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

Phase 3

Completed

• Conditions: Acute Pain; Ambulances
• Interventions: Drug: Morphine hydrochloride; Drug: Methoxyflurane; Drug: Fentanyl

• Registration Number: NCT05137184
• Lead Sponsor: Oslo University Hospital

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):

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2021-11-01
• Study Start: 2021-11-12
• Study First Submitted QC: 2021-11-29
• Study First Posted: 2021-11-30
• Primary Completion: 2023-04-22
• Study Completion: 2023-04-22
• Status Verified: 2023-11
• Last Update Submitted: 2023-11-13
• Last Update Posted: 2023-11-14

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 338

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

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Morphine IV	Morphine hydrochloride	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
Methoxyflurane	Methoxyflurane	3 ml inhalation Can be repeated once (3 ml) Maximum total dose of 6 ml
Fentanyl IN	Fentanyl	100 µg IntraNasal, Patients \>70 years: 50 µg IN Can be repeated Maximum total dose 500 µg IN

Primary Outcome Measures

Name	Time	Method
Change in pain Numeric Rating Scale after 10 minutes	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

Secondary Outcome Measures

Name	Time	Method
Change in pain Numeric Rating Scale after 5 minutes	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
Dose of rescue analgesia	2 hours	Dose of rescue analgesia administered
Need for rescue analgesia	2 hours	Number of patients with administration of rescue analgesia
Change in level of sedation	30 minutes	Change in GCS from baseline to 10 and 30 minutes
Change in pain Numeric Rating Scale after 30 minutes	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
Change in pain Numeric Rating Scale after 20 minutes	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
Time from ambulance arrival to 2-point NRS reduction	1 hour	Time from ambulance arrival to first measure of a reduction in NRS of 2 points or more
Change in blood pressure	30 minutes	Change in systolic blood pressure from baseline to 10 and 30 minutes
Health Care Personnel Likert Scale	2 hours	Likert Scale (1 to 5, higher is better) of health care professional satisfaction at end of mission
Patient Likert Scale	2 hours	Likert Scale (1 to 5, higher is better) of patient satisfaction at end of mission
Type of rescue analgesia	2 hours	Type of rescue analgesia administered
Route of administration of rescue analgesia	2 hours	Route of administration of rescue analgesia
Time from ambulance arrival to IMP administration	1 hour	Time from arrival of ambulance personnel by the patient to administration of IMP
Change in respiration	30 minutes	Change in respiratory rate from baseline to 10 and 30 minutes
Numbers of patients with adverse events in each treatment group	2 hours	Registration of adverse events during study period until end of intervention and compare numbers of patient with adverse events in each group

Trial Locations

Locations (1)

Sykehuset Innlandet; 🇳🇴 Gjøvik, Norway