(March 2023)

Ketorolac is an NSAID with a potent analgesic effect that is very frequently indicated in the ED worldwide to treat moderate to severe acute pain. 

• There are many formulations available, including oral, sublingual, intravenous, intramuscular, intranasal and ophthalmic. 

• The US-FDA labeling recommends usage only for moderate to severe pain (defined as requiring analgesia at the opioid level), and for a short period of time of no more than 5 days to reduce NSAIDs adverse effects (15, 16, 17).

• Ketorolac reduces opioid requirements (12), and it may have a similar potency than meperidine and morphine in certain doses, sparing the opioids adverse effects (6, 11). 

• CMax: 40-45min. Time to peak effect: 1 to 2 hours (4).

Adult dose for acute moderate to severe pain

• IV: 10 to 30mg every 6 hours IV (max 120mg/day)*

• PO: 10mg every 6 hours PO (max 40mg/day)

• Nasal spray: 31.5 mg SPRIX (one 15.75 mg spray in each nostril) every 6 to 8 hours (max  126 mg/day –four doses–).
  
  

Dosing considerations:

• *For adults ≥65 years: 10-15mg every 6 hours (max 60mg/day).

• Ketorolac can be administered as a bolus injection.

Adult dose for acute moderate to severe pain

• IV: 10 to 30mg every 6 hours IV (max 120mg/day)*

• PO: 10mg every 6 hours PO (max 40mg/day)

• Nasal spray: 31.5 mg SPRIX (one 15.75 mg spray in each nostril) every 6 to 8 hours (max  126 mg/day –four doses–). 

Dosing considerations:

• *For adults ≥65 years: 10-15mg every 6 hours (max 60mg/day).

• Ketorolac can be administered as a bolus injection.

• US-FDA labeled (16, 17)

  • Short-term management of moderate to severe acute pain that requires analgesia at the opioid level

• Off-label

  • Mild pain

  • Chronic pain

• Most studies comparing different doses of ketorolac have been conducted outside the emergency department. There are trials in progress that will provide valuable information on this issue (eg. Clinical Trial NCT03464461). 

• In summary, there is no available evidence to support a 60-90mg parenteral dose for acute pain alleviation, on the contrary, studies have shown a similar efficacy of 15mg versus 60mg intramuscular ketorolac for acute musculoskeletal pain (13), and multiple studies tend to establish an analgesic ceiling of parenteral administration of 10 to 15mg. 

• Undifferentiated pain in the ED
  Data comparing IV ketorolac 10 vs 15 vs 30mg suggests that the analgesic ceiling of IV ketorolac is 10mg for acute pain management in the ED (10), and many experts in emergency medicine support this dosing. 

• • Postoperative pain

    • Studies comparing 10 versus 30mg have shown similar results (2, 3). 

    • 2.5 and 5mg versus higher doses, have shown that a ≥10mg dose is more effective than lower doses (2). 

• Cancer pain
  Different dosing schemes of IM ketorolac (10 vs 30 vs 90mg) have shown no efficacy differences for cancer pain, being all superior to placebo (1). 

• It reduces opioid requirements about 25 to 45% in postoperative pain (8, 12). Added to these benefits is avoiding the adverse effects of opioids. 

• It may have a comparable analgesic effect compared with morphine for acute long bone fractures (5, 11), and postoperative pain (2, 3). 

• A recent review of 32 studies about perioperative opioid-sparing strategies shows that this outcome has been achieved by the most commonly prescribed NSAIDs, without a patent advantage of one over another (12):

NSAID Opioid reduction (%)

Ketorolac 9-66

Diclofenac 17-50

Ibuprofen 34-66

Ketoprofen 36-50

Meloxicam No benefit (1 study)

• All NSAIDs have warnings for cardiovascular thrombotic events (myocardial infarction, stroke) and gastrointestinal (bleeding, ulceration, perforation) adverse events, which can occur early in therapy. Ketorolac has been associated with acute kidney failure and transient hyperkalemia, especially when risk factors are present ( age ≥65 years, renal disease, concomitant use of nephrotoxic agents). It is not recommended in patients with chronic kidney disease. 

  • Thus, it is appropriate to recommend using it in the lowest effective dose for the shortest duration possible. 

• Adverse effects of ketorolac
  A meta-analysis that assessed efficacy and adverse effects of a single dose of ketorolac compared with opioids or other NSAIDs for post-operative pain found that overall adverse events may occur at a slightly higher rate with ketorolac than with other NSAIDs, and a rate similar to opioids. Nonetheless, there was insufficient high-quality data to determine whether rates of bleeding, renal dysfunction, or cardiovascular events were different with ketorolac, compared with other NSAIDs (14). 

• Black Box Warning - full text (16, 17): 

  • Ketorolac tromethamine, a nonsteroidal anti-inflammatory drug (NSAID), is indicated for the short-term (up to 5 days in adults) management of moderately severe acute pain that requires analgesia at the opioid level. Oral ketorolac tromethamine is indicated only as continuation treatment following intravenous or intramuscular dosing of ketorolac tromethamine, if necessary. The total combined duration of use of oral ketorolac tromethamine and ketorolac tromethamine injection should not exceed 5 days.

  • Ketorolac tromethamine is not indicated for use in pediatric patients and it is NOT indicated for minor or chronic painful conditions. Increasing the dose of ketorolac tromethamine beyond the label recommendations will not provide better efficacy but will increase the risk of developing serious adverse events.

  • Gastrointestinal risk
    Ketorolac tromethamine can cause peptic ulcers, gastrointestinal bleeding and/or perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Therefore, ketorolac tromethamine is CONTRAINDICATED in patients with active peptic ulcer disease, in patients with recent gastrointestinal bleeding or perforation, and in patients with a history of peptic ulcer disease or gastrointestinal bleeding. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS).

  • Cardiovascular Thrombotic Events

    • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (see WARNINGS and PRECAUTIONS).

    • Ketorolac tromethamine is CONTRAINDICATED in the setting of coronary artery bypass graft (CABG) surgery (see CONTRAINDICATIONS and WARNINGS).

  • Renal Risk
    Ketorolac tromethamine is CONTRAINDICATED in patients with advanced renal impairment and in patients at risk for renal failure due to volume depletion (see WARNINGS).

  • Risk of Bleeding

    • Ketorolac tromethamine inhibits platelet function and is, therefore, CONTRAINDICATED in patients with suspected or confirmed cerebrovascular bleeding, patients with hemorrhagic diathesis, incomplete hemostasis and those at high risk of bleeding (see WARNINGS  and PRECAUTIONS).

    • Ketorolac tromethamine is CONTRAINDICATED as prophylactic analgesic before any major surgery. 

  • Hypersensitivity
    Hypersensitivity reactions, ranging from bronchospasm to anaphylactic shock, have occurred and appropriate counteractive measures must be available when administering the first dose of ketorolac tromethamine injection (see CONTRAINDICATIONS and WARNINGS). Ketorolac tromethamine is CONTRAINDICATED in patients with a previously demonstrated hypersensitivity to ketorolac tromethamine or allergic manifestations to aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs).

  • Intrathecal Or Epidural Administration
    Ketorolac tromethamine is CONTRAINDICATED for intrathecal or epidural administration due to its alcohol content.

  • Risk During Labor And Delivery
    The use of ketorolac tromethamine in labor and delivery is CONTRAINDICATED because it may adversely affect fetal circulation and inhibit uterine contractions.

  • Concomitant Use With NSAIDs
    Ketorolac tromethamine is CONTRAINDICATED in patients currently receiving aspirin or NSAIDs because of the cumulative risk of inducing serious NSAID-related side effects.

  • Special Populations
    Dosage should be adjusted for patients 65 years or older, for patients under 50 kg (110 lbs.) of body weight (see DOSAGE AND ADMINISTRATION) and for patients with moderately elevated serum creatinine (see WARNINGS). Doses of ketorolac tromethamine injection are not to exceed 60 mg (total dose per day) in these patients.

  • Dosage And Administration
    Ketorolac Tromethamine Tablets

    • Ketorolac tromethamine tablets are indicated only as continuation therapy to ketorolac tromethamine injection, and the combined duration of use of ketorolac tromethamine injection and ketorolac tromethamine tablets is not to exceed 5 (five) days, because of the increased risk of serious adverse events.

    • The recommended total daily dose of ketorolac tromethamine tablets (maximum 40 mg) is significantly lower than for ketorolac tromethamine injection (maximum 120 mg) (see DOSAGE AND ADMINISTRATION).
      
      

• High-dose short-term use of ketorolac (<14 days of more than 120mg/day) is associated with spinal fusion non-union (9). The manufacturer recommends a dose not higher than 120mg/day (intravenous) and 60mg/day (oral).

Pregnancy risk classification

• AU TGA pregnancy category: C

• US FDA pregnancy category:

  • C prior to 30 weeks gestation

  • D starting at 30 weeks gestation

1. Staquet MJ. A double-blind study with placebo control of intramuscular ketorolac tromethamine in the treatment of cancer pain. J Clin Pharmacol. 1989;29(11):1031-1036. doi:10.1002/j.1552-4604.1989.tb03274.x
   Pubmed

2. Brown CR, Moodie JE, Wild VM, Bynum LJ. Comparison of intravenous ketorolac tromethamine and morphine sulfate in the treatment of postoperative pain. Pharmacotherapy. 1990;10(6 ( Pt 2)):116S-121S.
   Pubmed

3. Peirce RJ, Fragen RJ, Pemberton DM. Intravenous ketorolac tromethamine versus morphine sulfate in the treatment of immediate postoperative pain. Pharmacotherapy. 1990;10(6 ( Pt 2)):111S-115S.
   Pubmed

4. Resman-Targoff BH. Ketorolac: a parenteral nonsteroidal antiinflammatory drug. DICP. 1990;24(11):1098-1104. doi:10.1177/106002809002401115
   Pubmed

5. Rainer TH, Jacobs P, Ng YC, et al. Cost effectiveness analysis of intravenous ketorolac and morphine for treating pain after limb injury: double blind randomised controlled trial. BMJ. 2000;321(7271):1247-1251. doi:10.1136/bmj.321.7271.1247
   BMJ (Open Access)

6. Veenema KR, Leahey N, Schneider S. Ketorolac versus meperidine: ED treatment of severe musculoskeletal low back pain. Am J Emerg Med. 2000;18(4):404-407. doi:10.1053/ajem.2000.7314
   Pubmed

7. Dula DJ, Anderson R, Wood GC. A prospective study comparing i.m. ketorolac with i.m. meperidine in the treatment of acute biliary colic. J Emerg Med. 2001;20(2):121-124. doi:10.1016/s0736-4679(00)00311-5
   Pubmed

8. Cepeda MS, Carr DB, Miranda N, Diaz A, Silva C, Morales O. Comparison of morphine, ketorolac, and their combination for postoperative pain: results from a large, randomized, double-blind trial. Anesthesiology. 2005;103(6):1225-1232. doi:10.1097/00000542-200512000-00018
   Anesthesiology (Open Access)

9. Li Q, Zhang Z, Cai Z. High-dose ketorolac affects adult spinal fusion: a meta-analysis of the effect of perioperative nonsteroidal anti-inflammatory drugs on spinal fusion. Spine (Phila Pa 1976). 2011;36(7):E461-E468. doi:10.1097/BRS.0b013e3181dfd163
   Pubmed

10. Motov S, Yasavolian M, Likourezos A, et al. Comparison of Intravenous Ketorolac at Three Single-Dose Regimens for Treating Acute Pain in the Emergency Department: A Randomized Controlled Trial. Ann Emerg Med. 2017;70(2):177-184. doi:10.1016/j.annemergmed.2016.10.014
    Pubmed

11. Masoumi B, Farzaneh B, Ahmadi O, Heidari F. Effect of Intravenous Morphine and Ketorolac on Pain Control in Long Bones Fractures. Adv Biomed Res. 2017;6:91. Published 2017 Jul 28. doi:10.4103/2277-9175.211832
    Pubmed Central (Open Access)

12. 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
    Pubmed

13. Turner NJ, Long DA, Bongiorno JR, et al. Comparing two doses of intramuscular ketorolac for treatment of acute musculoskeletal pain in a military emergency department. Am J Emerg Med. 2021;50:142-147. doi:10.1016/j.ajem.2021.07.054
    Pubmed

14. McNicol ED, Ferguson MC, Schumann R. Single-dose intravenous ketorolac for acute postoperative pain in adults. Cochrane Database Syst Rev. 2021;5(5):CD013263. Published 2021 May 17. doi:10.1002/14651858.CD013263.pub2
    Pubmed Central (Open Access)

15. DailyMed. NIH-NLM (National Institutes of Health - National Library of Medicine). Label: SPRIX- ketorolac tromethamine spray, metered. Updated March 2022. Accessed March 3, 2023.
    DailyMed - ketorolac intranasal

16. DailyMed. NIH-NLM (National Institutes of Health - National Library of Medicine). Label: Ketorolac Tromethamine tablet, film coated. Updated July 2021. Accessed March 2, 2023.
    DailyMed  - ketorolac tablets

17. DailyMed. NIH-NLM (National Institutes of Health - National Library of Medicine). Label: Ketorolac Tromethamine injection, solution. Updated October 2021. Accessed March 2, 2023.
    DailyMed  - ketorolac injection