Should Dose Capping Parenteral Ketorolac Be the Standard?

This article was collaboratively written with Elnaz Arabian and Moriah Elusta, fourth-year PharmD candidates at Chicago State University College of Pharmacy.

Ketorolac tromethamine is classified as a non-steroidal agent with potent analgesic and moderate anti-inflammatory properties.¹ Like other non-steroidal anti-inflammatory drugs (NSAIDs), ketorolac works on cyclooxygenase enzymes (COX) and inhibits prostaglandin synthesis. The systemic analgesic effects of ketorolac are higher than most other anti-inflammatory drugs, thus, the parenteral formulation of ketorolac is most commonly used for acute pain management. Recent literature has begun to question dosing of ketorolac used in clinical practice. Namely, does a higher dose of the drug provide more analgesic properties in comparison to lower doses and do higher doses increase the risk of side effects?

Like other drugs in this class, common side effects of ketorolac include such as headache, dizziness, nausea, constipation, and diarrhea.¹ The most troublesome concern with ketorolac administration is development of gastrointestinal bleeding, specifically in patients older than 65 years of age, who are receiving daily doses greater than 60 mg/day for up to 5 days, and have a history of GI perforation, ulcers, or bleeding. Comparing ketorolac to opioids, ketorolac exhibits a higher risk of bleeding. According to Gallagher and colleagues, the rate of bleeding is higher in patients who are given ketorolac (10.1%) than patients who are given opioids (2.2%) after tonsillectomy.² In addition, there are risks of renal and hepatic dysfunction along with worsening of congestive heart failure. The risk increases with higher doses of ketorolac.³

One of the first studies evaluating various ketorolac dosing regimens was a double-blinded trial conducted by Staquet that assessed the efficacy of ketorolac in individuals with moderate to severe cancer pain.⁴ Three dose strategies were utilized including intramuscularly administered doses of 10, 30, and 90 mg. The study revealed that there were no differences in the dosing regimens of ketorolac to alleviate cancer related pain. A dose of 10 mg was effective in relieving pain and associated with fewer side effects. This began the basis for the ceiling effect hypothesis of ketorolac at 10 mg. This analgesic ceiling dose delineates that increasing the dose does not increase the efficacy or analgesic effect of the drug, but predisposes patients to higher risk of adverse effects.

Further studies have corroborated this hypothesis. A study conducted by Reuben and colleagues studied different doses of ketorolac as an adjunct to morphine sulfate in patients who had spinal stabilization surgery.⁵ It was a randomized, blinded study in which the patients received placebo or ketorolac at 5 mg, 7.5 mg, 10 mg, 15 mg, or 30 mg. The results showed increasing the doses of ketorolac did not increase the efficacy of the drug, and the 7.5 mg dose had the same efficacy as larger doses of ketorolac. Minotti and colleagues compared the analgesic effects among intramuscular ketorolac 10 mg, intramuscular ketorolac 30 mg, and diclofenac 75 mg in cancer patients.⁶ In the double-blinded study, the results showed no difference in pain relief among all three groups. Other studies have found similar results regarding ketorolac dosing. ^7,8

The most recent study on the subject, conducted by Motov and colleagues evaluated the analgesic efficacy of 3 doses of intravenous ketorolac including 10, 15, and 30 mg doses in 240 patients in the emergency department who suffered from acute pain.⁹ This was a randomized, double blind clinical trial to determine how effective the three doses of intravenous ketorolac were in patients between 18 and 65 years old. The study found that patients showed a reduction in pain within thirty minutes and ketorolac was very similar in efficacy for all three doses.

In clinical practice, however, ketorolac is often dosed higher than the analgesic ceiling dose. A single center study conducted by Soleyman-Zomalan and colleagues aimed to investigate the patterns of ketorolac dosing conducted by emergency physicians and whether they follow the analgesic ceiling dose hypothesis.¹⁰ Data was collected over ten years in an electronic medical record within an urban community. The data indicated that ketorolac was prescribed above the 10 mg ceiling dose in 97% of patients receiving intravenous doses and 96% of patients receiving intramuscular dosages.

In conclusion, ketorolac can be used as an alternative to or in combination with opioids to decrease the use of opioids. Based on the available literature, there is limited evidence to support utilization of higher doses of ketorolac with data indicating that 10 mg is the ceiling dose in terms of efficacy and brings about the least side effects. Based on the formulations of ketorolac currently available in the United States (15 mg, 30 mg, and 60 mg vials), it may be prudent to recommend a 15 mg max dose based on the available evidence and ease of administration compared to a 10 mg dose. It is important to consider the role of pharmacists in evaluating the doses of ketorolac prescribed and working with prescribers to consider capping doses at 15 mg due to the available evidence regarding efficacy and safety.

References

1. Ketorolac Tromethamine Injection [package insert]. Schaumburg, IL: SAGENT Pharmaceuticals; 2015.

2. Gallagher JE, Blauth J, Fornadley JA. Perioperative Ketorolac tromethamine and postoperative hemorrhage in cases of tonsillectomy and adenoidectomy. Laryngoscope. 1995;105:606-609.

3. Rodriguez L, Cattaruzzi C, Troncon M, 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;158:33-39

4. 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.

5. Reuben SS, Connelly NR, Lurie S, et al. Dose-response of ketorolac as an adjunct to patient-controlled analgesia morphine in patients after spinal fusion surgery. Anesth Analg.1998;87:98-102.

6. Minotti V, Betti M, Ciccarese G, Fumi G, Tonato M, Del Favero A. A double-blind study comparing two single dose regimens of ketorolac with diclofenac in pain due to cancer. Pharmacotherapy.1998,18:504-508.

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

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

9. 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. 2016;(16):31244-31246

10. Soleyman-Zomalan E, Motov, S, Likourezos A, et al. Patterns of ketorolac dosing by emergency physicians. World J Emerg Med. 2017;8(1):43—46.