Drug Safety

, Volume 22, Issue 6, pp 487–497

Minimising the Adverse Effects of Ketorolac

Review Article

Abstract

Gastrointestinal bleeding and perforation, platelet inhibition with altered haemostasis, and renal impairment are among the list of adverse effects associated with the administration of ketorolac. The incidence of serious adverse events has declined since dosage guidelines were revised. Most of the published literature suggests that the overall risk of gastrointestinal or operative site bleeding related to ketorolac therapy is only slightly higher than with opioids. The risk for adverse events, however, increases with high doses, with prolonged therapy (>5 days) or in vulnerable patients (e.g. the elderly). Acute renal failure has been reported after ketorolac treatment but is usually reversible after discontinuation of the drug. As with other nonsteroidal anti-inflammatory drugs (NSAIDs), ketorolac may trigger allergic or hypersensitivity reactions.

Careful patient selection is essential if use of ketorolac is considered. Contraindications to ketorolac use include a history of, or current risk of, gastrointestinal bleeding, risk of renal failure, compromised haemostasis, hypersensitivity to aspirin (acetylsalicylic acid) or other NSAIDs, labour, delivery and nursing. Ketorolac should be prescribed at the lowest dosage necessary to control pain; the duration of therapy should also be limited to as few days as possible. Practitioners should be familiar with, and follow, label warnings and dosage guidelines.

References

  1. 1.
    Council of International Organizations of Medical Sciences. Final report of CIOMS Working Group II. International reporting of periodic drug-safety update summaries. Geneva: Council of International Organizations of Medical Sciences, World Health Organization, 1992Google Scholar
  2. 2.
    Lewis S. Ketorolac in Europe [letter]. Lancet 1994; 343: 784CrossRefGoogle Scholar
  3. 3.
    Gillis JC, Brogden RN. Ketorolac: a reappraisal of its pharmacodynamic and pharmacokinetic properties and therapeutic use in pain management. Drugs 1997; 53: 139–88PubMedCrossRefGoogle Scholar
  4. 4.
    Anonymous. New ketorolac dosage recommendations. Pharm J 1993; 251: 49Google Scholar
  5. 5.
    Ketorolac: restrictions on parenteral dosage, WHO Drug Info 1993; 7 (2): 64Google Scholar
  6. 6.
    Bruno JJ, Yang D, Taylor LA. Differing effects of ticlopidine and two prostaglandins synthetase inhibitors on maximum rate of ADP-induce aggregation [abstract]. Thromb Haemost 1981; 46: 412Google Scholar
  7. 7.
    Antiplatelet Trialists’Collaboration. Collaborative overview of randomised trials of antiplatelet therapy. I. Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994; 308: 81–106Google Scholar
  8. 8.
    Greer IA. Effects of ketorolac tromethamine on hemostasis. Pharmacotherapy 1990; 10(6): 71S–6SPubMedGoogle Scholar
  9. 9.
    Conrad KA, Fagan TC, Mackie MJ, et al. Effects of ketorolac tromethamine on hemostasis in volunteers. Clin Pharmacol Ther 1988; 43: 542–6PubMedCrossRefGoogle Scholar
  10. 10.
    Concannon MJ, Meng L, Welsh CF, et al. Inhibition of perioperative platelet aggregation using toradol (ketorolac). Ann Plast Surg 1993; 30(3): 264–6PubMedCrossRefGoogle Scholar
  11. 11.
    Thwaites BK, Nigus D, Bouska GW, et al. Intravenous ketorolac tromethamine worsened platelet function during knee arthroscopy under spinal anesthesia. Anesth Analg 1996; 82: 1176–81PubMedGoogle Scholar
  12. 12.
    Thwaites BK, Nigus D, Bouska GW, et al. Intravenous ketorolac tromethamine does not worsen platelet function during knee arthroscopy under general anesthesia. Anesth Analg 1995; 81: 119–24PubMedGoogle Scholar
  13. 13.
    Weale AE, Durant N, Warwick DJ, et al. Is there a clinical interaction between low molecular weight heparin and nonsteroidal analgesics after total hip replacement? Ann R Coll Surg Engl 1995; 77: 35–7PubMedGoogle Scholar
  14. 14.
    Koh SCL, Pua HL, Tay DHB, et al. The effects of gynaecological surgery on coagulation activation, fibrinolysis and fibrinolytic inhibitor in patients with and without ketorolac infusion. Thromb Res 1995; 79: 501–14PubMedCrossRefGoogle Scholar
  15. 15.
    Varrasi G, Panella L, Piroli A. The effects of perioperative ketorolac infusion on postoperative pain and endocrine-metabolic response. Anesth Analg 1994; 78: 514–9CrossRefGoogle Scholar
  16. 16.
    Watcha MF, Ramirez-Ruiz M, White PF, et al. Perioperative effects of ketorolac and acetaminophen in children undergoing bilateral myringotomy. Can J Anaesth 1992; 39: 649–54PubMedCrossRefGoogle Scholar
  17. 17.
    Watcha MF, Barry Jones M, Lagueruela RG, et al. Comparison of ketorolac and morphine as adjuvants during pediatric surgery. Anesthesiology 1992; 76: 368–72PubMedCrossRefGoogle Scholar
  18. 18.
    Munro HM, Riegger LQ, Reynolds PI, et al. Comparison of the analgesic and emetic properties of ketorolac and morphine for paediatric outpatient strabismus surgery. Br J Anaesth 1994; 72: 624–8PubMedCrossRefGoogle Scholar
  19. 19.
    Hall SC. Tonsillectomies, ketorolac, and the march of progress. Can J Anaesth 1996; 436: 544–8PubMedCrossRefGoogle Scholar
  20. 20.
    Gunter JB, Varughese AM, Harrington JF, et al. Recovery and complications after tonsillectomy in children: a comparison of ketorolac and morphine. Anesth Analg 1995; 81: 1136–41PubMedGoogle Scholar
  21. 21.
    Judkins JH, Dray TG, Hubbell RN. Intraoperative ketorolac and posttonsillectomy bleeding. Arch Otolaryngol Head Neck Surg 1996; 112: 937–40CrossRefGoogle Scholar
  22. 22.
    Splinter WM, Rhine EJ, Roberts DW, et al. Preoperative ketorolac increases bleeding after tonsillectomy in children. An J Anaesth 1996; 43; 6: 560–3Google Scholar
  23. 23.
    Bailey R, Sinha C, Burgess PA. Ketorolac tromethamine and hemorrhage in tonsillectomy: a prospective, randomized, doubleblind study. Laryngoscope 1997; 107: 166–9PubMedCrossRefGoogle Scholar
  24. 24.
    Gallagher JE, Blauth J, Fornadley JA. Perioperative ketorolac tromethamine and postoperative hemorrhage in cases of tonsillectomy and adenoidectomy. Laryngoscope 1995; 105: 606–9PubMedCrossRefGoogle Scholar
  25. 25.
    Sutters KA, Levine JD, Dibble S, et al. Analgesic efficacy and safety of single-dose intramuscular ketorolac for postoperative pain management in children following tonsillectomy. Pain 1995; 16: 145–53CrossRefGoogle Scholar
  26. 26.
    Toradol package insert. Nutley, (NJ): Hoffman LaRoche, 1995Google Scholar
  27. 27.
    Buck M. Clinical experience with ketorolac in children. Ann Pharmacother 1994; 28: 1009–13PubMedGoogle Scholar
  28. 28.
    Rømsing J, Walther-Larsen S. Peri-operative use of nonsteroidal anti-inflammatory drugs in children: analgesic efficacy and bleeding. Anaesthesia 1997; 52: 673–83PubMedCrossRefGoogle Scholar
  29. 29.
    Strom BL, Berlin JA, Kinman JL, et al. Parenteral ketorolac and risk of gastrointestinal and operative site bleeding. JAMA 1996 Feb; 275; 5: 376–82CrossRefGoogle Scholar
  30. 30.
    Kehlet H, Dahl JB. Are perioperative nonsteroidal anti-inflammatory drugs ulceragenic in the short term? Drugs 1992; 44Suppl. 5: S38–S41CrossRefGoogle Scholar
  31. 31.
    Vane JR, Botting RM. The mode of action of anti-inflammatory drugs. Postgrad Med J 1990; 66Suppl. 4: S2–S17PubMedGoogle Scholar
  32. 32.
    Bjaranason I, Thjodleifsson B. Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs: the effect of nimesulide compared with naproxen on the human gastrointestinal tract. Rheumatology (Oxford) 1999; 38Suppl. 1: 24–32CrossRefGoogle Scholar
  33. 33.
    Fosslein E. Adverse effect of nonsteroidal anti-inflammatory drugs on the gastrointestinal system. Ann Clin Lab Sci 1998; 28(2): 67–81Google Scholar
  34. 34.
    Garcia Rodriguez LA, Cattaruzzi C, Troncon MG, et al. Risk of hospitalization for upper gastrointestinal tract bleeding associated with ketorolac, other nonsteroidal anti-inflammatory drugs, calcium antagonists, and other antihypertensive drugs. Arch Intern Med 1998; 12: 33–9CrossRefGoogle Scholar
  35. 35.
    Traversa G, Walker AM, Ippolito FM, et al. Gastroduodenal toxicity of different anti-inflammatory drugs. Epidemiology 1995; 6(1): 49–54PubMedCrossRefGoogle Scholar
  36. 36.
    Menniti-Ippolito F, Maggini M, Raschetti R, et al. Ketorolac use in outpatients and gastrointestinal hospitalization: a comparison with other non-steroidal anti-inflammatory drugs in Italy. Eur J Clin Pharmacol 1998; 54(5): 393–7PubMedCrossRefGoogle Scholar
  37. 37.
    Henry D, Lim LL, Garcia Rodriguez LA, et al. Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis. BMJ 1996; 312: 1563–6PubMedCrossRefGoogle Scholar
  38. 38.
    Garcia Rodriguez LA, Jick H. The risk of upper gastrointestinal bleeding and/or perforation associated with individual nonsteroidal anti-inflammatory drugs. Lancet 1994; 343: 769–72PubMedCrossRefGoogle Scholar
  39. 39.
    Cummings DM, Amadio P. A review of selected newer nonsteroidal anti-inflammatory drugs. Am Family Physician 1994 Apr; 49; 5: 1197–202Google Scholar
  40. 40.
    Kenny GN. Potential renal, haematological and allergic adverse effects associated with nonsteroidal anti-inflammatory drugs. Drugs 1992; 44Suppl. 5: S31–S6CrossRefGoogle Scholar
  41. 41.
    Murray MD, Brater DC. Adverse effects of nonsteroidal anti-inflammatory drugs on renal function. Ann Intern Med 1990; 112(8): 559–60PubMedGoogle Scholar
  42. 42.
    Henrich WL, Agodoa LE, Barrett B, et al. National Kidney Foundation Position Paper: analgesics and the kidney: summary and recommendations to the Scientific Advisory Board of the National Kidney Foundation from an Ad Hoc Committee of the National Kidney Foundation. Am J Kidney Dis 1996; 27: 162–5PubMedCrossRefGoogle Scholar
  43. 43.
    DuBose Jr TD, Molony DA, Verani R, et al. Nephrotoxicity of non-steroidal anti-inflammatory drugs. Lancet 1994; 344: 515–8CrossRefGoogle Scholar
  44. 44.
    Aitken HA, Burns JW, McArdle CS, et al. Effects of ketorolac trometamol on renal function. Br J Anaesth 1992; 68: 481–5PubMedCrossRefGoogle Scholar
  45. 45.
    Ready LB, Bown CR, Stahigren LH, et al. Evaluation of intravenous ketorolac administered by bolus or infusion for treatment of postoperative pain. Adouble-blind, placebo-controlled, multicenter study. Anesthesiology 1994; 80: 1277–86PubMedCrossRefGoogle Scholar
  46. 46.
    Rao TRK, Naidu MUR, Shobha JC, et al. Renal effects of oral ketorolac in patients with mild to moderate pain. Clin Drug Invest 1995; 9: 111–5CrossRefGoogle Scholar
  47. 47.
    Myles PS, Power I. Does ketorolac cause postoperative renal failure: how do we assess the evidence? Br J Anaesth 1998; 80: 420–1PubMedCrossRefGoogle Scholar
  48. 48.
    Feldman HL, Kinman JL, Berlin JA, et al. Parenteral ketorolac: the risk for acute renal failure. Ann Intern Med 1997; 126: 193–9PubMedGoogle Scholar
  49. 49.
    Sackett DL, Haynes RB, Guyatt GH, et al. Clinical epidemiology: a basic science for clinical medicine, 2nd ed. Boston: Little Brown, 1991: 283–302Google Scholar
  50. 50.
    Szezeklik A, Gryglewski RJ, Czerniawska-Mysik G. Relationship of inhibition of prostaglandin biosynthesis by analgesics to asthma attacks in aspirin-sensitive patients. BMJ 1975; 1: 67–9CrossRefGoogle Scholar
  51. 51.
    Szezeklik A. aspirin-induced asthma: new insights into pathogenesis and clinical presentation of drug intolerance. Int Arch Allergy Immunol 1989; 90: 70–5CrossRefGoogle Scholar
  52. 52.
    Piado C, Castillo JA, Montserrat JM, et al. Aspirin intolerance as a precipitating factor of life-threatening attacks of asthma requiring mechanical ventilation. Eur Respir J 1989; 2: 127–9Google Scholar
  53. 53.
    Szezeklik A, Gryglewski RJ, Czerniawska-Mysik G. Clinical patterns of hypersensitivity to nonsteroidal anti-inflammatory drugs and their pathogenesis. J Allergy Clin Immunol 1977; 60: 276–84CrossRefGoogle Scholar
  54. 54.
    Hebert WG, Scopelitis E. Ketorolac-precipitated asthma. South Med J 1994; 87; 2: 282–3CrossRefGoogle Scholar
  55. 55.
    Vicks SD, Dean RJ, Tenholder MF. Ketorolac induced respiratory failure in an aspirin sensitive asthmatic. Immunol Allergy Pract 1991; 13: 23–5Google Scholar
  56. 56.
    Dias MA, Biedlingmaier JF. Ketorolac-induced status asthmaticus after endoscopic sinus surgery in a patient with Samter’s triad. Arch Otolaryngol Head Neck Surg 1997; 117: S176–S8CrossRefGoogle Scholar
  57. 57.
    Zikowski D, Hord AH, Haddox JD. Ketorolac-induced bronchospasm. Anesth Analg 1993; 76: 417–9PubMedGoogle Scholar
  58. 58.
    Haddow GR, Riley E, Isaacs R, et al. Ketorolac, nasal polyposis, and bronchial asthma: a cause for concern. Anesth Analg 1993; 76: 420–2PubMedGoogle Scholar
  59. 59.
    Hammonds WD, Donnigan D. Problems in anesthesia: clinical use of ketorolac tromethamine 1993; 3: 268–80Google Scholar
  60. 60.
    Litvak KM, McEvoy GK. Ketorolac: an injectable non-narcotic analgesic. Clin Pharm 1990; 9(12): 912–35Google Scholar
  61. 61.
    Hennesey S, Kinman JL, Berlin JA, et al. Lack of hepatotoxic effects of parenteral ketorolac in the hospital setting. Arch Intern Med 1997; 157: 2510–4CrossRefGoogle Scholar
  62. 62.
    Walker JJ, Johnstone J, Lloyd J, et al. The transfer of ketorolac tromethamine from maternal to foetal blood. Eur J Pharmacol 1988; 3495: 509–11Google Scholar
  63. 63.
    Greer IA, Johnstone J, Tulloch I, et al. Effect of maternal ketorolac administration on platelet function in the newborn. Eur J Obstet Gynecol Reprod Biol 1988; 29(4): 257–60PubMedCrossRefGoogle Scholar
  64. 64.
    Diemunsch P, Alt M, Diemunsch AM, et al. Post cesarean analgesia with ketorolac tromethamine and uterine atonia. Eur J Obstet Gynecol Reprod Biol 1997; 72(2): 205–6PubMedCrossRefGoogle Scholar
  65. 65.
    Schorr SJ, Ascarelli MH, Rust OA, et al. A comparative study of ketorolac (Toradol) and magnesium sulfate for arrest of preterm labor. South Med J 1998; 91(11): 1028–32PubMedCrossRefGoogle Scholar
  66. 66.
    Ostensen M, Ramsey-Goldman R. Treatment of inflammatory rheumatic disorders in pregnancy: what are the safest treatment options? Drug Saf 1998; 19(5): 389–410PubMedCrossRefGoogle Scholar
  67. 67.
    Ostensen M. Nonsteroidal anti-inflammatory drugs during pregnancy. Scand J Rheumatol 1998; 107Suppl.: S128–S32Google Scholar
  68. 68.
    Schaab KC, Dickinson ET, Setzen G. Acute sensorineural hearing loss following intravenous ketorolac administration. J Emerg Med 1995; 13(4): 509–13PubMedCrossRefGoogle Scholar
  69. 69.
    Otti T, Weindel M, Bastani B. Ketorolac induced acute reversible hearing loss in a patient maintained on CAPD. Clin Nephrol 1997; 47; 3: 208–9Google Scholar
  70. 70.
    Ragheb M. The clinical significance of lithium-nonsteroidal anti-inflammatory drug interactions. J Clin Psychopharmacol 1990; 10: 350–4PubMedGoogle Scholar
  71. 71.
    Langlois R, Paquette D. Increased serum lithium levels due to ketorolac therapy. Can Med Assoc J 1994; 150(9): 1455–6Google Scholar
  72. 72.
    Iyer V. Ketorolac (Toradol) induced lithium toxicity. Headache 1994 Jul/Aug: 442–4Google Scholar
  73. 73.
    British National Formulary. 36th ed. London: British Medical Association and Royal Pharmaceutical Society of Great Britain, 1998Google Scholar
  74. 74.
    Summers K, Wilson R. Ketorolac injection: a review of its safety and rational use in day case and major surgery. Pharmaceut Med 1994; 8; 115–34Google Scholar

Copyright information

© Adis International Limited 2000

Authors and Affiliations

  1. 1.University of Utah School of Medicine, McKay-Dee Hospital, Department of Anaesthesiology, Salt Lake City, Utah, and Weber State UniversityOgdenUSA

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