In this episode, I will discuss the analgesic ceiling dose of ketorolac.
Back in episode 151, I discussed a trial by Sergey Motov that demonstrated IV ketorolac has an analgesic ceiling dose of 10 mg. Recently, Ken Milne discussed this study on the Skeptics Guide to Emergency Medicine. Ken’s post on the subject led me to the lecture I had lost from freeemergencytalks.net where I first heard the concept of ceiling doses for NSAIDs from Dr. Larry Raney.
This analgesic ceiling dose of ketorolac was also established in several articles over 20 years ago. But the strangest thing happened on the way from the original studies to the FDA-approved prescribing information for ketorolac. Despite clear evidence that 10 mg of IV ketorolac was the ceiling dose, the FDA approved 15 and 30 mg doses instead. I am completely stumped as to how this happened – if anyone knows, please post in the comments below!
While the study by Motov is a popular one for discussion, I would also like to review the earlier studies where the analgesic ceiling dose of ketorolac was hiding in plain site:
This study in the Journal of Clinical Pharmacology compared 10, 30, and 90 mg of IM ketorolac with placebo in 126 patients with cancer pain. While all doses were more effective than placebo, there was no difference in effectiveness between 10, 30, or 90 mg of IM ketorolac.
1990 – Peirce et al
This study in Pharmacotherapy compared 2 or 4 mg IV morphine with 10 or 30 mg IV ketorolac in 125 women undergoing major abdominal gynecologic surgery. There was no statistical difference between any of the four groups in pain intensity difference, summed pain intensity difference, or total pain relief. The study did have a tremendous dropout rate of 90% from all groups at 3 hours due to inadequate pain control. This was likely because no pre or intraoperative analgesics were given.
1990 Brown et al
This study in Pharmacotherapy compared 2 or 4 mg IV morphine with 10 or 30 mg IV ketorolac in 122 patients who had undergone major surgery. Both doses of ketorolac were as effective as 4 mg morphine and more effective than 2 mg morphine in providing pain control. There was no difference in efficacy between 10 and 30 mg of ketorolac.
1990 Litvak & McEvoy
This comprehensive review in Clinical Pharmacology of ketorolac notes that a dose of 10 mg IM is as effective as 6 mg IM morphine.
This letter to the editor of the journal Anaesthesia points out that in the UK in 1993, the manufacturer of ketorolac (Syntex) recommended reducing the initial parenteral dose of ketorolac to 10 mg. This reduction was due to reports of dose-related serious effects including GI hemorrhage, perforation, and renal failure.
The most recent trial by Motov using IV ketorolac leaves no doubt about the analgesic ceiling dose.
The older studies seem to suggest that the analgesic ceiling holds for IM ketorolac. I asked if others agree with a ceiling for IM ketorolac on Twitter, and Dr. Motov responded:
— Sergey Motov (@painfreeED) April 23, 2017
The real question in my mind is what should be done with this knowledge of the ceiling dose and its contradiction with the FDA labeling for ketorolac or tertiary drug reference dosing recommendations? The FDA and manufacturer have little incentive to update prescribing information for an old generic drug like ketorolac.
Knowledge translation to individual clinicians is slow, and many clinicians will probably be hesitant to adopt lower dosing regimens given years of anecdotal experience with higher doses. One option to speed the adoption of lower doses of ketorolac is to use hospital P&T committees to automatically reduce all doses of ketorolac ordered to 10 mg.
Is this an option you would pursue? Do you have a different idea to speed adoption of this knowledge? Let me know in the comments below!
Given the known analgesic ceiling effect of ketorolac of 10 mg, should hospital P&T committees automatically reduce all doses to 10mg? — Pharmacy Joe ?? (@PharmacyJoe) April 23, 2017
— PW (@yousentwhohome) April 23, 2017
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