In a follow-up to his recent Annals paper, Dr. Sergey Motov discusses optimal dosing of Ketorolac and a functional approach to measuring pain in the emergency department.
Interview by Nicholas Genes, MD, PhD
EPM: Congratulations on your recent Annals paper, where you show 10mg of IV ketorlac led to the same pain relief in ED patients as 15mg or 30mg. What made you look into appropriate ketorolac dosing?
Sergey Motov: Appropriate ketorolac dosing, based on the concept of an analgesic ceiling, has been promulgated by some of our colleagues in EM for the past 20 years, but without much attention or acceptance. I learned of it in 2006, when my mentor Dr. Joe Lex introduced this concept to me and pointed towards some remarkable papers by Michael Catapano and Laurence Raney.
What Dr. Catapano wrote about proper dosing of ketorolac in JEM back in 1996, in my opinion, should have been a practice-changing work. He pointed out a few prescient things that included an avoidance of ketorolac’s supra-analgesic dosing (doses greater than 10 mg PO or 30 mg IV) due to lack of additional pain relief and potential to cause more side effects: slow onset of analgesia (30-60min), pain upon injection, and lack of analgesia in 25% of patients upon administration of 60 mg of IM ketorolac. Those anecdotal reports of fast onset of pain relief from IM ketorolac injection are probably due to a placebo effect of the injection. Lastly, he drew on studies and practice from other specialties to reinforce the idea that we’re dosing IV and IM ketorolac too high.
Dr. Raney’s article in EMedHome in 2001 was truly eye-opening for me. This brilliantly written work emphasized several concepts that changed my practice of dosing NSAIDs as a class of analgesics. For example, in the setting of acute pain, the degree of tissue inflammation is not large enough to require a full anti-inflammatory dose of NSAIDs; thus, the analgesic ceiling dosing is appropriate to control pain and inflammation. He argued that in the ED there’s no indication to exceed the ceiling dose; a supra-ceiling regimen does not add any additional pain relief and increases the risk of adverse events. Unfortunately, neither of these papers got the coverage they deserved.
Finally, there was a paper by Drs. Arora, Wagner and Herbert that was published in 2007 in CJEM, debunking the myths of analgesic superiority of IV/IM ketorolac to PO ibuprofen. This paper got some attention. The paper reviewed evidence from ED trials that demonstrated similar analgesic efficacy between IM ketorolac and PO Ibuprofen, with slightly faster onset of analgesia with IV ketorolac. The authors also noted that in patients with acute painful conditions who can tolerate PO, ibuprofen should be the NSAID of choice. This is because of ibuprofen’s similar analgesic efficacy, lower cost and better safety profile.
The gem of the paper was an observation that ketorolac is the only analgesic whose parental dosing is higher—actually 3 to 6 times higher—than its oral equivalent. The package insert clearly lists a dosing of 10mg PO, 30mg IV and 60mg IM. That is mind-blowing. And as the authors stated, there’s never been a satisfactory explanation for this. Maybe the original investigators were trying to lower the risk of GI bleed with a lower PO dose, but that still leads to questions about optimal dosing for pain, particularly for parenterally administered ketorolac.
These papers are the origins for our recent trial. I think every practicing emergency physician should go back and re-read these classic papers. The data has always been there, but didn’t get the credit it deserved. My research team and I give all the credit to these amazing authors who originally did this research, as well as Dr. Chris Bond who has been a big advocate of utilizing the analgesic ceiling dose of NSAIDs for managing acute pain in the ED. His series on optimum and safe NSAID dosing is an invaluable read for all our colleagues. (http://socmob.org/2013/02/nsaids-part-2-the-ceiling-effect/ )
EPM: Well, there’s the analgesic ceiling and the anti-inflammatory ceiling. Aren’t patients benefiting from the anti-inflammatory effect of NSAIDs at these high doses?
Motov: There’s no benefit to exceed the analgesic ceiling dose of NSAIDs for treating acute painful condition in the ED. Inflammation seen in the acute setting is effectively blocked with the analgesic ceiling dose. It’s true that NSAID’s anti-inflammatory properties do not have a ceiling, i.e, the only limiting factor for pure anti-inflammatory (3-6 higher) dosing regimens is the severity of side effects. But in the acute setting, inflammation doesn’t equal analgesia. Benefits of the anti-inflammatory effect of NSAIDs at these high doses, such as in patients with chronic rheumatoid arthritis, must be weighed against the serious, at times deadly, side effects.
But let’s take renal colic patients as an example. In renal colic, we’re seeking pain relief but also some anti-inflammatory effects from NSAIDs, in order to decrease distension and intraluminal pressure in the renal pelvis and ureter, as well as decrease edema, inflammation and ureteral contractility. All this can be achieved with an analgesic ceiling dosing regimen. -The magnitude of the ureteral inflammation simply does not warrant larger doses.
Also remember, as far as NSAID anti-inflammatory effects go, ketorolac is a lousy anti-inflammatory agent. It’s less effective than ibuprofen, ketoprofen or diclofenac for inflammation. The anti-inflammatory effect of ketorolac is achieved only at doses higher than those needed for analgesia. So if you’re really looking for an inflammatory change, choose something other than ketorolac instead of dosing ketorolac above its analgesic ceiling.
EPM: So in your paper, you looked at pain scale scores in your ED patients with a wide variety of complaints, 30 minutes after receiving IV ketorolac. Your groups of 80 patients each (randomized, about 40% men, average age around 40) was double-blinded to receive either10mg, 15mg or 30 mg of IV ketorolac. They had pain score improvement from the high 7’s to around 5, at the 30 min mark. The need for rescue morphine wasn’t any different in the groups, either. Some questions on the study design: Why not just focus on the traditional applications for ketorolac? And why hone in on pain relief at the 30 minute mark?
Motov: Ketorolac is typically the first-line analgesic for renal colic and frankly, based on all the prior research, that is the only indication that ketorolac should be used in the ED. However, there are large variations of ketorolac use amongst our colleagues that include headache, acute musculoskeletal pain, pain related to pyelonephritis, pelvic inflammatory disease and even biliary colic. That is why we didn’t want to exclude any complaint. We wanted this study to be as broad as possible and as close to real clinical practice. But in practicality, ketorolac administration in the aforementioned situations is indicated only for patents who cannot tolerate oral NSAID’s and are clearly in need of this analgesic.
As for the timing, checking pain scores at the 30 minute mark is standard in many research studies and has relevance to us in the ED. Specifically for intravenous ketorolac, the onset of analgesia begins at the 10 min mark, with peak of analgesic efficacy at 1-2 h. That is why we used a change in pain score via Numeric Rating Scale [NRS] at 30 min as the main outcome and subsequently followed patients up to 120 min. One of the limitations of the using NRS is that the change from high 7’s to 5 does not give a reader any information about the willingness of patients to accept that degree of change in pain intensity. Unfortunately, that is one of the biggest disadvantages of using numerical values for pain assessment in clinical practice and even in research.
EPM: You’re not a fan of “the fifth vital sign,” in clinical practice?
Motov: This whole “fifth vital sign” thing is plain awful. It’s been forced upon practicing ED doctors by several prominent organizations and agencies to meet certain metrics or benchmarks. These numerical values increased visibility of pain but did not affect the quality of pain management. I am all for frequent assessments and re-assessments of pain in ED patients, but I’m not for assigning a number to pain. It is impossible to assign a numerical value in order to objectify a purely subjective, intimate, individual experience such as pain. For research purposes, we use uni-dimensional pain scales as they are easy to implement, reproduce and repeat at different points of time. These scales, however, do not give us any information about the quality of pain or level of acceptance by patients. As an example, if we ought to use uni-dimensional pain scales, is a change from 10 to 8 the same as a change from 3 to 1? Both have a drop of 2, but I think you’d agree there’s a difference in clinical significance. Multi-dimensional pain scales exist, but they are fairly cumbersome and may not be practical to use in the ED due to their length.
I am a firm advocate for ED pain assessments based on patient’s functionality status and subsequent need for analgesia rather than simply on the basis of a patient’s reported pain score.
My goal in the ED is to get patients back to their regular daily activities by engaging them in shared-decision making about analgesics and the level of pain are they willing to accept that would not interfere with their ability to return to their normal functioning. It allows me to use language patients can understand or relate to and let me gauge progress over time.
EPM: Last time we spoke, you mentioned a far-reaching goal for making resources available to ED providers, about alternatives to opioids for a variety of common emergencies. Does this paper fit into that vision?
Motov: IV ketorolac is useful in renal colic patients who can’t tolerate PO either as a single agent or in combination with other opioid and non-opioid analgesics. I am convinced that we are over-utilizing ketorolac in our EDs, and I am advocating for broader use of analgesic ceiling doses of Ibuprofen as supported by prior research. We do, however, need to study the impact of a single analgesic and supraanalgesic dosing regimens of ketorolac in the ED on renal functions and rates of gastrointestinal hemorrhage and cardiovascular effects (like worsening CHF, etc.)
EPM: What’s next for your research?
Motov: As you know, I am a big proponent of non-opioid analgesia when feasible. Specifically, my research team is looking into non-opioid analgesic modalities for renal colic patients. You and I have discussed lidocaine for renal colic before. Lidocaine’s effect on the ureter makes sense, and there are two trials showing a single IV dose of 1.5mg/kg is effective and safe. We are conducting a trial comparing a combination of IV lidocaine and ketorolac to both agents alone in patients with renal colic. We are also working on a study evaluating the comparative rates of opioid prescribing before and after implementation of an opioid reduction initiative in our ED.
EPM: Ambitious stuff! I’m looking forward to our next conversation.
Motov: Me too. Thank you very much.