A Comparison of Three Regimens of Acute Pain Management: Methoxyflurane; Intranasal Fentanyl; Intravenous Morphine

NCT05137184 | Completed Phase 3 DMC

• 2 other identifiers: 2551592021-000549-42
• Study Type: interventional
• Target: 338
• Locations: 1 country
• Sites: 1

Brief Summary

The study rationale is to provide evidence for early, safe and effective pain management in the ambulance service with non-invasive and fast acting analgesics. Low-dose methoxyflurane and intranasal fentanyl are non-invasive medications that are well-suited for use by ambulance personnel under difficult pre-hospital settings. This is a randomized, controlled, open label, three-arm, non-inferiority, phase 3 drug trial performed in the ambulance service. The randomization will be 1:1:1 to the three treatment groups. Patients 18 years or older with acute pain with Numeric Rating Scale (NRS) ≥4 with normal physiology and capable of giving informed consent will be included null hypothesis (H0) (tested in hierarchic order a-b-c):

• Methoxyflurane: 3 ml inhalation, can be repeated once to a total dose of 6 ml.
• Fentanyl intranasal spray: 100 µg IntraNasal, (patients \>70 years 50 µg), can be repeated to maximum total dose 500 µg IN.
• Morphine hydrochloride intravenous: 0.1 mg/kg IV (patients \>70 years or fragile 0.05 mg/kg IV), can be repeated to a maximum total dose 0.5 mg/kg IV. Rescue analgesia is all analgesics other than the allocated IMP. If rescue medication is administered before the assessment of primary endpoint at 10 minutes, the patient will not be part of the per-protocol analysis. The hypothesis will be tested and the primary endpoint will be evaluated by the 95% confidence limits (95% CI), and a conclusion of non-inferiority will be made if the 95% CI of the estimated treatment difference fully lie within the inferiority margin. Non-inferiority is determined on the basis of a 1-sided equivalence t test on the per protocol population and confirmed, for sensitivity reasons, on the modified intention to treat population.

Conditions

Acute Pain; Ambulances

Keywords

Methoxyflurane; Fentanyl; Morphine

Outcome Measures

Primary Outcomes (1)

• Change in pain Numeric Rating Scale after 10 minutes

  Change in Pain Numeric Rating Scale (minimum 0 and maximum 10, higher is worse) from baseline to 10 minutes after start of IMP administration

  10 minutes

Secondary Outcomes (15)

• Change in pain Numeric Rating Scale after 5 minutes

  5 minutes

• Change in pain Numeric Rating Scale after 20 minutes

  20 minutes

• Change in pain Numeric Rating Scale after 30 minutes

  30 minutes

• Need for rescue analgesia

  2 hours

• Type of rescue analgesia

  2 hours

Other Outcomes (6)

• Change in pain Numeric Rating Scale after 10 minutes stratified by diagnosis groups

  30 minutes

• Need for rescue medication related to painful procedures

  2 hours

• Number of vascular cannulation attempts in each patient

  2 hours

Study Arms (3)

Methoxyflurane

EXPERIMENTAL

3 ml inhalation Can be repeated once (3 ml) Maximum total dose of 6 ml

Drug: Methoxyflurane

Fentanyl IN

EXPERIMENTAL

100 µg IntraNasal, Patients \>70 years: 50 µg IN Can be repeated Maximum total dose 500 µg IN

Drug: Fentanyl

Morphine IV

ACTIVE COMPARATOR

0.1 mg/kg Intravenous (IV) Patients ≥ 70 years or fragile: 0.05 mg/kg IV Can be repeated Maximum total dose 0.5 mg/kg IV

Drug: Morphine hydrochloride

Interventions

Methoxyflurane DRUG

Inhalation of Methoxyflurane

Methoxyflurane

Fentanyl DRUG

Intranasal Fentanyl

Fentanyl IN

Morphine hydrochloride DRUG

Intravenous Morphine

Morphine IV

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• ≥ 18 years of age
• Acute moderate to severe pain defined by self-reporting pain ≥4 on NRS
• Capable of giving informed consent
• Normal physiology

You may not qualify if:

• Life-threatening or limb-threatening condition requiring immediate management
• Pregnancy or breastfeeding
• Know allergies, hypersensitivity or serious side effects to opioids or methoxyflurane or other excipients
• Head injury or medical conditions with neurological impairment (Glasgow Coma Scale (GCS)\<14)
• Previous malignant hyperthermia or persons with suspect genetic predisposition for malignant hyperthermia
• Massive facial trauma, visible nasal blockage or on-going nose bleeding
• History of severe liver disease with jaundice and scleral icterus
• Dialysis or history of severe renal disease (known chronic kidney failure stage 4 or 5)
• Mono Amine Oxidase-inhibitors last 14 days (pharmacological treatment of depression, Mb Parkinson or narcolepsy)
• Myasthenia gravis
• Any condition that in the view of the study worker would suggest that the patient is unable to comply with study protocol and procedures.

Sponsors & Collaborators

• Oslo University Hospital: lead
• Sykehuset Innlandet HF: collaborator
• Norwegian Air Ambulance Foundation: collaborator
• University of Oslo: collaborator

Study Sites (1)

Sykehuset Innlandet

Gjøvik, Norway

Location

Related Publications (1)

• Simensen R, Fjose LO, Thorsen K, Olsen IC, Rehn M, Hagemo J, Smalberget L, Heyerdahl F. Comparison of inhalational methoxyflurane, intranasal fentanyl, and intravenous morphine for treatment of prehospital acute pain in Norway (PreMeFen): a randomised, non-inferiority, three-arm, phase 3 trial. Lancet. 2026 Dec 20;406(10522):2957-2967. doi: 10.1016/S0140-6736(25)01575-2. Epub 2025 Nov 20.

  PMID: 41275876 DERIVED

MeSH Terms

Conditions

Acute Pain

Interventions

Methoxyflurane; Fentanyl

Condition Hierarchy (Ancestors)

Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Ethyl Ethers; Ethers; Organic Chemicals; Methyl Ethers; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Fridtjof Heyerdahl, MD PhD

  Senior Consultant

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: Masking Statistician
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Senior Consultant

Study Record Dates

• First Submitted: November 1, 2021
• First Posted: November 30, 2021
• Study Start: November 12, 2021
• Primary Completion: April 22, 2023
• Study Completion: April 22, 2023
• Last Updated: November 14, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

NO (1)