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SGEM#175: Dancing on the Ceiling with Ketorolac for Pain

SGEM#175: Dancing on the Ceiling with Ketorolac for Pain

Podcast Link: SGEM175

Date: April 20th, 2017

Reference: Motov 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 Dec 2016

Guest Skeptic: Dr. Ken Milne is a front line community emergency medicine physician passionate about skepticism, evidence based medicine and knowledge translation. He is also the moderator for Emergency Medical Abstracts, faculty member of Best Evidence in Emergency Medicine and creator of the Skeptics’ Guide to Emergency Medicine.

Case: A 37-year-old, presents to the emergency department with sudden onset right-sided flank pain, hematuria and vomiting. He rates his pain as 8/10 and is writhing around on the stretcher. He says it feels like his previous kidney stones. His vital signs are within normal limits.

You perform a quick bedside ultrasound, which reveals a normal aorta and mild right-sided hydronephrosis. You diagnose him with renal colic and he is requesting analgesia. He says morphine has made him nauseous in the past, but a shot of 30mg of ketorolac has helped. You decide to start by giving ketorolac and an anti-emetic. What dose of ketorolac do you give?

Background: Ketorolac is a commonly used non-steroidal anti-inflammatory drug (NSAID) used in the emergency department for treatment of moderate to severe acute pain (1)

Unlike opioid analgesics, NSAID dosing is limited by their “analgesic ceiling”, meaning there is a dose-analgesic response. Above certain doses, NSAIDs produce more side effects or harms, without providing additional analgesia (2). Previous literature suggests that the ketorolac analgesic ceiling dose is 10 mg, which is much lower than the doses of 30mg to 60 mg recommended in textbooks (3-7).

This is especially important as ketorolac has a greater gastrointestinal hemorrhage risk than other NSAIDs, and this appears to increase at higher doses (8) Furthermore, intramuscular doses of 15mg, 30mg and 60mg appear to increase post-operative bleeding (9-10).


Clinical Question: Does 10mg of ketorolac intravenously (IV) provide similar analgesic efficacy for treatment of acute pain compared to doses of 15mg or 30mg?


Reference: Motov 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 Dec 2016

  • Population: Adults aged 18 to 64 years of age presenting to the emergency department with acute flank, abdominal, back, musculoskeletal, headache or dental pain with an intensity of ≥5 on a numerical rating scale (NRS) going from zero to ten.
    • Exclusion criteria: Age ≥65, pregnancy or breastfeeding, active peptic ulcer disease, acute GI hemorrhage, known history of renal or hepatic insufficiency, allergy to NSAIDs, unstable vital signs (SBP < 90 or >180; heart rate < 50 or >150)
  • Intervention: 10mg, 15mg or 30mg of ketorolac intravenously
  • Control: None
  • Outcome:
    • Primary Outcome: Reduction in numeric rating scale scores at 30 minutes
    • Secondary Outcomes: Adverse events and rescue analgesia
Dr. Sergey Motov

Dr. Sergey Motov

Dr. Sergey Motov is the lead author of this paper. He is an Emergency Physician in the  Department of Emergency Medicine, Maimonides Medical Center in New York City.

Authors’ Conclusions: “Ketorolac has similar analgesic efficacy at intravenous doses of 10, 15, and 30 mg, showing that intravenous ketorolac administered at the analgesic ceiling dose (10 mg) provided effective pain relief to ED patients with moderate to severe pain without increased adverse effects”.

checklistQuality Checklist for Randomized Clinical Trial:

  1. The study population included or focused on those in the emergency department. Yes
  2. The patients were adequately randomized. Yes
  3. The randomization process was concealed. Yes
  4. The patients were analyzed in the groups to which they were randomized. Yes
  5. The study patients were recruited consecutively (i.e. no selection bias). No. Screening and enrolment were Monday to Friday, 8am to 8pm.
  6. The patients in both groups were similar with respect to prognostic factors. Unsure. There were many more patients with headaches in the 30mg group
  7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes and No. Providers, participants and data collectors were blinded but pharmacist, research manager and statistician were aware of group allocation.
  8. All groups were treated equally except for the intervention. Yes
  9. Follow-up was complete (i.e. at least 80% for both groups). Yes
  10. All patient-important outcomes were considered. Yes
  11. The treatment effect was large enough and precise enough to be clinically significant. Yes

Key Results: There were 240 patients enrolled in the study with 80 in each group. Mean age was around 40 years with about 2/3 being male. The mean pain score was in the mid seven’s out of ten.


Primary Outcome: No significant difference in the reduction of pain score from baseline across the three groups.


  • Primary Outcome:
    • 10mg Group: Reduced NRS from 7.7 to 5.2 (difference 2.5)
    • 15mg Group: Reduced NRS from 7.5 to 5.1 (difference 2.4)
    • 30mg Group: Reduced NRS from 7.8 to 4.8 (difference 3.0)
  • Secondary Outcomes:
    • No concerning adverse events with the most common adverse effects were dizziness, nausea and headache with no difference across the three doses.
    • No difference between the groups in need of rescue morphine at any time.

Exploratory outcomes showed no statistically significant differences in pain score reduction across the three groups from 15 to 120 minutes after ketorolac administration.

Screen Shot 2015-04-25 at 3.11.12 PM

We asked Sergey five questions about his study. Listen to the podcast on iTunes to hear his responses.

  1. Selection Bias: You did not enrol patients consecutively but rather from 8am-8pm Monday to Friday when an emergency department pharmacist was available for blinded medication preparation. Do you think this could have introduced some selection bias?
  2. Blinding: Providers, participants and data collectors were blinded but pharmacist, research manager and statistician were aware of group allocation. Do you think that could have introduced some bias?
  3. Primary Outcome: Why did you choose 30-minute pain scores as the primary endpoint? Why did you stop recording pain scales at two hours? Some may argue that the longer duration of action of ketorolac is one of its benefits.
  4. Intention-to Treat: Data was based on the intention to treat principle but technically it was not a pure intention-to treat analysis. Can you explain what you did to account for missing data and to fulfill this requirement?
  5. Single Center: This was done in large urban community teaching hospital with you as a pain treatment champion. Even your twitter handle is @PainFreeED. Do you think these results would apply to other practice environments without your leadership?

Comment on authors’ conclusion compared to SGEM Conclusion: We agree with the authors’ conclusion.


SGEM Bottom Line: Use 10mg IV ketorolac when treating moderate to severe pain in the emergency department.


Case Resolution: You give the patient 10mg IV of ketorolac, his pain improves from a 8/10 to 5/10 and he would like to go home. He is given a prescription for analgesic to take home and discharge instructions.

Clinical Application: Based on this high quality randomized control trail and other information, I am going to begin using 10mg IV ketorolac for the management of moderate to severe pain in the emergency department.

Dr. Ken Milne

Dr. Ken Milne

What do I tell my patient? I can see you are in a lot of pain. We are going to give you a powerful drug called ketorolac through the intravenous line. Traditionally doctors have used 30mg of this drug but a recent high quality study showed there is a ceiling to the effective dose and 10mg works just as well.

Keener Kontest: Last weeks’ winner was Melissa Pearson, an RN living in Houston, Texas pursuing her DNP but originally from Vancouver, BC. She knew James Lind was the Scottish physician who conducted the scurvy trial.

Listen to the SGEM podcast on iTunes for this weeks’ keener question. If you think you know the answer then send an email to TheSGEM@gmail.com with “keener” in the subject line. The first correct answer will receive a cool skeptical prize.

FOAM logoOther FOAMed:

 


Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.


References:

  1. Catapano MS. The analgesic efficacy of ketorolac for acute pain. J Emerg Med. 1996; 14(1): 67–75.
  2. Baker H. Lotus illustrated dictionary of medical. New Delhi: Lotus Press; 2006.
  3. Tintinalli JE, Stapczynski JS, Ma O, et al. Tintinalli’s Emergency Medicine Manual, 7e. New York, NY: McGraw-Hill Medical; 2012.
  4. US Food and Drug Administration. Toradol® oral (ketorolac tromethamine tablets). Roche Laboratories Inc. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019645s019lbl.pdf. Accessed February 17, 2016.
  5. Reuben SS, Connelly NR, Lurie S, Klatt M, Gibson CS. Dose-response of ketorolac as an adjunct to patient-controlled analgesia morphine in patients after spinal fusion surgery. Anesth Analg. 1998; 87(1): 98–102
  6. 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.
  7. Minotti V, Betti M, Ciccarese G, et al. A double-blind study comparing two single-dose regimens of ketorolac with diclofenac in pain due to cancer. Pharmacotherapy. 1998; 18(3): 504–508.
  8. 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.
  9. Gallagher JE, Blauth J, Fornadley JA. Perioperative ketorolac tromethamine and postoperative hemorrhage in cases of tonsillectomy and adenoidectomy. Laryngoscope. 1995; 105(6): 606–609.
  10. Cawthorn TR, Phelan R, Davidson JS, Turner KE. Retrospective analysis of perioperative ketorolac and postoperative bleeding in reduction mammoplasty. Can J Anaesth. 2012; 59(5): 466–472.
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  • Ken Milne

    Very honoured to have this episode picked as some of the best global #FOAMed this week. https://lifeinthefastlane.com/litfl-review-279/?utm_medium=feed&utm_source=twitter.com&utm_campaign=Feed:+LITFL

  • Ken Milne

    Very honoured to have this episode picked as some of the best global #FOAMed this week. https://uploads.disquscdn.com/images/5b7ab9834f172805a251f8c9c345a8c9ef562db7f8de5914ec0374607b29fb20.png

  • Kirsty Challen
  • SAEM EBM IG

    Excellent topic and nice job in the “driver’s seat” Chris Bond! Note that we also reviewed this manuscript in ACP Journal Club this month: http://annals.org/aim/article/2618401/patients-emergency-department-acute-pain-10-15-30-mg-ketorolac

    After listening to the interview, I have a question and a comment. My question is that during the interview Sergey describes the Intention to Treat analysis and notes data imputation for missing data – that confuses me. Intention to Treat or Per-Protocol analyses depend on the actual intervention received not the outcomes which is probably the missing data to which Sergey used data imputation. Can you please clarify what data imputation has to do with ITT analysis? I’m assuming that the treatment received (ketorolac dosing) was not the missing data that was imputed?

    My comment is that Sergey notes that ED providers are experts at acute and chronic pain management. I fully agree that ED providers are the best at acute pain management – that’s our job. I disagree that ED providers are best suited or content experts on chronic pain management. By default (lack of access to Pain Medicine, ready access to every ED), emergency medicine providers often manage chronic pain, but I think that the ED is a really poor choice for chronic pain and a system-level problem that needs solutions.

    Congrats on another terrific episode of the SGEM!

    Chris

    • Sergey

      Dear Chris,

      Thank you very much for your comments. I do apologize for the confusion. You are correct that ITT analysis of the results is based on the initial ( original) treatment assignments without any exclusion of patients after randomization. However, in order to fully perform the ITT analysis we needed to have a complete outcome data for all randomized subjects. But, in our trial we had patients missing as early as 15 min in each group for data collection ( pain scores). The missing data I was eluding to were the pain scores at pre-specified study times for patients who were missing and not the treatment received ( as you pointed out). Thus we used imputations to account for this so at the end we can still analyze and compare ( within and between groups) the original number of patients.
      I wholeheartedly agree with you regarding the fact that ED’s across the country is a really poor choice for patients with chronic pain. But since we do manage this patients, it is prudent for ED Doctors to acquire necessary knowledge and expertise in this field of pain management by providing safe and effective multimodal analgesia with combinations of non-pharmacological and pharmacological modalities.
      Thank you very much,
      Sergey

      • SAEM EBM IG

        Имеет смысл. Спасибо! Keep up the great work!!!

        • Sergey

          Whoa! You blew my mind! Thank you!

  • Shawn Dowling

    Chris/Sergey:

    I wonder if I can get both of your perspectives. In which clinical scenarios do you reach for ketorolac IV first over other NSAID’s?

    • Sergey

      The only indication for IV Ketorolac I use is the pain of renal colic origin that is associated with intractable vomiting.

      • Shawn Dowling

        Thx! I tend to reserve it for situations where they cannot tolerate PO and I think the NSAID is the preferred analgesic to give (renal colic, migrainers not responding to dopamine antagonist). I think it’s worth highlighting this because, and I think you would agree, that for the most part ketorolac is over-utilized in the ED when often ibuprofen would be equally as effective.

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