Determination of Analgesic Equipotent Doses of Inhaled Metoxyflurane vs. Intravenous Fentanyl

Phase 4

Completed

• Conditions: Acute Pain; Trauma; Hypovolemia
• Interventions: Drug: Methoxyflurane (M); Drug: Fentanyl (F1); Drug: Fentanyl (F2); Drug: NaCl (C)

• Registration Number: NCT03894800
• Lead Sponsor: Oslo University Hospital

Brief Summary

The aim of this study is to determinate the equipotent doses of inhaled metoxyflurane vs. intravenous fentanyl.

Detailed Description

Traumatized patients frequently experience pain prehospital due to the fear of adverse cardiovascular effects (e.g. hypotension) and respiration depression of opioid treatment, leading to insufficient analgesia. Therefore, there is of interest to investigate other analgesics that do not have these adverse effects.

In Norway, methoxyflurane has been approved for the emergency relief of moderate to severe trauma pain in conscious adult patients. Metoxyflurane (Penthrox®) do not have these adverse effects (hypotension and respiration depression). It is easy to administrate via an inhalator, and is therefore suitable for use prehospital. This would possible help to treat pain better prehospital.

There exists no data of how effective metoxyflurane is as an analgesic compared to an opioid. The aim of this study is to determinate the equipotent doses of inhaled metoxyflurane vs. intravenous fentanyl.

Ten healthy volunteers (18 - 64 years) will be enrolled in a randomized, double blind, placebo-controlled, crossover study using a standard experimental pain model: CPT- Cold pressor test (ice water). Our group has used this experimental pain model in earlier studies and a crossover study is suitable to compare different drugs.

Possible side effects will be recorded for both metoxyflurane and fentanyl: sedation, dizziness, itching, nausea and vomiting. Respiration frequency and non-invasive blood pressure will be recorded every as possible low blood pressure or respiration depression can occur.

The aim of this study is to determinate equipotent doses of inhaled metoxyflurane vs. intravenous fentanyl. We have chosen to compare with fentanyl (the comparator) because it is a well-known drug in clinical practice for acute pain treatment. In addition, both drugs have a fast onset (minutes) and the analgesic effect last for approximately the same time interval (20-30 min). Therefore, they are comparable in a clinical setting.

There exists no exact data of equipotent doses between metoxyflurane and fentanyl, only retrospective clinical data. One retrospective study compared intranasal fentanyl with inhaled metoxyflurane for visceral pain prehospital in 1024 patients. The initial dose of fentanyl was 0.018 mg and the total mean dose at hospital arrival was 0.036 mg. In the metoxyflurane group 51.9% received 3 ml, a second dose was used in 41.9% and 6.2% received a third dose. Metoxyflurane produced the greatest initial pain scores reduction, and intranasal fentanyl provided greater pain reduction by hospital arrival.

From these data we have chosen two doses of fentanyl to be compared with 3 ml Penthrox: 0.025 mg and 0.05 mg intravenous. Both drugs will also be compared to placebo (NaCl 9 mg/ml).

Study Timeline

• Study First Submitted: 2019-03-04
• Study First Submitted QC: 2019-03-26
• Study First Posted: 2019-03-29
• Study Start: 2019-04-23
• Primary Completion: 2019-10-29
• Study Completion: 2019-10-29
• Status Verified: 2019-11
• Last Update Submitted: 2019-11-18
• Last Update Posted: 2019-11-19

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 12

Inclusion Criteria

1. Healthy volunteers
2. Age 18 - 64
3. Both sex
4. No chronic disease
5. No regular medication
6. Recruited from the general population
7. Signed informed consent and expected cooperation of the subjects for the treatment and follow up must be obtained and documented according to ICH GCP, and national/local regulations

Exclusion Criteria

1. Use of pain medication the last 2 days before a session

2. Use of complementary medicine the last 2 days before a session

3. Use of regular medication

4. Previous substance abuse

5. Pregnancy

6. Know allergies or serious side effects to opioids or metoxyflurane

7. Use of alcohol last 24 h before each session

8. Exclusion criteria with respect to fentanyl:

9. Hypersensitivity opposite the active substance (fentanyl) or other opioids

10. Hypersensitivity opposite the excipients (to fentanyl): sodiumclorid, water for injection, hydrochloric acid or sodium hydroxide

11. Respiratory depression without artificial ventilation

12. Use of MAO-inhibitor or use of MAO-inhibitor by two weeks before inclusion

13. Elevated intracranial pressure or brain trauma

14. Hypovolemia or hypotension

15. Myasthenia gravis

16. Exclusion criteria with respect to metoxyflurane:

17. Use metoxyflurane as anesthetic

18. Hypersensitivity opposite metoxyflurane or fluorinated anesthetics

19. Hypersensitivity opposite the excipient (to metoxyflurane):

    Butylhydroksytoulen

20. Malignant hyperthermia or persons with suspect genetic predisposition for malignant hyperthermia

21. History (to the volunteer or family) of serious adverse effects after administration of inhalation anesthetics

22. Volunteers showing sign of liver damage after use of metoxyflurane or halogenated anesthetics

23. History of liver disease

24. Clinical significant reduced kidney function or history of kidney disease

25. Changed of level of consciousness of any cause, including brain trauma, drugs or alcohol

26. Clinical detected cardiovascular unstability

27. Clinical detected respiratory depression

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Methoxyflurane (M)	NaCl (C)	A session starts with a CPT - cold pressor test (time -15 minutes). Then a 10 minutes rest before the subject receives a syringe of NaCl intravenous (time -5 minutes). At the same time the subject begin to inhale metoxyflurane through the inhalator. The subject should first take 10 breath through the inhalator. This will take approximately 1-1.5 minutes. The subject then take a break, and then inhale the rest of the dosage before time zero. At time zero a new CPT will be performed. At time 15 minutes the last CPT will be performed. The subjects will undergo CPT (cold pressor test) to determine the analgesic effect of the drugs. Each test lasts up to 90 seconds and endpoints are NRS scores every 10 second.
Fentanyl (F1)	NaCl (C)	A session starts with a CPT (time -15 minutes). Then a 10 minutes rest before the subject receives a syringe of fentanyl 0.025 mg intravenous (time -5 minutes). At the same time the subject begin to inhale NaCl through the inhalator. The subject should first take 10 breath through the inhalator. This will take approximately 1-1.5 minutes. The subject then take a break, and then inhale the rest of the dosage before time zero. At time zero a new CPT will be performed. At time 15 minutes the last CPT will be performed. The subjects will undergo CPT (cold pressor test) to determine the analgesic effect of the drugs.Each test lasts up to 90 seconds and endpoints are NRS scores every 10 second.
Fentanyl (F2)	NaCl (C)	A session starts with a CPT (time -15 minutes). Then a 10 minutes rest before the subject receives a syringe of fentanyl 0.05 mg intravenous (time -5 minutes). At the same time the subject begin to inhale NaCl through the inhalator. The subject should first take 10 breath through the inhalator. This will take approximately 1-1.5 minutes. The subject then take a break, and then inhale the rest of the dosage before time zero. At time zero a new CPT will be performed. At time 15 minutes the last CPT will be performed. The subjects will undergo CPT (cold pressor test) to determine the analgesic effect of the drugs. Each test lasts up to 90 seconds and endpoints are NRS scores every 10 second.
NaCl (C)	NaCl (C)	A session starts with a CPT (time -15 minutes). Then a 10 minutes rest before the subject receives a syringe of NaCl intravenous (time -5 minutes). At the same time the subject begin to inhale NaCl through the inhalator. The subject should first take 10 breath through the inhalator. This will take approximately 1-1.5 minutes. The subject then take a break, and then inhale the rest of the dosage before time zero. At time zero a new CPT will be performed. At time 15 minutes the last CPT will be performed. The subjects will undergo CPT (cold pressor test) to determine the analgesic effect of the drugs. Each test lasts up to 90 seconds and endpoints are NRS scores every 10 second.
Methoxyflurane (M)	Methoxyflurane (M)	A session starts with a CPT - cold pressor test (time -15 minutes). Then a 10 minutes rest before the subject receives a syringe of NaCl intravenous (time -5 minutes). At the same time the subject begin to inhale metoxyflurane through the inhalator. The subject should first take 10 breath through the inhalator. This will take approximately 1-1.5 minutes. The subject then take a break, and then inhale the rest of the dosage before time zero. At time zero a new CPT will be performed. At time 15 minutes the last CPT will be performed. The subjects will undergo CPT (cold pressor test) to determine the analgesic effect of the drugs. Each test lasts up to 90 seconds and endpoints are NRS scores every 10 second.
Fentanyl (F1)	Fentanyl (F1)	A session starts with a CPT (time -15 minutes). Then a 10 minutes rest before the subject receives a syringe of fentanyl 0.025 mg intravenous (time -5 minutes). At the same time the subject begin to inhale NaCl through the inhalator. The subject should first take 10 breath through the inhalator. This will take approximately 1-1.5 minutes. The subject then take a break, and then inhale the rest of the dosage before time zero. At time zero a new CPT will be performed. At time 15 minutes the last CPT will be performed. The subjects will undergo CPT (cold pressor test) to determine the analgesic effect of the drugs.Each test lasts up to 90 seconds and endpoints are NRS scores every 10 second.
Fentanyl (F2)	Fentanyl (F2)	A session starts with a CPT (time -15 minutes). Then a 10 minutes rest before the subject receives a syringe of fentanyl 0.05 mg intravenous (time -5 minutes). At the same time the subject begin to inhale NaCl through the inhalator. The subject should first take 10 breath through the inhalator. This will take approximately 1-1.5 minutes. The subject then take a break, and then inhale the rest of the dosage before time zero. At time zero a new CPT will be performed. At time 15 minutes the last CPT will be performed. The subjects will undergo CPT (cold pressor test) to determine the analgesic effect of the drugs. Each test lasts up to 90 seconds and endpoints are NRS scores every 10 second.

Primary Outcome Measures

Name	Time	Method
NRS (numeric rating scale) scores during the second CPT, which starts 5 minutes after drug administration and lasts for 90 seconds. NRS is a scale from 0 to 10 (0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10). 0 = no pain and 10 = worst pain imaginable.	90 seconds	NRS (numeric rating scale) scores during CPT (Cold pressor test) 5 minutes after drug administration. The CPT lasts for 90 seconds. The endpoints are NRS scores every 10. second during the CPT.

Secondary Outcome Measures

Name	Time	Method
NRS (numeric rating scale) scores during the second CPT, which starts 20 minutes after drug administration and lasts for 90 seconds. This is a scale from 0 to 10 (0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10). 0 = no pain and 10 = worst pain imaginable.	90 seconds	NRS scores during CPT (Cold pressor test) 20 minutes after drug administration (15 minutes after last CPT).The CPT lasts for 90 seconds. The endpoints are NRS scores every 10. second during the CPT.

Trial Locations

Locations (1)

Harald Lenz; 🇳🇴 Oslo, Norway