What evidence is there for the 5-day maximum with the use of ketorolac?
Frequently used as a component of multimodal analgesia in post-surgical patients, the use of injectable non-steroidal anti-inflammatory drugs (NSAIDs) such as ketorolac tromethamine have been shown to reduce opioid consumption by 25 to 45% and are relatively well tolerated, without negative cardiorespiratory effects, constipation, and addictive properties as with opioids.1-3 In widespread clinical use in its injectable and oral forms, ketorolac possesses both anti-inflammatory and analgesic activity and is considerably more potent than other NSAIDs.4,5 Approved by the U.S. Food and Drug Administration (FDA) in March 1990, ketorolac was the first approved parenteral NSAID in the U.S. for analgesia.6 The use of ketorolac, however, is limited to a 5-day time maximum as indicated by a boxed warning, due to an increased risk for gastrointestinal (GI) bleeding beyond that time frame.7 While the FDA’s boxed warning was later added, the initial duration of therapy recommendation was based on the lack of data evaluating ketorolac beyond the 5-day time frame.6 Due to the unclear origins of the 5-day recommendation, the evidence supporting this limit is a frequently asked question at the University of Illinois at Chicago (UIC) Drug Information Center.
After its introduction to clinical use in the nineties, ketorolac has produced more bleeding episodes than was anticipated based on premarketing studies.4 In the first 3 years of use after ketorolac was approved in 1990, 97 fatalities were reported, and more than half were associated with GI bleeding, with over 16 million patients receiving the drug. As a focus of regulatory concern due to the expected risks of ketorolac, a large post-marketing study was planned a priori, with a focus on GI and operative site bleeding outcomes.6 Based on the post-marketing surveillance data published in 1996 that showed a dose-dependent increase in clinically serious GI bleeds, ketorolac labeling was updated to alter dosing, duration, and age-based recommendations.4,6,7 At the time of the study, the drug’s U.S. labeling recommended an initial 60 mg dose, followed by 30 mg every 6 hours for up to 5 days of treatment. In many countries across the world, the use of ketorolac has been the subject of many regulatory hearings, with the European Medicines Evaluation Agency reducing the recommended starting dose to 10 mg, the maximum dose for nonelderly patients to 90 mg per day, and the duration of treatment with parenteral ketorolac to 2 days.4 The following is a summary of the evidence supporting the FDA’s boxed warning regarding the 5-day limit.
Evidence for the limitation of ketorolac use to 5 days
A retrospective closed cohort study published of 10,272 courses of parenteral ketorolac across 35 U.S hospitals evaluated treatment with matched patients who received 10,247 courses of parenteral opioid therapy.7 Patients were matched on the basis of hospital, admitting service (medical versus surgical), and study drug initiation date. All patients who received either intramuscular or intravenous ketorolac during the approximate 2-year data collection period were included in the exposed treatment group, regardless of whether they had received opioid therapy, and were matched to patients receiving parenteral opioid treatment. In the study, a ketorolac or opioid course of therapy was defined as the time from the first dose through the third day following the last dose of medication; if more than 3 days had elapsed, a new course was documented. Of the 9,900 ketorolac-exposed patients, only 328 (3.3%) received more than 1 course of treatment; 292, 28, and 8 patients received 2, 3, and 4 courses of treatment, respectively. Baseline characteristics between groups were similar, with slightly more women in the ketorolac group and fewer patients in the ketorolac group with a previous history of GI bleeding versus the opioid group. Based on data collected from chart review, overall rates of GI bleeding occurred in 4% of ketorolac versus 3.6% of opioid courses of therapy, with clinically important GI bleeding occurring in 2.1% versus 1.9% of patients. In the study, clinically important bleeding was defined as associated with documented hypotension or a hemoglobin level less than 80 g/dL or requiring 4 units of transfusion within one week of bleeding start. When the effects of age were evaluated on GI bleeding between ketorolac and opioid groups in patients 75 years of age and older, the rate of GI bleeding was significantly increased (odds ratio [OR], 1.66; 95% confidence interval [CI], 1.23 to 2.25), as well as rates of clinically important bleeding (OR, 1.72; 95% CI, 1.05 to 2.81), while no other age groups showed significant increases in bleeding risk. When operative site bleeding was evaluated across age groups, no significant increases were found. Based on the duration of therapy, treatment durations greater than 5 days in length more than doubled the rate of GI bleeding with ketorolac versus opioids (OR, 2.20; 95% CI, 1.36 to 3.57), and was even higher for clinically important bleeding (OR, 2.72; 95% CI, 1.22 to 6.10). The risk of GI bleeding was also determined to be dose-dependent, with patients exhibiting more GI bleeding than those receiving lower-dose courses. Among those over 65 years of age, doses of 105 to 120 mg/day more than doubled the risk of GI bleeding versus opioids (OR, 2.40; 95% CI, 1.37 to 4.21). Based on clinical trial data, it was determined that 1000 patients receiving ketorolac treatment would result in 11 cases of GI bleeding, of which 4 would be clinically important, and 8 cases of operative bleeding, of which 1 would be clinically important. When limiting treatment to those below 65 years of age at a maximum dose of 105 mg/day for a maximum of 5 days of treatment, the risks of GI bleeding and operative site bleeding were not increased (OR, 1.03; 95% CI; 0.80 to 1.34 and OR, 0.90; 95% CI, 0.82 to 0.98), respectively.
In addition to the 1996 cohort study, numerous studies have been published detailing the GI effects of ketorolac use.8-10 In a case-control study comprising 600 outpatients with a confirmed endoscopic diagnosis of gastroduodenal lesions matched with 6,000 community controls, prescription history was reviewed and found that use of an NSAID was not associated with a significant increase in GI lesion formation (OR, 1.3; 95% CI, 0.98 to 1.8).8 Out of the NSAIDs, ketorolac was the only agent associated with a significant risk of gastroduodenal lesion occurrence (OR, 4.2; 95% CI, 1.9 to 9.4), after adjustment for recent or prior gastrotoxic therapy, gastroprotective drugs, or any other drug. In most cases, the study found that ketorolac was administered for 6 days or less. A retrospective cohort study of 1,505 patients hospitalized for upper GI bleeding and/or perforation also found the use of ketorolac associated with a 5 times greater risk compared with other NSAIDs (relative risk [RR], 5.5; 95% CI, 2.1 to 14.4).9 In another cohort study of patients receiving NSAID therapy, ketorolac use, when administered over a median of 6 days was associated with the second highest rate of GI lesion development, and the highest rates of GI hemorrhage or perforation when compared to other NSAIDs.10
Several case reports have also reported on the risk of GI ulceration with intermittent or shorter durations of use.11,12 In the first case report, a 77-year-old female developed a perforated GI ulcer after 4 days of parenteral ketorolac treatment.11 In the second case report, a 39-year-old female who received intramuscular ketorolac at a dosage of 60 mg intermittently over a period of 2.5 months, developed gastric ulceration and subsequent GI perforation.12
The use of ketorolac in clinical practice has been well demonstrated in reducing the need for opioid therapy, however, its use is limited by its GI toxicity and duration of use. The current evidence for this limitation of use is supported by a large post-marketing surveillance study, which resulted in subsequent labeling updates, several cohort studies, and case reports. Greater risk of GI bleeding and/or ulceration with ketorolac use is associated most often with advanced age, increased dose, and longer durations of treatment.
- Martinez L, Ekman E, Nakhla N. Perioperative opioid-sparing strategies: Utility of conventional NSAIDs in adults. Clin Ther. 2019;41(12):2612-2628. doi:10.1016/j.clinthera.2019.10.002
- Kenny GN, McArdle CS, Aitken HH. Parenteral ketorolac: opiate-sparing effect and lack of cardiorespiratory depression in the perioperative patient. Pharmacotherapy. 1990;10(6 ( Pt 2)):127S-131S.
- Garimella V, Cellini C. Postoperative pain control. Clin Colon Rectal Surg. 2013;26(3):191-196. doi:10.1055/s-0033-1351138
- Macario A, Lipman AG. Ketorolac in the era of cyclo-oxygenase-2 selective nonsteroidal anti-inflammatory drugs: a systematic review of efficacy, side effects, and regulatory issues. Pain Med. 2001;2(4):336-351. doi:10.1046/j.1526-4637.2001.01043.x
- Fiedler MA. Clinical implications of ketorolac for postoperative analgesia. J Perianesth Nurs. 1997;12(6):426-433. doi:10.1016/s1089-9472(97)90006-x
- Strom BL, Berlin JA, Kinman JL, et al. Parenteral ketorolac and risk of gastrointestinal and operative site bleeding. A postmarketing surveillance study. JAMA. 1996;275(5):376-382.
- Ketorolac tromethamine. Package insert. Hikma Pharmaceuticals; 2021.
- Traversa G, Walker AM, Ippolito FM, et al. Gastroduodenal toxicity of different nonsteroidal antiinflammatory drugs. Epidemiology. 1995;6(1):49-54. doi:10.1097/00001648-199501000-00010
- García Rodríguez LA, Cattaruzzi C, Troncon MG, Agostinis L. 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;158(1):33-39. doi:10.1001/archinte.158.1.33
- Menniti-Ippolito F, Maggini M, Raschetti R, Da Cas R, Traversa G, Walker AM. 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):393-397. doi:10.1007/s002280050481
- Estes LL, Fuhs DW, Heaton AH, Butwinick CS. Gastric ulcer perforation is associated with the use of injectable ketorolac. Ann Pharmacother. 1993;27(1):42-43. doi:10.1177/106002809302700111
- Yarboro TL Sr. Intramuscular Toradol, gastrointestinal bleeding, and peptic ulcer perforation: a case report. J Natl Med Assoc. 1995;87(3):225-227.
Christie Denton, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
The information presented is current as August 22, 2022. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.