Comparison of Ketorolac at 3 Doses in Children With Acute Pain: Protocol for A Randomized Controlled Trial.

Background: Intravenous ketorolac is a potent nonopioid analgesic commonly used to treat vigorous pain in children and adults. Despite its widespread use in pediatric emergency settings, ketorolac dosing in children remains "off-label," with limited high-quality evidence to guide practice. Pharmacokinetic differences between children and adults suggest that lower ceiling doses adopted from adult practice may lead to suboptimal analgesia in pediatric populations. Inconsistent ketorolac dosing practices across centers reflect substantial clinical uncertainty. Amid efforts to reduce opioid use and provide effective nonopioid alternatives, rigorous pediatric trials evaluating ketorolac dosing are urgently needed.

Objective: The primary objective is to determine whether 2 lower-dose intravenous ketorolac strategies (0.25 mg/kg-30 mg or 0.5 mg/kg-10 mg) are noninferior to the standard dosing regimen (0.5 mg/kg-30 mg) in reducing mean pain scores at 60 minutes postadministration in children aged 6-17 years presenting with vigorous pain. The secondary hypothesis is that ketorolac 0.5 mg/kg up to 10 mg will be superior to 0.25 mg/kg up to 30 mg by at least the minimally important difference of 2.0 points on the verbal Numerical Rating Scale (vNRS).

Methods: The KETODOSE trial is a single-center, randomized, double-blind, double-dummy, noninferiority trial conducted at McMaster Children's Hospital. Eligible participants aged 6 to <18 years with vigorous pain (vNRS >4) are randomized in a 1:1:1 ratio to standard dosing or one of 2 low-dose ketorolac regimens. Study drugs are administered via intravenous push over 5 minutes. Pain scores are assessed at baseline, 30, 60, 90, and 120 minutes. The primary endpoint is the mean change in vNRS score at 60 minutes. Secondary outcomes include pain scores at other time points, time to effective analgesia, rescue analgesia requirements, opioid consumption, and adverse events. Caregiver perceptions regarding analgesic use are evaluated using a mixed-methods semistructured survey. A sample size of 180 participants (60 per group) provides 80% power to detect noninferiority within a margin of 1.0 on the vNRS, assuming an SD of 1.5. Intention-to-treat and per-protocol analyses will be performed.

Results: Recruitment is ongoing. Final analyses will be performed once follow-up is completed for all participants. Results will be disseminated through peer-reviewed publications, conference presentations, caregiver- and clinician-facing educational tools, and national knowledge mobilization networks.

Conclusions: The KETODOSE trial will provide urgently needed evidence to guide ketorolac dosing for acute pain in children. If lower-dose regimens are shown to be noninferior to standard dosing, this may promote safer prescribing practices, reduce adverse events, and support efforts to minimize pediatric opioid use, thereby improving acute pain management in pediatric emergency care.

Trial registration: ClinicalTrials.gov NCT05641363; https://clinicaltrials.gov/study/NCT05641363.

International registered report identifier (irrid): DERR1-10.2196/76554.