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Pain Reduction With Intranasal Medications for Extremity Injuries

A Randomized Controlled Trial of Intranasal Sub-dissociative Dosing of Ketamine Compared to Intranasal Fentanyl for Treatment of Pain Associated With Acute Extremity Injuries in Children

Status
Completed
Phases
Phase 3
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT02778880
Acronym
PRIME
Enrollment
90
Registered
2016-05-20
Start date
2016-03-31
Completion date
2017-03-21
Last updated
2020-09-01

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Pain, Traumatic Limb Injury

Brief summary

This study compares the analgesic effect of intranasal sub-dissociative dosing of ketamine and intranasal fentanyl in children presenting to the Emergency Department with acute extremity injuries.

Detailed description

Inadequate pain control, especially in the emergency department (ED), is a major public health concern. Despite increased awareness, pain continues to be underdiagnosed and undertreated, particularly in the pediatric population. Children often encounter long delays in medication administration, possibly due to the time required to obtain intravenous access. The intranasal administration route offers a more efficient alternative for faster and noninvasive delivery of pain medication. This route is gaining popularity secondary to its rapid onset of active, minimal discomfort and relative simplicity. Opioids are the most commonly used class of analgesic pain medication for children presenting in severe pain due to traumatic injuries. Despite their potential effectiveness, opioids have several concerning adverse effects, particularly when administered prior to procedural sedation in children. Administration of pre-procedural sedation opioids is associated with an increased risk of serious adverse events (oxygen desaturation, apnea, and hypotension) as well as the need for significant interventions, such as bag-mask ventilation, intubation, and pharmacologic blood pressure support. In addition, due to genetic variations that may lead to increased or diminished opioid sensitivity, ideal dosing to adequately control severe pain yet avoid adverse medication-related side effects is difficult to ascertain. Many children in severe pain do not receive opioids, receive doses that are below those recommended or experience long delays in receiving opioids. The reasons for this are unclear, but the investigators speculate that this may be due in part to fear of adverse effects of opioids, provider inexperience with opioid use in children or fear of contributing to opioid tolerance or abuse. For all of these reasons, providers often seek non-opioid alternatives for pediatric patients with acute, severe pain. Ketamine, in sub-dissociative doses administered by the intravenous or intranasal route, is emerging as an alternative medication for the treatment of moderate to severe pain in multiple settings. In adults, low dose ketamine is well tolerated and has been used successfully as an adjuvant and an alternative to opioids to provide rapid pain relief in the ED. As a dissociative anesthetic, ketamine is the most commonly used agent to facilitate painful procedures in the pediatric emergency department. At lower doses, it has been used in children to provide analgesia in a variety of acute and chronic pain settings, including terminal diagnoses, sickle cell disease, perioperative pain, traumatic injuries, extensive burns and conditions where opioids are contraindicated. Similar to adults, ketamine has been used via the intranasal route to provide adequate analgesia and sedation in children in the pre-hospital setting and in those undergoing procedures. The objective of this study is to compare intranasal sub-dissociative ketamine with intranasal fentanyl for treatment of acute pain associated with traumatic limb injuries in children presenting to the ED and to document an objective respiratory side effect profile utilizing noninvasive capnometry. If found to be an effective analgesic, intranasal ketamine would be particularly useful in children who experience adverse effects with opioids, have developed opioid tolerance as a result of chronic painful conditions, have poor opioid sensitivity due to their genetic predisposition or in pediatric trauma patients with the potential for hypotension. Additionally, for patients that require procedural sedation for fracture reduction, avoiding opioids early in the emergency department visit may decrease sedation recovery time and the risk of serious adverse events during sedation.

Interventions

DRUGKetamine
DRUGFentanyl

Sponsors

Children's Hospital Medical Center, Cincinnati
Lead SponsorOTHER

Study design

Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender
ALL
Age
8 Years to 17 Years
Healthy volunteers
No

Inclusion criteria

* 8 years to 17 years (up to the 18th birthday) * Presenting to emergency department with one or more extremity injuries * Visual analog scale score 35 mm or greater * Parent or legal guardian present and willing to provide written consent

Exclusion criteria

* Received narcotic pain medication prior to arrival * Evidence of significant head, chest, abdomen, or spine injury * Glasgow coma score less than 15 or unable to self report pain score * Nasal trauma or aberrant nasal/airway anatomy * Active epistaxis * Allergy to ketamine, fentanyl or meperidine * Non-English speaking parent and/or child * History of psychosis * Postmenarchal female without a urine or serum assay documenting the absence of pregnancy * Brought in my juvenile detention center or in police custody * Pregnancy

Design outcomes

Primary

MeasureTime frameDescription
Difference From Baseline in Visual Analog Scale Pain Score30 minutes after study medicationA VAS score is a self reported pain score of 0-100 millimeters (0 = no pain; 100 = worst possible pain). A decrease in a VAS score indicates a decrease in pain severity.

Secondary

MeasureTime frameDescription
Highest Achieved University of Michigan Sedation Scale (UMSS) Score15, 30, and 60 minutes after study medication administrationThe University of Michigan Sedation Scale is a valid and reliable tool that allows for rapid assessment of the depth of sedation in children. It is a simple observational tool that assesses the level of alertness on a five-point scale. It has been validated in children and has shown to have significant inter-rater reliability. Score is 0-4 (0 = awake and alert; 1= minimally sedated; 2 = moderately sedated; 3 = deeply sedated; 4 = unarousable)
Rescue AnalgesiaWithin the first 60 minutes after study medicationDocumentation of additional pain medication after study medication administration
Heart Rate15 minutes after study medication
Respiratory Rate15 minutes after study medication
Difference From Baseline in Visual Analog Scale Pain Score15 minutes after study medicationA VAS score is a self reported pain score of 0-100 millimeters (0 = no pain; 100 = worst possible pain). A decrease in a VAS score indicates a decrease in pain severity.
Diastolic Blood Pressure15 minutes after study medication
Oxygen Saturation15 minutes after study medication
Capnometry Value15 minutes after study medication
Systolic Blood Pressure15 minutes after study medication

Countries

United States

Participant flow

Recruitment details

This clinical trial took place at a tertiary care children's hospital emergency department from March 2016 to February 2017. The study sample was identified through an established triage process identifying children with an acute painful extremity injury. These patients were ages 8-17 years with a visual analog scale (VAS) score greater than 35 mm.

Participants by arm

ArmCount
Ketamine
Ketamine 1.5 mg/kg intranasally for one dose
44
Fentanyl
Fentanyl 2 mcg/kg intranasally for one dose
42
Total86

Baseline characteristics

CharacteristicKetamineFentanylTotal
Age, Continuous11.8 years
STANDARD_DEVIATION 2.6
12.2 years
STANDARD_DEVIATION 2.3
12.0 years
STANDARD_DEVIATION 2.5
Analgesic Prior to Arrival
Acetaminophen
1 Participants2 Participants3 Participants
Analgesic Prior to Arrival
Ibuprofen
4 Participants4 Participants8 Participants
Analgesic Prior to Arrival
Naproxen
0 Participants1 Participants1 Participants
Analgesic Prior to Arrival
No Analgesic
39 Participants35 Participants74 Participants
Baseline Diastolic Blood Pressure78.9 mmHg
STANDARD_DEVIATION 13.6
73.5 mmHg
STANDARD_DEVIATION 12.9
76.3 mmHg
STANDARD_DEVIATION 13.5
Baseline End Tidal Captometry36.6 mmHg
STANDARD_DEVIATION 6.4
38.0 mmHg
STANDARD_DEVIATION 4.4
37.3 mmHg
STANDARD_DEVIATION 5.5
Baseline Heart Rate90.8 beats per minute
STANDARD_DEVIATION 15.2
88.6 beats per minute
STANDARD_DEVIATION 14.8
89.7 beats per minute
STANDARD_DEVIATION 15
Baseline Oxygen Saturation99.8 percent
STANDARD_DEVIATION 0.6
99.6 percent
STANDARD_DEVIATION 0.6
99.7 percent
STANDARD_DEVIATION 0.6
Baseline Respiratory Rate22.1 breaths per minute
STANDARD_DEVIATION 6.6
23.0 breaths per minute
STANDARD_DEVIATION 7.4
22.5 breaths per minute
STANDARD_DEVIATION 7
Baseline Systolic Blood Pressure126.5 mmHg
STANDARD_DEVIATION 19.1
128.9 mmHg
STANDARD_DEVIATION 19.6
127.7 mmHg
STANDARD_DEVIATION 19.4
Diagnosis
Dislocation
4 participants2 participants6 participants
Diagnosis
Fracture
39 participants34 participants73 participants
Diagnosis
Other
2 participants1 participants3 participants
Diagnosis
Sprain/Strain
1 participants5 participants6 participants
Dose of Study Medication Administered (Fentanyl)1.9 micrograms per kilogram (mcg/kg)1.9 micrograms per kilogram (mcg/kg)
Dose of Study Medication Administered (Ketamine)1.5 milligrams per kilogram (mg/kg)1.5 milligrams per kilogram (mg/kg)
Extremity
Lower Extremity
13 participants15 participants28 participants
Extremity
Upper Extremity
33 participants28 participants61 participants
Initial VAS score74.7 score on a scale
STANDARD_DEVIATION 15.3
72.0 score on a scale
STANDARD_DEVIATION 18.6
73.4 score on a scale
STANDARD_DEVIATION 17
Mechanism of Injury
Fall
10 Participants13 Participants23 Participants
Mechanism of Injury
Motor Vehicle Accident
1 Participants2 Participants3 Participants
Mechanism of Injury
Other
3 Participants1 Participants4 Participants
Mechanism of Injury
Sports Related/Recreational
30 Participants26 Participants56 Participants
Race/Ethnicity, Customized
Race/Ethnicity
Black
11 Participants10 Participants21 Participants
Race/Ethnicity, Customized
Race/Ethnicity
Hispanic
0 Participants2 Participants2 Participants
Race/Ethnicity, Customized
Race/Ethnicity
Other
3 Participants1 Participants4 Participants
Race/Ethnicity, Customized
Race/Ethnicity
White
30 Participants29 Participants59 Participants
Reduction Required19 Participants23 Participants42 Participants
Sedation Required19 Participants20 Participants39 Participants
Sex: Female, Male
Female
18 Participants11 Participants29 Participants
Sex: Female, Male
Male
26 Participants31 Participants57 Participants
Time of injury prior to arrival43.0 minutes51.5 minutes47.3 minutes
Time to Study Medication from Arrival26.6 minutes
STANDARD_DEVIATION 9.9
26.1 minutes
STANDARD_DEVIATION 10.3
26.4 minutes
STANDARD_DEVIATION 10.1
Volume of Study Medication Administered1.3 milliliters1.8 milliliters1.6 milliliters
Weight45.8 kilograms
STANDARD_DEVIATION 14.4
50.8 kilograms
STANDARD_DEVIATION 22.8
48.3 kilograms
STANDARD_DEVIATION 18.6

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
deaths
Total, all-cause mortality
0 / 440 / 42
other
Total, other adverse events
34 / 4413 / 42
serious
Total, serious adverse events
0 / 440 / 42

Outcome results

Primary

Difference From Baseline in Visual Analog Scale Pain Score

A VAS score is a self reported pain score of 0-100 millimeters (0 = no pain; 100 = worst possible pain). A decrease in a VAS score indicates a decrease in pain severity.

Time frame: 30 minutes after study medication

Population: One patient in the ketamine group did not have a baseline pain score documented and four patients withdrew from the study (1 in the ketamine group, 3 in the fentanyl group), resulting in 43 patients randomized to the ketamine group and 42 patients randomized to the fentanyl group included in the primary outcome analysis.

ArmMeasureValue (MEAN)
KetamineDifference From Baseline in Visual Analog Scale Pain Score-30.6 score on a scale
FentanylDifference From Baseline in Visual Analog Scale Pain Score-31.9 score on a scale
Secondary

Capnometry Value

Time frame: 60 minutes after study medication

ArmMeasureValue (MEAN)Dispersion
KetamineCapnometry Value38.7 mmHgStandard Deviation 4.2
FentanylCapnometry Value38.9 mmHgStandard Deviation 5.4
Secondary

Capnometry Value

Time frame: 15 minutes after study medication

ArmMeasureValue (MEAN)Dispersion
KetamineCapnometry Value36.6 mmHgStandard Deviation 5.2
FentanylCapnometry Value38.3 mmHgStandard Deviation 4.2
Secondary

Capnometry Value

Time frame: 30 minutes after study medication

ArmMeasureValue (MEAN)Dispersion
KetamineCapnometry Value38.6 mmHgStandard Deviation 5.6
FentanylCapnometry Value40.4 mmHgStandard Deviation 6.8
Secondary

Diastolic Blood Pressure

Time frame: 15 minutes after study medication

ArmMeasureValue (MEAN)Dispersion
KetamineDiastolic Blood Pressure76.1 mmHgStandard Deviation 10.7
FentanylDiastolic Blood Pressure73.4 mmHgStandard Deviation 12.7
Secondary

Diastolic Blood Pressure

Time frame: 60 minutes after study medication

ArmMeasureValue (MEAN)Dispersion
KetamineDiastolic Blood Pressure70.8 mmHgStandard Deviation 9.2
FentanylDiastolic Blood Pressure70.6 mmHgStandard Deviation 10.4
Secondary

Diastolic Blood Pressure

Time frame: 30 minutes after study medication

ArmMeasureValue (MEAN)Dispersion
KetamineDiastolic Blood Pressure76.3 mmHgStandard Deviation 10.3
FentanylDiastolic Blood Pressure73.6 mmHgStandard Deviation 11.2
Secondary

Difference From Baseline in Visual Analog Scale Pain Score

A VAS score is a self reported pain score of 0-100 millimeters (0 = no pain; 100 = worst possible pain). A decrease in a VAS score indicates a decrease in pain severity.

Time frame: 60 minutes after study medication

Population: One patient in the ketamine group did not have a baseline pain score documented and four patients withdrew from the study (1 in the ketamine group, 3 in the fentanyl group), resulting in 43 patients randomized to the ketamine group and 42 patients randomized to the fentanyl group included in this secondary outcome analysis.

ArmMeasureValue (MEAN)
KetamineDifference From Baseline in Visual Analog Scale Pain Score-27.7 score on a scale
FentanylDifference From Baseline in Visual Analog Scale Pain Score-29.0 score on a scale
Secondary

Difference From Baseline in Visual Analog Scale Pain Score

A VAS score is a self reported pain score of 0-100 millimeters (0 = no pain; 100 = worst possible pain). A decrease in a VAS score indicates a decrease in pain severity.

Time frame: 15 minutes after study medication

Population: One patient in the ketamine group did not have a baseline pain score documented and four patients withdrew from the study (1 in the ketamine group, 3 in the fentanyl group), resulting in 43 patients randomized to the ketamine group and 42 patients randomized to the fentanyl group included in this secondary outcome analysis.

ArmMeasureValue (MEAN)
KetamineDifference From Baseline in Visual Analog Scale Pain Score-24.4 score on a scale
FentanylDifference From Baseline in Visual Analog Scale Pain Score-25.3 score on a scale
Secondary

Heart Rate

Time frame: 15 minutes after study medication

ArmMeasureValue (MEAN)Dispersion
KetamineHeart Rate90.1 beats per minuteStandard Deviation 12.8
FentanylHeart Rate84.4 beats per minuteStandard Deviation 14.1
Secondary

Heart Rate

Time frame: 60 minutes after study medication

ArmMeasureValue (MEAN)Dispersion
KetamineHeart Rate85.1 beats per minuteStandard Deviation 12.4
FentanylHeart Rate82.9 beats per minuteStandard Deviation 12.9
Secondary

Heart Rate

Time frame: 30 minutes after study medication

ArmMeasureValue (MEAN)Dispersion
KetamineHeart Rate90.5 beats per minuteStandard Deviation 12.8
FentanylHeart Rate85.6 beats per minuteStandard Deviation 13.5
Secondary

Highest Achieved University of Michigan Sedation Scale (UMSS) Score

The University of Michigan Sedation Scale is a valid and reliable tool that allows for rapid assessment of the depth of sedation in children. It is a simple observational tool that assesses the level of alertness on a five-point scale. It has been validated in children and has shown to have significant inter-rater reliability. Score is 0-4 (0 = awake and alert; 1= minimally sedated; 2 = moderately sedated; 3 = deeply sedated; 4 = unarousable)

Time frame: 15, 30, and 60 minutes after study medication administration

ArmMeasureCategoryValue (COUNT_OF_PARTICIPANTS)
KetamineHighest Achieved University of Michigan Sedation Scale (UMSS) ScoreUMSS 023 Participants
KetamineHighest Achieved University of Michigan Sedation Scale (UMSS) ScoreUMSS 117 Participants
KetamineHighest Achieved University of Michigan Sedation Scale (UMSS) ScoreUMSS 24 Participants
FentanylHighest Achieved University of Michigan Sedation Scale (UMSS) ScoreUMSS 032 Participants
FentanylHighest Achieved University of Michigan Sedation Scale (UMSS) ScoreUMSS 19 Participants
FentanylHighest Achieved University of Michigan Sedation Scale (UMSS) ScoreUMSS 21 Participants
Secondary

Oxygen Saturation

Time frame: 60 minutes after study medication

ArmMeasureValue (MEAN)Dispersion
KetamineOxygen Saturation99.3 percentStandard Deviation 0.9
FentanylOxygen Saturation99.3 percentStandard Deviation 0.9
Secondary

Oxygen Saturation

Time frame: 30 minutes after study medication

ArmMeasureValue (MEAN)Dispersion
KetamineOxygen Saturation99.5 percentStandard Deviation 0.7
FentanylOxygen Saturation99.4 percentStandard Deviation 0.9
Secondary

Oxygen Saturation

Time frame: 15 minutes after study medication

ArmMeasureValue (MEAN)Dispersion
KetamineOxygen Saturation99.6 percentStandard Deviation 0.7
FentanylOxygen Saturation99.2 percentStandard Deviation 0.9
Secondary

Rescue Analgesia

Documentation of additional pain medication after study medication administration

Time frame: Within the first 60 minutes after study medication

ArmMeasureCategoryValue (COUNT_OF_PARTICIPANTS)
KetamineRescue AnalgesiaIbuprofen1 Participants
KetamineRescue AnalgesiaFentanyl1 Participants
KetamineRescue AnalgesiaMorphine7 Participants
KetamineRescue AnalgesiaKetamine1 Participants
KetamineRescue AnalgesiaToradol1 Participants
KetamineRescue AnalgesiaNo rescue analgesia33 Participants
FentanylRescue AnalgesiaToradol0 Participants
FentanylRescue AnalgesiaIbuprofen3 Participants
FentanylRescue AnalgesiaKetamine0 Participants
FentanylRescue AnalgesiaFentanyl3 Participants
FentanylRescue AnalgesiaNo rescue analgesia33 Participants
FentanylRescue AnalgesiaMorphine3 Participants
Secondary

Respiratory Rate

Time frame: 15 minutes after study medication

ArmMeasureValue (MEAN)Dispersion
KetamineRespiratory Rate23.1 breaths per minuteStandard Deviation 11.9
FentanylRespiratory Rate22.3 breaths per minuteStandard Deviation 5.8
Secondary

Respiratory Rate

Time frame: 60 minutes after study medication

ArmMeasureValue (MEAN)Dispersion
KetamineRespiratory Rate21.8 breaths per minuteStandard Deviation 8.1
FentanylRespiratory Rate19.7 breaths per minuteStandard Deviation 5.7
Secondary

Respiratory Rate

Time frame: 30 minutes after study medication

ArmMeasureValue (MEAN)Dispersion
KetamineRespiratory Rate23.3 breaths per minuteStandard Deviation 8.7
FentanylRespiratory Rate19.9 breaths per minuteStandard Deviation 5.7
Secondary

Systolic Blood Pressure

Time frame: 30 minutes after study medication

ArmMeasureValue (MEAN)Dispersion
KetamineSystolic Blood Pressure126.3 mmHgStandard Deviation 15
FentanylSystolic Blood Pressure123.4 mmHgStandard Deviation 15.6
Secondary

Systolic Blood Pressure

Time frame: 15 minutes after study medication

ArmMeasureValue (MEAN)Dispersion
KetamineSystolic Blood Pressure127.3 mmHgStandard Deviation 18
FentanylSystolic Blood Pressure127.9 mmHgStandard Deviation 19.3
Secondary

Systolic Blood Pressure

Time frame: 60 minutes after study medication

ArmMeasureValue (MEAN)Dispersion
KetamineSystolic Blood Pressure122.3 mmHgStandard Deviation 14.9
FentanylSystolic Blood Pressure122.0 mmHgStandard Deviation 15.1

Source: ClinicalTrials.gov · Data processed: Feb 22, 2026