Fentanyl or Esketamine for Traumatic PAIN (FORE-PAIN) Trial (FORE-PAIN)

Fentanyl and esketamine are both standard of care for treatment of acute severe traumatic pain in the prehospital setting in the Netherlands. However, it is not known whether they are equally effective and safe. It is also not known whether intranasal (IN) administration of fentanyl or esketamine is equally effective and safe as intravenous (IV) administration.

The FORE-PAIN trial is a double-blind multi-arm randomized non-inferiority trial comparing Fentanyl IN, esketamine IV and esketamine IN (intervention arms) to fentanyl IV (comparator arm) for prehospital management of traumatic pain. The investigators hypothesize that all intervention arms provide analgesia that is non-inferior to the comparator arm, and that all study arms are equally safe.

Study Overview

• Status: Recruiting
• Conditions: Analgesia; Emergency Medical Services; Acute Pain Due to Trauma; Fentanyl; Esketamine
• Intervention / Treatment: Drug: Fentanyl Citrate; Drug: Esketamine

• Study Type: Interventional
• Enrollment (Estimated): 608
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Robert P Weenink, PhD; Phone Number: +31 205669111; Email: forepain@amsterdamumc.nl

Study Locations

• Netherlands
  • Amsterdam, Netherlands
    • Recruiting
    • Ambulance Amsterdam
    • Contact: Midas de Grunt, MD; Email: forepain@amsterdamumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• age ≥ 18 years
• pain has been caused by a trauma (any trauma mechanism) that occurred on the same day
• Emergency Medical Services personnel determines that administration of a strong opioid or esketamine for analgesia is required
• patient will be transported to a hospital

Exclusion Criteria:

• (estimated) weight <40 or >100 kg
• subject does not understand Dutch or English
• inability to report pain score
• inability to give IN or IV medication
• known severe cardiovascular disease
• pre-eclampsia
• Glasgow Coma Scale score < 11
• subject is known to have previously declined participation in medical research

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Fentanyl IV; Opioid analgesic Form: fentanyl solution for injection/infusion Administration: intravenous Initial dose: 1 ug/kg Second dose (if required): 0.6ug/kg	Drug: Fentanyl Citrate; Subjects receive one dose of study medication (fentanyl or esketamine) at baseline, either intravenous or intranasal
Experimental: Fentanyl IN; Opioid analgesic Form: fentanyl solution for injection/infusion Administration: intranasal using nasal atomizer Initial dose: 1.25 ug/kg to a maximum of 100ug Second dose (if required): 1ug/kg to a maximum total dose of 2ug/kg	Drug: Fentanyl Citrate; Subjects receive one dose of study medication (fentanyl or esketamine) at baseline, either intravenous or intranasal
Experimental: Esketamine IV; Anesthetic, in lower doses the analgesic effect is dominant Form: esketamine solution for injection/infusion Administration: intravenous Initial dose: 0.2mg/kg Second dose (if required): 0.12mg/kg	Drug: Esketamine; Subjects receive one dose of study medication (fentanyl or esketamine) at baseline, either intravenous or intranasal
Experimental: Esketamine IN; Anesthetic, in lower doses the analgesic effect is dominant Form: esketamine solution for injection/infusion Administration: intranasal using a nasal atomizer Initial dose: 0.625mg/kg to a maximum of 50mg Second dose (if required): 0.5mg/kg to a maximum total dose of 1mg/kg	Drug: Esketamine; Subjects receive one dose of study medication (fentanyl or esketamine) at baseline, either intravenous or intranasal

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in pain score as measured with Numeric Rating Scale (NRS)	NRS is an 11 point Likert scale ranging from 0 to 10, where 0 means 'no pain' and 10 means 'worst pain imaginable'	10 minutes after first drug administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of subjects requiring a second dose of study medication	If the patient requires additional analgesia, study medication can be repeated once	10 and 20 minutes after first drug administration
Number of patients experiencing adverse events	Including side effects	Up to time of arrival at the hospital (expected within 30 minutes after first drug administration)
Number of patients requiring unblinding	E.g. because of treatment failure or side effects	Up to time of arrival at the hospital (expected within 30 minutes after first drug administration)
Change in pain score as measured with NRS	NRS is an 11 point Likert scale ranging from 0 to 10, where 0 means 'no pain' and 10 means 'worst pain imaginable'	20 minutes after first drug administration; time of arrival at the hospital (expected within 30 minutes after first drug administration)
Relative change in pain score as measured with NRS	NRS is an 11 point Likert scale ranging from 0 to 10, where 0 means 'no pain' and 10 means 'worst pain imaginable'	10 and 20 minutes after first drug administration; time of arrival at the hospital (expected within 30 minutes after first drug administration)
Patient satisfaction with pre-hospital analgesia	Patient satisfaction is measured using an 11 point Likert scale ranging from 0 to 10, where 0 means 'extremely unsatisfactory' and 10 means 'extremely satisfactory'	Time of arrival at the hospital (expected within 30 minutes after first drug administration)

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Collaborators: Ambulance Amsterdam; Stichting ZiektekostenVerzekering Krijgsmacht
• Investigators: Principal Investigator: Markus W Hollmann, Prof. dr. dr., Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Study record dates

Study Major Dates

• Study Start (Actual): January 11, 2024
• Primary Completion (Estimated): March 1, 2026
• Study Completion (Estimated): March 1, 2026

Study Registration Dates

• First Submitted: September 13, 2023
• First Submitted That Met QC Criteria: September 20, 2023
• First Posted (Actual): September 22, 2023

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 28, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: Pain management; Drug-Related Side Effects and Adverse Reactions; Anesthetics; Analgesics; Administration, intranasal; Administration, intravenous; Ketanest
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Pathologic Processes; Disease Attributes; Emergencies; Acute Pain; Physiological Effects of Drugs; Peripheral Nervous System Agents; Anesthetics; Central Nervous System Depressants; Sensory System Agents; Analgesics; Analgesics, Opioid; Narcotics; Adjuvants, Anesthesia; Psychotropic Drugs; Anesthetics, Intravenous; Anesthetics, General; Antidepressive Agents; Esketamine; Fentanyl
• Other Study ID Numbers: FP-2023; 2022-500176-63-00 (Other Identifier: EU Clinical Trials Information System); U1111-1287-7486 (Other Identifier: ICTRP); 2022-000039-22 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Metadata and final data will be published. Conditions for reuse apply.
• IPD Sharing Time Frame: Metadata are published before locking of the database. The final data are published at the time of the journal article's publication.
• IPD Sharing Access Criteria: Conditions for reuse of data are described in the patient information folder. Access to the data can be granted by the Principal Investigator based on these criteria.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No