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):

1. Methoxyflurane regimen is inferior to intranasal fentanyl regimen or
2. Methoxyflurane regimen is inferior to IV morphine regimen or
3. 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.

Inclusion Criteria:

1. ≥ 18 years of age
2. Acute moderate to severe pain defined by self-reporting pain ≥4 on NRS
3. Capable of giving informed consent
4. Normal physiology

Exclusion Criteria:

1. Life-threatening or limb-threatening condition requiring immediate management
2. Pregnancy or breastfeeding
3. Know allergies, hypersensitivity or serious side effects to opioids or methoxyflurane or other excipients
4. Head injury or medical conditions with neurological impairment (Glasgow Coma Scale (GCS)<14)
5. Previous malignant hyperthermia or persons with suspect genetic predisposition for malignant hyperthermia
6. Massive facial trauma, visible nasal blockage or on-going nose bleeding
7. History of severe liver disease with jaundice and scleral icterus
8. Dialysis or history of severe renal disease (known chronic kidney failure stage 4 or 5)
9. Mono Amine Oxidase-inhibitors last 14 days (pharmacological treatment of depression, Mb Parkinson or narcolepsy)
10. Myasthenia gravis
11. Use of investigational medicinal product (IMP) analgesics 12 hours prior to inclusion
12. Any condition that in the view of the study worker would suggest that the patient is unable to comply with study protocol and procedures.

Masking Statistician