti-inflammatory, antipyretic, and analgesic agents: pharmacotherapy of gout. In, Brunton LL, Chabner BA, Knollman BC. Goodman & Gilman’s The pharmacological basis of therapeutics, 12th ed. New York: McGraw-Hill, 2011. p. 959-1004.

  (Textbook of pharmacology and therapeutics).
• Brocks DR, Jamali F. Clinical pharmacokinetics of ketorolac tromethamine. Clin Pharmacokinet 1992; 23: 415-27. [PubMed: 1458761]

  (Ketorolac is produced as a tromethamine salt to allow water solubility and parenteral administration, is rapidly absorbed, has a half life of 4-6 hours, is highly protein bound, extensively conjugated in the liver and excreted in urine).
• Erstad BL, Rappaport WD. Subcapsular hematoma after laparoscopic cholecystectomy, associated with ketorolac administration. Pharmacotherapy 1994; 14: 613-5. [PubMed: 7997396]

  (

  35 year old woman developed subcapsular hepatic hematoma 10 hours after after receving intravenous ketorolac after laparoscopic cholecystectomy).
• Hennessy S, Kinman JL, Berlin JA, Feldman HI, Carson JL, Kimmel SE, et al. Lack of hepatotoxic effects of parenteral ketorolac in the hospital setting. Arch Intern Med 1997; 157: 2510-4. [PubMed: 9385304]

  (Analysis of safety based upon 10,272 courses of ketorolac given to 9900 patients in 35 hospitals, average duration of therapy was for 2.6 days [range 1-44]; ALT elevations >3 fold occurred in 0.7% of ketorolac vs 0.9% of opioid courses).
• Zimmerman HJ. Update of hepatotoxicity due to classes of drugs in common clinical use: non-steroid drugs, anti-inflammatory drugs, antibiotics, antihypertensives, and cardiac and psychotropic agents. Semin Liver Dis 1990; 10: 322-8. [PubMed: 2281340]

  (Extensive review article on liver injury due to NSAIDs; ketorolac is not discussed).
• Vuilleumier H, Halkic N. Ruptured subcapsular hematoma after laparoscopic cholecystectomy attributed to ketorolac-induced coagulopathy. Surg Endosc 2003; 17: 659. [PubMed: 12574932]

  (23 year old woman received ketorolac after routine laparoscopic cholecystectomy and presented 18 hours later with subcapsular hematoma of the liver attributed to platelet effects of ketorolac).
• Björnsson E, Jerlstad P, Bergqvist A, Olsson R. Fulminant drug-induced hepatic failure leading to death or liver transplantation in Sweden. Scand J Gastroenterol 2005; 40: 1095-101. [PubMed: 16165719]

  (Survey of all cases of drug induced liver injury with fatal outcome from Swedish Adverse Drug Reporting system from 1966-2002; among 103 cases, 3 attributed to naproxen, but none to ketorolac).
• Lapeyre-Mestre M, de Castro AM, Bareille MP, Del Pozo JG, Requejo AA, Arias LM, et al. Non-steroidal anti-inflammatory drug-related hepatic damage in France and Spain: analysis from national spontaneous reporting systems. Fundam Clin Pharmacol 2006; 20:391-5. [PubMed: 16867024]

  (Analysis of reports of liver injury from NSAIDs from France and Spain from 1982-2001; among more than 29,000 liver adverse event reports, 11 were for ketorolac; no clinical details given; ketorolac withdrawn from France in 1994 because of gastrointestinal side effects).
• Guercio G, Sandonato L, Cintorino D, Ricotta C, Diana G. [Hemoperitoneum from rupture of liver subcapsular hematoma after laparoscopic cholecystectomy attributed to ketorolac. Report of a case]. G Chir 2008; 29: 351-3. Italian. [PubMed: 18834567]

  (39 year old woman undergoing laparoscopic cholecystectomy received intravenous ketorolac postoperatively and developed a subcapsular hepatic hematoma 7 hours later).
• Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. [PMC free article: PMC3654244] [PubMed: 18955056]

  (Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, NSAIDs were implicated as a sole agent in 8 cases [4 diclofenac, 2 celecoxib, 1 meloxicam and 1 oxaprozin] and as one of several agents in 3 cases [1 diclofenac, 1 celecoxib, 1 ibuprofen]; none were attributed to ketorolac).
• Minaya Bravo AM, González González E, Ortíz Aguilar M, Larrañaga Barrera E. Two rare cases of intrahepatic subcapsular hematoma after laparoscopic cholecystectomy. Indian J Surg 2010; 72: 481-4. [PMC free article: PMC3077204] [PubMed: 22131659]

  (Two women, ages 29 and 69 years, developed symptomatic subcapsular hepatic hematomas 1 and 5 days after laparoscopic cholecystectomy while receiving intravenous ketorolac for pain; both required surgery and recovered uneventfully).
• Bessone F. Non-steroidal anti-inflammatory drugs: What is the actual risk of liver damage? World J Gastroenterol 2010; 16: 5651-61. [PMC free article: PMC2997980] [PubMed: 21128314]

  (Review of estimated frequency of drug induced liver injury due to NSAIDs from large published epidemiological studies; ketorolac is not discussed).
• Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. [PMC free article: PMC3992250] [PubMed: 20949552]

  (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, of which 7 were attributed to NSAIDs including 4 to bromfenac, 2 diclofenac and 1 etodolac, but none to ketorolac).
• Gulmez SE, Larrey D, Pageaux GP, Lignot S, Lassalle R, Jové J, Gatta A, et al. Transplantation for acute liver failure in patients exposed to NSAIDs or paracetamol (acetaminophen): the multinational case-population SALT study. Drug Saf 2013; 36: 135-44. [PMC free article: PMC3568201] [PubMed: 23325533]

  (Among 600 patients undergoing liver transplantation for acute liver failure at 52 European liver transplant centers between 2005 and 2007, 301 were considered idiopathic and had received a medication within 30 days of onset, including acetaminophen in 192 and NSAIDs in 40, including ketorolac in 2 for a rate of 19.5 per million-treatment years).
• Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013; 144: 1419-25. (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, including 6 attributed to diclofenac [ranking 2nd], but none for ketorolac or other NSAIDs). [PubMed: 23419359]
• Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol 2014; 13: 231-9. [PubMed: 24552865]

  (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, the most common class of implicated agents being NSAIDS [n=62, 32%], but specific agents were nimesulide [n=53], piroxicam [5], diclofenac [2], gold salts [1], and naproxen [1]; ketorolac was not listed]).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 28 were attributed to NSAIDs, but none to ketorolac [Schmeltzer 2016]).
• Schmeltzer PA, Kosinski AS, Kleiner DE, Hoofnagle JH, Stolz A, Fontana RJ, Russo MW; Drug-Induced Liver Injury Network (DILIN). Liver injury from nonsteroidal anti-inflammatory drugs in the United States. Liver Int 2016; 36: 603-9. [PMC free article: PMC5035108] [PubMed: 26601797]

  (Among 1221 cases of drug induced liver injury enrolled in a prospective, US database between 2004 and 2014, 30 cases [2.5%] were attributed to NSAIDs, most common diclofenac; none were attributed to ketorolac).
• Donati M, Conforti A, Lenti MC, Capuano A, Bortolami O, Motola D, Moretti U, et al; DILI-IT Study Group. Risk of acute and serious liver injury associated to nimesulide and other NSAIDs: data from drug-induced liver injury case-control study in Italy. Br J Clin Pharmacol 2016; 82: 238-48. [PMC free article: PMC4917796] [PubMed: 26991794]

  (Among 179 cases of acute liver injury and 1770 controls admitted to 9 Italian hospitals between 2010 and 2014, NSAIDs used more frequently in cases compared to controls included nimesulide [17% vs 10%: odds ratio 1.88] and ibuprofen [14% vs 10%: odds ratio 1.59] and risk was higher in those taking higher doses; ketorolac was not mentioned).
• Zoubek ME, González-Jimenez A, Medina-Cáliz I, Robles-Díaz M, Hernandez N, Romero-Gómez M, Bessone F, et al. High Prevalence of ibuprofen drug-induced Liver injury in Spanish and Latin-American registries. Clin Gastroenterol Hepatol 2018; 16: 292-4. [PubMed: 28782674]

  (Analysis of a Spanish and Latin-American registries identified 73 cases of NSAID induced liver injury, the most common agents being nimesulide [38%], diclofenac [34%] and ibuprofen [17%]; ketorolac was not mentioned).
• Maslin B, Lipana L, Roth B, Kodumudi G, Vadivelu N. Safety considerations in the use of ketorolac for postoperative pain. Curr Drug Saf 2017; 12: 67-73. PubMed Citation. [PubMed: 27440142]

  (Review of the safety of ketorolac in the perioperative period focusing upon renal dysfunction and bleeding; no discussion of ALT elevations or hepatotoxicity).