Acute PainPhase 3PreMeFenNCT05137184
A Comparison of Three Regimens of Acute Pain Management: Methoxyflurane; Intranasal Fentanyl; Intravenous Morphine
A Phase 3 study testing Methoxyflurane, Fentanyl and Morphine hydrochloride in people with Acute Pain and Ambulances, run by Oslo University Hospital at 1 site in Norway.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Acute Pain, Ambulances
- What is being tested?
- Methoxyflurane, Fentanyl and Morphine hydrochloride
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 338 participants
- Where
- 1 siteNorway
- Study dates
- 12 Nov 2021to 22 Apr 2023
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- ≥ 18 years of age
- Acute moderate to severe pain defined by self-reporting pain ≥4 on NRS
- Capable of giving informed consent
- Normal physiology
Who cannot join
- 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
Show all 12Show fewer
- 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
- Use of investigational medicinal product (IMP) analgesics 12 hours prior to inclusion
- Any condition that in the view of the study worker would suggest that the patient is unable to comply with study protocol and procedures.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Randomized Controlled, Open-label, Non-inferiority, Three Arm Clinical Study to Assess Inhalation of Low-dose Methoxyflurane, Intranasal Fentanyl, and Intravenous Morphine for Acute Pain in the Pre-hospital Setting
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):
Read more
- Methoxyflurane regimen is inferior to intranasal fentanyl regimen or
- Methoxyflurane regimen is inferior to IV morphine regimen or
- Intranasal fentanyl regimen is inferior to IV morphine regimen for treating moderate to severe pain, measured by reduction in Numeric Rating Scale (NRS) 10 minutes after administration.
The study duration for each participant will be from ambulance scene arrival to patient handover in emergency department.
Number of participants: Patient enrolment until successful inclusion of 270 per protocol patients.
Primary endpoint is change in NRS from before administration (t0) to 10 minutes after start of administration (t10).
The study intervention is one of the three IMPs:
- 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
- Being tested
- Methoxyflurane, Fentanyl, Morphine hydrochloride
- Keywords
- Methoxyflurane, Fentanyl, Morphine
- Medical subject headings
- Acute Pain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MethoxyfluraneDrug
Inhalation of Methoxyflurane
FentanylDrug
Intranasal Fentanyl
Morphine hydrochlorideDrug
Intravenous Morphine
| Study group | Role | What they receive |
|---|---|---|
| Methoxyflurane | Experimental | 3 ml inhalation Can be repeated once (3 ml) Maximum total dose of 6 ml Receives: Drug: Methoxyflurane |
| Fentanyl IN | Experimental | 100 µg IntraNasal, Patients >70 years: 50 µg IN Can be repeated Maximum total dose 500 µg IN Receives: 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 Receives: Drug: Morphine hydrochloride |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 10 minutes
Secondary outcomes (15)
Change in pain Numeric Rating Scale after 5 minutes
Change in Pain Numeric Rating Scale (minimum 0 and maximum 10, higher is worse) from baseline to 5 minutes after start of IMP administration
Measured: 5 minutes
Change in pain Numeric Rating Scale after 20 minutes
Change in Pain Numeric Rating Scale (minimum 0 and maximum 10, higher is worse) from baseline to 20 minutes after start of IMP administration
Measured: 20 minutes
Change in pain Numeric Rating Scale after 30 minutes
Change in Pain Numeric Rating Scale (minimum 0 and maximum 10, higher is worse) from baseline to 30 minutes after start of IMP administration
Measured: 30 minutes
Need for rescue analgesia
Number of patients with administration of rescue analgesia
Measured: 2 hours
Type of rescue analgesia
Type of rescue analgesia administered
Measured: 2 hours
Dose of rescue analgesia
Dose of rescue analgesia administered
Measured: 2 hours
Route of administration of rescue analgesia
Route of administration of rescue analgesia
Measured: 2 hours
Time from ambulance arrival to IMP administration
Time from arrival of ambulance personnel by the patient to administration of IMP
Measured: 1 hour
Time from ambulance arrival to 2-point NRS reduction
Time from ambulance arrival to first measure of a reduction in NRS of 2 points or more
Measured: 1 hour
Change in level of sedation
Change in GCS from baseline to 10 and 30 minutes
Measured: 30 minutes
Change in respiration
Change in respiratory rate from baseline to 10 and 30 minutes
Measured: 30 minutes
Change in blood pressure
Change in systolic blood pressure from baseline to 10 and 30 minutes
Measured: 30 minutes
Health Care Personnel Likert Scale
Likert Scale (1 to 5, higher is better) of health care professional satisfaction at end of mission
Measured: 2 hours
Patient Likert Scale
Likert Scale (1 to 5, higher is better) of patient satisfaction at end of mission
Measured: 2 hours
Numbers of patients with adverse events in each treatment group
Registration of adverse events during study period until end of intervention and compare numbers of patient with adverse events in each group
Measured: 2 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Nov 2021
- Study start12 Nov 2021
- Primary completion22 Apr 2023
- Study completion22 Apr 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Acute PainStudies of the same condition, open and under way.
- More trials run by Oslo University HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 338 participants (actual)
Sponsor and investigators
- Lead sponsor
- Oslo University Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- Sykehuset Innlandet HF, Norwegian Air Ambulance Foundation, University of Oslo
- Responsible party
- Principal investigator, Fridtjof Heyerdahl, Oslo University Hospital
- Investigators
- Fridtjof Heyerdahl, MD PhD, Principal investigator, Senior Consultant
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05137184
- Sponsor's protocol ID
- 255159
- Other IDs
- 2021-000549-42
- Acronym
- PreMeFen
- Status last verified
- Nov 2023
- First submitted
- 1 Nov 2021
- Last updated
- 14 Nov 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 41275876
Study at a glance
From the registry record, last updated by the sponsor on 14 Nov 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized Controlled, Open-label, Non-inferiority, Three Arm Clinical Study to Assess Inhalation of Low-dose Methoxyflurane, Intranasal Fentanyl, and Intravenous Morphine for Acute Pain in the Pre-hospital Setting
- ClinicalTrials.gov ID
- NCT05137184
- Acronym / sponsor ID
- PreMeFen / 255159
- Conditions
- Acute Pain, Ambulances
- Keywords
- Methoxyflurane, Fentanyl, Morphine
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 338 participants (actual)
- Lead sponsor
- Oslo University HospitalUniversity, hospital or other
- Collaborators
- Sykehuset Innlandet HF, Norwegian Air Ambulance Foundation, University of Oslo
- Study start
- 12 Nov 2021 (actual)
- Primary completion
- 22 Apr 2023 (actual)
- Study completion
- 22 Apr 2023 (actual)
- First posted
- 30 Nov 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 regimen is inferior to intranasal fentanyl regimen or
- Methoxyflurane regimen is inferior to IV morphine regimen or
- Intranasal fentanyl regimen is inferior to IV morphine regimen for treating moderate to severe pain, measured by reduction in Numeric Rating Scale (NRS) 10 minutes after administration.
The study duration for each participant will be from ambulance scene arrival to patient handover in emergency department.
Number of participants: Patient enrolment until successful inclusion of 270 per protocol patients.
Primary endpoint is change in NRS from before administration (t0) to 10 minutes after start of administration (t10).
The study intervention is one of the three IMPs:
- 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Methoxyflurane | Experimental | Drug: Methoxyflurane3 ml inhalation Can be repeated once (3 ml) Maximum total dose of 6 ml |
| Fentanyl IN | Experimental | Drug: Fentanyl100 µg IntraNasal, Patients >70 years: 50 µg IN Can be repeated Maximum total dose 500 µg IN |
| Morphine IV | Active comparator | Drug: Morphine hydrochloride0.1 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 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- ≥ 18 years of age
- Acute moderate to severe pain defined by self-reporting pain ≥4 on NRS
- Capable of giving informed consent
- Normal physiology
Key exclusion criteria (12 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MethoxyfluraneInhalation of Methoxyflurane | Drug | Methoxyflurane |
| FentanylIntranasal Fentanyl | Drug | Fentanyl IN |
| Morphine hydrochlorideIntravenous Morphine | Drug | Morphine IV |
Primary outcome
Change in pain Numeric Rating Scale after 10 minutes
Time frame: 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
15 secondary outcomes
Change in pain Numeric Rating Scale after 5 minutes
Time frame: 5 minutes
Change in pain Numeric Rating Scale after 20 minutes
Time frame: 20 minutes
Change in pain Numeric Rating Scale after 30 minutes
Time frame: 30 minutes
Need for rescue analgesia
Time frame: 2 hours
Type of rescue analgesia
Time frame: 2 hours
Dose of rescue analgesia
Time frame: 2 hours
Route of administration of rescue analgesia
Time frame: 2 hours
Time from ambulance arrival to IMP administration
Time frame: 1 hour
Time from ambulance arrival to 2-point NRS reduction
Time frame: 1 hour
Change in level of sedation
Time frame: 30 minutes
Change in respiration
Time frame: 30 minutes
Change in blood pressure
Time frame: 30 minutes
Health Care Personnel Likert Scale
Time frame: 2 hours
Patient Likert Scale
Time frame: 2 hours
Numbers of patients with adverse events in each treatment group
Time frame: 2 hours
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Nov 2023.
- Derived from this study: PubMed 41275876Simensen 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.
- Individual participant dataSharing planned: No
Related trials for Acute Pain
Not yet recruiting
Human Experimental Models of Pain (HEMP)
Acute Pain
RecruitingPhase 2
REctus Sheath Trial
Acute Pain, Postoperative Pain, Acute
Not yet recruitingPhase 2
A Clinical Trial of MK-6916 in Participants With Pain After Bunion Removal Surgery (MK-6916-007)
Pain Management
Not yet recruitingPhase 2
Investigating the Analgesic Potential of (2R,6R)-HNK in Acute Pain in Healthy Volunteers
Healthy Volunteers
Not yet recruiting
Post-operative Pain and Clinical Outcome After Single-cone Obturation With a Calcium Silicate-based Versus Epoxy Resin Sealer
Post Operative Pain, Acute, Irreversible Pulpitis (Toothache)
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Fridtjof Heyerdahl, MD PhD principal investigator
Senior Consultant
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Methoxyflurane, Fentanyl and Morphine hydrochloride in people with Acute Pain and Ambulances, run by Oslo University Hospital at 1 site in Norway.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 14 Nov 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Norway. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in pain Numeric Rating Scale after 10 minutes (time frame: 10 minutes). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05137184, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Nov 2023.