Pain Reduction With Intranasal Medications for Extremity Injuries (PRIME)

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

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.

Study Overview

• Status: Completed
• Conditions: Pain; Traumatic Limb Injury
• Intervention / Treatment: Drug: Fentanyl; Drug: Ketamine

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.

• Study Type: Interventional
• Enrollment (Actual): 90
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ketamine; Ketamine 1.5 mg/kg intranasally for one dose	Drug: Ketamine; Other Names: Ketalar
Active Comparator: Fentanyl; Fentanyl 2 mcg/kg intranasally for one dose	Drug: Fentanyl

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	30 minutes after study medication

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	15 minutes after study medication
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.	60 minutes after study medication
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)	15, 30, and 60 minutes after study medication administration
Rescue Analgesia	Documentation of additional pain medication after study medication administration	Within the first 60 minutes after study medication
Heart Rate		15 minutes after study medication
Heart Rate		30 minutes after study medication
Heart Rate		60 minutes after study medication
Respiratory Rate		15 minutes after study medication
Respiratory Rate		30 minutes after study medication
Respiratory Rate		60 minutes after study medication
Systolic Blood Pressure		15 minutes after study medication
Systolic Blood Pressure		30 minutes after study medication
Systolic Blood Pressure		60 minutes after study medication
Diastolic Blood Pressure		15 minutes after study medication
Diastolic Blood Pressure		30 minutes after study medication
Diastolic Blood Pressure		60 minutes after study medication
Oxygen Saturation		15 minutes after study medication
Oxygen Saturation		30 minutes after study medication
Oxygen Saturation		60 minutes after study medication
Capnometry Value		15 minutes after study medication
Capnometry Value		30 minutes after study medication
Capnometry Value		60 minutes after study medication

Collaborators and Investigators

• Sponsor: Children's Hospital Medical Center, Cincinnati
• Investigators: Principal Investigator: Theresa M Frey, MD, Children's Hospital Medical Center, Cincinnati; Principal Investigator: Matthew R Mittiga, MD, Children's Hospital Medical Center, Cincinnati

Publications and helpful links

General Publications

• Frey TM, Florin TA, Caruso M, Zhang N, Zhang Y, Mittiga MR. Effect of Intranasal Ketamine vs Fentanyl on Pain Reduction for Extremity Injuries in Children: The PRIME Randomized Clinical Trial. JAMA Pediatr. 2019 Feb 1;173(2):140-146. doi: 10.1001/jamapediatrics.2018.4582.

Study record dates

Study Major Dates

• Study Start (Actual): March 31, 2016
• Primary Completion (Actual): February 22, 2017
• Study Completion (Actual): March 21, 2017

Study Registration Dates

• First Submitted: April 19, 2016
• First Submitted That Met QC Criteria: May 19, 2016
• First Posted (Estimate): May 20, 2016

Study Record Updates

• Last Update Posted (Actual): September 1, 2020
• Last Update Submitted That Met QC Criteria: August 18, 2020
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Wounds and Injuries; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Analgesics, Opioid; Narcotics; Adjuvants, Anesthesia; Ketamine; Fentanyl
• Other Study ID Numbers: CIN_PRIME_001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO