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14 Articles in Volume 18, Issue #9
Assessing Arthralgia in Children
Children, Opioids, and Pain: The Stats & Clinical Guidelines
How to Fit into a New Practice
How to Talk to Your Chronic Pain Patients
How to Treat Opioid Use Disorder in Pregnant Women
Intranasal Ketamine for Acute Pain in Children
Medication Selection for Comorbid Pain Management (Part 3)
MR Neurography: Using Peripheral Nerve Imaging as a Pain Diagnostic
Naloxone in Schools; Buprenorphine Conversions; OUD Management
Opioid Conversion Calculations and Changes
Pes Anserine Tendino-Bursitis as Primary Cause of Knee Pain in Overweight Women
Self-Management of Chronic Pain in Primary Care
The Homebound Adolescent: Managing Chronic Pain Conditions in the Pediatric Population
The Opioid Band-Aid: The State of Pain Pills, Congressional Bills, and Healthcare in the US

Intranasal Ketamine for Acute Pain in Children

In this Ask the Expert, intranasal fentanyl and intranasal ketamine are compared for treatment of limb injuries.
Pages 27-28

Intranasal routes of medication administration are common in pediatric care, especially in emergency departments (EDs). The nasal mucosa is large and highly vascularized, which aids in systemic absorption and allows for quick onset. This route also helps to avoid gastrointestinal and hepatic first-pass metabolism, thereby increasing the duration of action and potentially improving tolerability over intravenous delivery.1

Evidence-based pediatric pain management recommendations are currently lacking. American Academy of Pediatrics and American Pain Society guidelines fail to mention intranasal administration of medications. Fentanyl citrate is the most common intranasal analgesic utilized in pediatrics. Due to recent opioid concerns, however, safer alternatives are being sought.

Current Dosing Limitations

Dosing limitations exist with more common concentrations (50 μg/mL) of fentanyl for patients over 50 kg due to weight-based pediatric dosing because over 1 mL of solution would need to be administered intranasally.2 Ideal volume is 0.2 to 0.3 mL per nostril for intranasal administration. If more than 0.5 mL is indicated, separate doses 5 to 10 minutes apart are recommended, which may not be practical for children in acute pain.3 Fentanyl citrate 50 μg/mL parenteral solution is the typical concentration carried in EDs due to availability and affordability. A dose of 1.0 to 1.5 μg/kg administered intranasally with an atomizer has been found in studies to be efficacious and safe in pediatrics for analgesia with extremity injuries.2,4

Intranasal ketamine has been studied for use in post-operative tonsillectomy pain and to establish its pharmacokinetic profile.5,6 A comparative study of intranasal ketamine with intranasal dexmedetomidine and midazolam to assess their sedation and analgesic properties in dentistry has also been performed.7 Two recent studies have assessed intranasal ketamine versus intranasal fentanyl for acute pediatric extremity injuries, as summarized below.

Comparison to Intranasal Fentanyl for Limb Injuries

A randomized, controlled, double-blinded, superiority trial led by Graudins A, et al,2 in the EDs of two Australian hospitals, compared intranasal fentanyl to ketamine for pediatric limb injuries with moderate to severe pain (6 or greater on a 0-to-10 scale) to determine whether intranasal ketamine would be a reasonable analgesic option. Subjects were 3 to 13 years old, weighing under 50 kg. Diagnoses included upper and lower limb fractures and soft tissue injuries. Comparators included: intranasal fentanyl citrate (50 μg/mL) and ketamine (200 mg/2 mL) at 1.5 μg/mL and 1 mg/kg doses, respectively. Oral ibuprofen 10 mg/kg was administered to all patients within 15 minutes of receiving the study drug, unless they had received it within the previous 4 hours. Use of rescue medication led to termination from the study. Children ages 3 to 6 years were assessed using the Faces Pain Scale-Revised (FPS-R). Children 7 years and older used the Visual Analog Scale (VAS). Pain ratings from both scales were combined for analysis.

After randomization, the ketamine group had 36 patients and the fentanyl group had 37. The primary outcome (median reduction in pain rating at 30 minutes post administration) yielded no statistical difference between the two groups nor did ratings at 60 minutes. Due to the wide range of the confidence intervals (attributed to the small sample sizes), clinical significance was unclear.

There was a significant difference between groups in the frequency of adverse events, however. A total of 24 events were reported by 15 out of 37 participants in the fentanyl group, and 67 events were reported by 28 out of 36 patients in the ketamine group. Of the total adverse events in the fentanyl arm (n = 24), 42% reported bad taste, 21% reported drowsiness, 17% reported dizziness, and 12% reported itchy nose. Of those in the ketamine group (n = 67), 25% reported bad taste, followed by 16% drowsiness, 30% dizziness, and 4% itchy nose. Hallucinations occurred only in the ketamine group (4 events). More fentanyl group participants required rescue analgesia (32%) compared to the ketamine group (14%).2

Comparison to Intranasal Fentanyl for Extremity Fractures

Reynolds S, et al,8 conducted a randomized, double-blinded, controlled, non-inferiority trial in a US-based ED to compare efficacy and tolerability of intranasal ketamine with intranasal fentanyl for analgesia in children with suspected extremity fractures. The primary outcome was frequency of adverse events and side effects within 60 minutes of drug administration. A secondary outcome was the difference in mean pain score reduction at 20 minutes. Children ages 4 to 17 years with a suspected, single-extremity fracture who required analgesia were screened. The FPS-R scale was utilized for patient ages 4 to 10 years (score ≥ 4 included) and the VAS was used for patients 11 to 17 years (score ≥ 3 included). Comparators included: intranasal subdissociative ketamine (1 mg/kg) and intranasal fentanyl (1.5 μg/ kg). At the physician’s discretion, an option was given of a second dose of the study drug 20 minutes after the first. All patients also received either oral acetaminophen 15 mg/kg (650 mg max) or ibuprofen 10 mg/kg (600 mg max). Adverse events were assessed periodically until 6 hours after administration or discharge.

After randomization, 43 patients were assigned to the ketamine arm and 44 to the fentanyl arm. Displaced forearm fractures were the most common injury. Primary analysis found that adverse events occurred 2.2 times more in the ketamine group, which was below the prior specified tolerability threshold (3). Adverse events were statistically and clinically significant, occurring in 100% of ketamine patients and in 61% of fentanyl patients (risk difference = 39% [95% CI 24% - 54%]). Although significantly more frequent in the ketamine group, adverse events in both groups were minor with the exception of one in the fentanyl group (hypotension). Reported side effects included: in the ketamine group – bad taste (90%), dizziness (73%,) sleepiness (46%); in the fentanyl group – sleepiness (37%), bad taste (22%), itchy nose (22%), and dizziness (15%). No difference in efficacy was found between the two arms. A clinically significant reduction in pain (20 mm decrease) at 20 minutes was achieved in 77% and 80% of the ketamine and fentanyl groups, respectively.


To summarize, neither study found a statistical difference in pain reduction using either intranasal fentanyl or intranasal ketamine. However, when comparing adverse events, ketamine was associated with more frequent events. Due to the inferior safety profile and the similar efficacy of the two trials presented, it does not appear that intranasal ketamine will replace intranasal fentanyl in the treatment of acute, moderate to severe pain in a pediatric population with an extremity injury. Collaboratively, these studies suggest that ketamine could be utilized as an alternative analgesic if there were a contraindication or drug shortage. More research is necessary to establish whether alternative intranasal analgesics have a possible opioid-sparing effect. 

Last updated on: April 12, 2019
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