Ketorolac Analgesic Ceiling

In Review

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. 2017. 70(2):177-184.
PubMed • Full text • ClinicalTrials.gov

Clinical Question

In adults that present to Emerg with main complaint of management of moderate abdominal, flank, musculoskeletal, or headache pain, single dose ketorolac 10mg IV offers the same analgesia as 15mg or 30mg over 120 minutes.

Bottom Line

In this single dose dose comparison study, ketorolac 10mg IV may offer the same analgesia as higher single doses of ketorolac over the short term.

Major Points

Ketorolac, a common non-steroidal anti-inflammatory drug (NSAID), is available in both oral and parenteral formulations. Like the rest of its class, it is associated with dizziness, nausea, gastric irritation and bleeding, and renal insufficiency and injury. It likely also has a dose-ceiling, like other NSAIDs.

In this single centre, parallel-group, randomized trial, the investigators compared three single doses of intravenous ketorolac (10/15/30mg) and tracked effects over 2 hours. Analgesic effects were measured on a 10-point visual analog scale (VAS), demonstrating a decrease of 5.2 / 5.1 / 4.8 points, respectively. Between groups this was not statistically different. There was also no statistical difference between utilization of rescue medications or adverse events between the three doses. This trial suggests that lower doses may be as effective as higher doses of IV ketorolac but this did not assess duration of analgesia which may be prolonged by the higher doses.

There are several potential issues with the design of this trial, the first is that they attempted to do a dose comparison trial and a non-inferiority design may have better addressed this question; there was no comparison group so it is unclear what affect placebo may have played in both effectiveness or adverse events; and enrolling during the day, Monday to Friday, may have introduced selection bias in the patients included. The guidelines and medical practices recommend using the lowest, effective dose for medical management of any condition, this trial suggests that 10mg of IV ketorolac may be effective and should be utilized until a patient proves otherwise.

Guidelines

American Academy of Emergency Medicine White Paper on Acute Pain Management in the Emergency Department (adapted, 2017):

Non-opioid Pharmacological Management:

• Non-steroidal anti-inflammatory drugs (NSIAD) at lowest effective doses
  • Topical NSAIDs or other topical analgesics (eg. lidocaine patches) if systemic NSAID contraindicated
• Oral/rectal acetaminophen
• Sub-dissociative dose ketamine (SDK) used alone or as part of a multimodal analgesic approach
• consider intravenous lidocaine for specific conditions (renal colic, herpetic/post-herpetic neuralgia) in patients without contraindications
• trigger point injections with local anesthetics
• nitrous oxide, alone or as an adjunct

Design

• Single-centre, double-blind, parallel-group, randomized trial
• N=240
  • Ketorolac 10mg IV (n=80)
  • Ketorolac 15mg IV (n=80)
  • Ketorolac 30mg IV (n=80)
• Setting: single, urban, community teaching hospital
• Enrollment: March 2014 - Dec 2015, Monday to Friday 8am to 8pm
• Analysis: ITT
• Primary Outcome: reduction of pain score at 30 minutes

Population

Inclusion Criteria

• Adults (18-65 years old)
• Present to Emerg primary complaint of: acute flank, abdominal, musculoskeletal, or headache pain with an intensity ≥ 5 on VAS

Exclusion Criteria

• older than 65 years
• pregnancy or breastfeeding
• active peptic ulcer disease
• acute gastrointestinal hemorrhage
• known history of renal or hepatic insufficiency
• allergy to nonsteroidal anti-inflammatory drugs
• unstable vital signs, defined as: systolic blood pressure <90 or >180 mm Hg; pulse rate <50 or >150 beats/min), and
• patients having already received analgesic medication

Baseline Characteristics

Ketorolac 10mg Group displayed

• Demographics: mean age 41.5 years, 48.8% male
• Physiologic parameters: mean pain score 7.7, mean BP 129/75, HR 80, Respiratory rate 18/min, O2 saturation 98%
• Main complain: abdominal 40%, flank 38%, MSK 20%, headache 1%
• Duration of pain, mean: abdominal 52 hrs, flank 68 hrs, MSK 60 hrs, headache 48 hrs

Interventions

• ketorolac 10/15/30mg in 10 mL of 0.9% normal saline IV push over 1-2 minutes
• rescue analgesia provided 30 minutes after study drug with morphine 0.1mg/kg IV

Outcomes

Comparisons are ketorolac 10mg vs. ketorolac 15mg vs. ketorolac 30mg. unless otherwise stated

Primary Outcomes

Mean pain score

Baseline 7.73 vs. 7.54 vs. 7.8

15 min 6.04 vs. 5.76 vs. 5.87

30 min 5.14 vs. 5.05 vs. 4.81

60 min 4.6 vs. 4.11 vs. 4.14

90 min 4.09 vs. 3.84 vs. 3.56

120 min 3.74 vs. 3.54 vs. 3.46

Secondary Outcomes

Use of Rescue Medication, per time point

15 min 0% vs. 0% vs. 0%

30 min 5% vs. 4% vs. 5%

60 min 5% vs. 9% vs. 5%

90 min 9% vs. 5.5% vs. 10%

120 min 5% vs. 13% vs. 3%

Adverse Events

Observed adverse events over 120 minutes

Dizziness 17.5% vs. 20% vs. 15%

Nausea 11% vs. 14% vs. 10%

Headache 10% vs. 3% vs. 4%

Itching 0% vs. 1% vs. 1%

Flushing 0% vs. 1% vs. 0%

Criticisms

• Enrollment only occurred during banker's hours (due to avaialbility of study pharmacist to prepare blinded drug) but this may have led to selection bias.
• single centre
• Erial had no control arm, so placebo effect could not be ruled out
• ~19% of data points was missing due to patients either being out of Emerg for testing or discharged, intruducing bias
• Duration of study (2 hours) was insufficient to assess for long term adverse events nor longer duration of analgesia with higher doses (duration of action of ketorolac 4-6 hours)
• Available IV formulation is 30mg/mL so to provide the 10mg IV dose may produce a challenge or waste

Funding

• Unrestricted grant from the New York State Department of Health Empire Clinical Research Investigator Program
• Maimonides Research and Development Foundation