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Is intranasal ketamine (1.5 mg/kg) noninferior to intranasal fentanyl (2 µg/kg) for reducing moderate to severe pain in children aged 8 to 17 years with traumatic extremity injuries?
In this noninferiority randomized clinical trial of 90 children presenting to emergency departments with pain due to traumatic limb injury, intranasal ketamine was noninferior to intranasal fentanyl for pain relief, with mean reductions in visual analog scale pain scores of 30.6 mm and 31.9 mm, respectively, at 30 minutes after intervention.
Ketamine provides effective analgesia that is not inferior to fentanyl, although participants who received ketamine had an increase in adverse events that were minor and transient; intranasal ketamine may be an appropriate alternative to opioids for pain associated with acute extremity injuries.
Timely analgesia is critical for children with injuries presenting to the emergency department, yet pain control efforts are often inadequate. Intranasal administration of pain medications provides rapid analgesia with minimal discomfort. Opioids are historically used for significant pain from traumatic injuries but have concerning adverse effects. Intranasal ketamine may provide an effective alternative.
To determine whether intranasal ketamine is noninferior to intranasal fentanyl for pain reduction in children presenting with acute extremity injuries.
Design, Setting, and Participants
The Pain Reduction With Intranasal Medications for Extremity Injuries (PRIME) trial was a double-blind, randomized, active-control, noninferiority trial in a pediatric, tertiary, level 1 trauma center. Participants were children aged 8 to 17 years presenting to the emergency department with moderate to severe pain due to traumatic limb injuries between March 2016 and February 2017. Analyses were intention to treat and began in May 2017.
Intranasal ketamine (1.5 mg/kg) or intranasal fentanyl (2 µg/kg).
Main Outcomes and Measures
The primary outcome was reduction in visual analog scale pain score 30 minutes after intervention. The noninferiority margin for this outcome was 10.
Of 90 children enrolled, 45 (50%) were allocated to ketamine (mean [SD] age, 11.8 [2.6] years; 26 boys [59%]) and 45 (50%) to fentanyl (mean [SD] age, 12.2 [2.3] years; 31 boys [74%]). Thirty minutes after medication, the mean visual analog scale reduction was 30.6 mm (95% CI, 25.4-35.8) for ketamine and 31.9 mm (95% CI, 26.6-37.2) for fentanyl. Ketamine was noninferior to fentanyl for pain reduction based on a 1-sided test of group difference less than the noninferiority margin, as the CIs crossed 0 but did not cross the prespecified noninferiority margin (difference in mean pain reduction between groups, 1.3; 90% CI, −6.2 to 8.7). The risk of adverse events was higher in the ketamine group (relative risk, 2.5; 95% CI, 1.5-4.0), but all events were minor and transient. Rescue analgesia was similar between groups (relative risk, 0.89; 95% CI, 0.5-1.6).
Conclusions and Relevance
Ketamine provides effective analgesia that is noninferior to fentanyl, although participants who received ketamine had an increase in adverse events that were minor and transient. Intranasal ketamine may be an appropriate alternative to intranasal fentanyl for pain associated with acute extremity injuries. Ketamine should be considered for pediatric pain management in the emergency setting, especially when opioids are associated with increased risk.
ClinicalTrials.gov Identifier: NCT02778880
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Corresponding Author: Theresa M. Frey, MD, Division of Emergency Medicine, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, MLC 2008, Cincinnati, OH 45229-3026 (firstname.lastname@example.org).
Accepted for Publication: October 24, 2018.
Published Online: December 28, 2018. doi:10.1001/jamapediatrics.2018.4582
Author Contributions: Drs Frey and Mittiga had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Frey, Florin, Barrett, Mittiga.
Acquisition, analysis, or interpretation of data: Frey, Florin, N. Zhang, Y. Zhang, Mittiga.
Drafting of the manuscript: Frey, Y. Zhang, Mittiga.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: N. Zhang, Y. Zhang, Mittiga.
Obtained funding: Frey.
Administrative, technical, or material support: Frey, Barrett, Mittiga.
Supervision: Frey, Florin, N. Zhang, Mittiga.
Conflict of Interest Disclosures: Dr Frey reports grants from the American Academy of Pediatrics during the conduct of the study. No other disclosures were reported.
Funding/Support: This work was supported by funding from the Division of Emergency Medicine at Cincinnati Children’s Hospital Medical Center, where the trial was completed, and by American Academy of Pediatrics Section on Emergency Medicine through the 2016 Ken Graff Young Investigator Award.
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Data Sharing Statement: See Supplement 3.
Additional Contributions: We acknowledge Jenna Dyas, BS, Cincinnati Children’s Hospital Medical Center, and Nicole Herron, BA, Cincinnati Children’s Hospital Medical Center, who coordinated and supervised data collection; Mary Frey, MSN, CPN, RN, CNL, CPEN, Cincinnati Children’s Hospital Medical Center, who provided access to all patient video recordings (data acquisition); Scott Reeves, MD, University of Cincinnati College of Medicine and Cincinnati Children’s Hospital Medical Center, who served as the medical monitor, and therefore, was responsible for all safety monitoring; the Clinical Research Coordinator team, physicians, nurses, medics, patient care assistants, and child life specialists of the Division of Emergency Medicine at Cincinnati Children’s Hospital Medical Center who assisted with study enrollment; the Office of Clinical and Translational Research who assisted with US Food and Drug Administration correspondence and provided interim monitoring visits throughout the study; and all the patients and families who participated in the PRIME study. No individuals received compensation for their work outside of their salary.
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