The Ketorolac Analgesic Ceiling

19 Jan
January 19, 2017

Ketorolac Analgesic CeilingBackground: Ketorolac is a commonly used parenteral analgesic in the Emergency Department (ED) for a variety of indications ranging from musculoskeletal injuries to renal colic. This non steroidal anti-inflammatory drug (NSAID) is available in oral, intranasal and parenteral routes. Ketorolac has a number of side effects including nausea, vomiting, gastrointestinal bleeding and renal insufficiency. The risk of GI bleeding appears to be related to the use of higher doses and prolonged use. As with all NSAIDs, the drug has an analgesic ceiling – the dose at which additional dosing will not provide additional analgesia but can lead to more side effects. The current FDA dosing is 30 mg intravenously and 60 mg intramuscularly for patients < 65 years of age. However, the necessity of these doses is unclear and prior studies have demonstrated efficacy of considerably lower doses. The use of lower doses, if effective, may mitigate the potential for harm.

Article: Motov S 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. PMID: 27993418

Clinical question: Do higher doses of IV ketorolac provide improved analgesia in the ED?

Population: Patients 18 – 65 years of age presenting to the ED with acute flank, abdominal, musculoskeletal or headache pain that was >/= 5 on a standard 10 point pain scale in whom the attending physician though ketorolac would be an appropriate medication choice.

Intervention: 10-, 15- or 30- mg doses of ketorolac prepared in identical syringes

Control: No Control Group

Outcome (Primary): Pain reduction at 30 minutes

Outcomes (Secondary): Rates and percentages of subjects experiencing adverse effects and requiring rescue analgesia

Design: Single-center, randomized, double-blind trial performed at a large urban ED.

Excluded:

  • Age > 65
  • Pregnancy or breastfeeding
  • Active peptic ulcer disease
  • Acute GI hemorrhage
  • Known renal or hepatic insufficiency
  • Allergy to NSAIDs
  • Unstable vital signs
  • Patients that had already received an analgesic

Primary Results:

  • Enrollment: 24o patients (80 in each group)
  • 312 patients approached, 72 refused to participate
  • All 240 patients included in analysis

Pain Reduction at 30 Minutes (Primary Outcome):

  • 80% power to detect a 1.3 point difference in pain score at 30 minutes
  • 10mg Group: Pain score 7.7 —> 5.2 (diff 2.5)
  • 15 mg Group: Pain score 7.5 —> 5.1 (diff 2.4)
  • 30 mg Group: Pain score 7.8 —> 4.8 (diff 3.0)
  • No statistically or clinically significant difference between doses

Secondary Outcomes:

  • Adverse Events
    • No significant events in any group
    • Common events were dizziness and nausea which were equal across groups
  • Need for rescue analgesia was not different across groups

Strengths:

  • Study asks a clinically important question with a patient centered outcome
  • Randomization conducted by computer generation and blinding was appropriate
  • Clinically relevant adverse events were tracked
  • For the primary endpoint, only 2 data points were missing out of 240 patients

Limitations:

  • Single center study decreasing external application of results
  • Convenience sampling used introducing selection bias
  • Study is too small to comment on rare or uncommon adverse events
  • The study investigates the analgesic ceiling effect but does not provide information regarding the anti-inflammatory ceiling.

Author’s 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.”

Our Conclusions:

This high-quality RDCT demonstrates that the analgesic ceiling for ketorolac appears to be 10 mg if given intravenously. Administration of higher doses is unlikely to improve analgesic results.

Potential Impact to Current Practice:

The results and conclusions of this study implore providers to embrace lower dosing of ketorolac than what is standardly employed (i.e. 30 mg IV). This study did not find an increase in adverse events with the higher dosing of ketorolac but, the study was too small to establish safety. Additionally, if there is no added benefit to analgesia of higher doses, higher doses only hold potential for harm.

Clinical Bottom Line:

Based on the best available literature at this time, providers should switch to giving 10 mg of ketorolac IV for acute pain in the ED.

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Post Peer Reviewed By: Salim Rezaie (Twitter: @srrezaie)

This post is cross-posted over at Core EM.

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Anand Swaminathan

Clinical Assistant Professor of Emergency Medicine at Bellvue/NYU
REBEL EM Associate Editor and Author

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8 replies
  1. António Gonçalves says:

    It’s interesting and potentially practice changing. But what about analgesia duration? I wouldn’t want the patient coming back with relapsing pain after 2 hours.

    Reply
    • Salim Rezaie says:

      Hi Antonio,
      Agreed…we really only know up to 2 hours, but if we can get pain controlled in ED, the standard is to transition to oral pain control as an outpatient for most things. I think this study helps show us that this is possible.

      Salim

      Reply
    • Anand Swaminathan says:

      Antonoio – oral dosing of ketorlac is typically 10 mg and duration is around 8 hours. I think we can extrapolate from that but you are right that we don’t know for sure.

      Reply
  2. Peter Reardon says:

    Hi Anand,

    The study data suggests an analgesic ceiling for Ketorolac and aligns with previous literature. However, it would be worthwhile to mention a few limitations with the methodology. The population was heterogenous with respect to type and duration of pain (notably more flank pain in the 10mg group and more long duration headaches in the 30mg group), which may have affected the results. Also, the outcome used was a continuous variable, and it’s unclear what proportion of patients met a clinically important reduction in pain. All told, the data certainly trends towards equal efficacy of the three doses, although I’d say it is difficult to draw any definitive conclusions from this study.

    Reply
    • Anand Swaminathan says:

      Peter – excellent points. I think based on the lack of any evidence suggesting that larger doses are beneficial along with this well-done study, we can make a change. The oral doses of the medication are considerably lower than parenteral which is quite unusual. The FDA approved doses (60 mg IM and 30 mg IV) don’t even match with the insert.
      It would be great to see more RCT data on this but I’m not sure we’ll get there.

      Reply
  3. shawn says:

    As a patient who has received ketoralac, by itself has no effect for my migraines. They should have done this study using a concoction of ativan, ketoralac, benadryl, zofran and fioricet. Then show how the reaction to it was based on the different dosages.

    Reply

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