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

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE4

Total Enrollment

12 participants

Study Classification

INTERVENTIONAL

Study Start Date

2019-04-23

Study Completion Date

2019-10-29

Brief Summary

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

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Detailed Description

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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).

Conditions

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Acute Pain Trauma Hypovolemia

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

CROSSOVER

This is a randomized, double blind, placebo-controlled crossover study.

Primary Study Purpose

TREATMENT

Blinding Strategy

DOUBLE

Participants Investigators

Labeling of the IMPs will be done by one a nurse anesthetist not participating in the study. The study drugs, will be distributed in a pre-packed in identical, opaque envelopes (the same day as the drugs will be used). The envelopes are not to be broken until randomization of the patient is done

Study Groups

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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.

Group Type ACTIVE_COMPARATOR

Methoxyflurane (M)

Intervention Type DRUG

The subjects will undergo CPT (cold pressor test) to determine the analgesic effect of the drugs, in this intervention inhalation of metoxyflurane 3 ml and NaCl i.v. will be administered.(13,14) The CPT will be conducted using a temperature-controlled bath with circulating 3°C water (FP 45-HE Refrigerated/Heating Circulator, Julabo Labortechnic, 77960 Seelback, Germany). The subjects submerge their right hand to the wrist with fingers abducted for up to 90 s. The endpoints are NRS scores every 10 s.This test will be performed 3 times for each session.

NaCl (C)

Intervention Type DRUG

The subjects will undergo CPT (cold pressor test) to determine the analgesic effect of the drugs, in this intervention NaCl i.v. and NaCl inhal will be used - placebo(13,14) The CPT will be conducted using a temperature-controlled bath with circulating 3°C water (FP 45-HE Refrigerated/Heating Circulator, Julabo Labortechnic, 77960 Seelback, Germany). The subjects submerge their right hand to the wrist with fingers abducted for up to 90 s. The endpoints are NRS scores every 10 s.This test will be performed 3 times for each session.

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.

Group Type ACTIVE_COMPARATOR

Fentanyl (F1)

Intervention Type DRUG

The subjects will undergo CPT (cold pressor test) to determine the analgesic effect of the drugs, in this intervention fentanyl 0.025 mg i.v. and NaCl for inhalation will be administered(13,14) The CPT will be conducted using a temperature-controlled bath with circulating 3°C water (FP 45-HE Refrigerated/Heating Circulator, Julabo Labortechnic, 77960 Seelback, Germany). The subjects submerge their right hand to the wrist with fingers abducted for up to 90 s. The endpoints are NRS scores every 10 s.This test will be performed 3 times for each session.

NaCl (C)

Intervention Type DRUG

The subjects will undergo CPT (cold pressor test) to determine the analgesic effect of the drugs, in this intervention NaCl i.v. and NaCl inhal will be used - placebo(13,14) The CPT will be conducted using a temperature-controlled bath with circulating 3°C water (FP 45-HE Refrigerated/Heating Circulator, Julabo Labortechnic, 77960 Seelback, Germany). The subjects submerge their right hand to the wrist with fingers abducted for up to 90 s. The endpoints are NRS scores every 10 s.This test will be performed 3 times for each session.

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.

Group Type ACTIVE_COMPARATOR

Fentanyl (F2)

Intervention Type DRUG

The subjects will undergo CPT (cold pressor test) to determine the analgesic effect of the drugs, in this intervention fentanyl 0.05 mg i.v. and NaCl for inhalation will be administered.(13,14) The CPT will be conducted using a temperature-controlled bath with circulating 3°C water (FP 45-HE Refrigerated/Heating Circulator, Julabo Labortechnic, 77960 Seelback, Germany). The subjects submerge their right hand to the wrist with fingers abducted for up to 90 s. The endpoints are NRS scores every 10 s.This test will be performed 3 times for each session.

NaCl (C)

Intervention Type DRUG

The subjects will undergo CPT (cold pressor test) to determine the analgesic effect of the drugs, in this intervention NaCl i.v. and NaCl inhal will be used - placebo(13,14) The CPT will be conducted using a temperature-controlled bath with circulating 3°C water (FP 45-HE Refrigerated/Heating Circulator, Julabo Labortechnic, 77960 Seelback, Germany). The subjects submerge their right hand to the wrist with fingers abducted for up to 90 s. The endpoints are NRS scores every 10 s.This test will be performed 3 times for each session.

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.

Group Type PLACEBO_COMPARATOR

NaCl (C)

Intervention Type DRUG

The subjects will undergo CPT (cold pressor test) to determine the analgesic effect of the drugs, in this intervention NaCl i.v. and NaCl inhal will be used - placebo(13,14) The CPT will be conducted using a temperature-controlled bath with circulating 3°C water (FP 45-HE Refrigerated/Heating Circulator, Julabo Labortechnic, 77960 Seelback, Germany). The subjects submerge their right hand to the wrist with fingers abducted for up to 90 s. The endpoints are NRS scores every 10 s.This test will be performed 3 times for each session.

Interventions

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Methoxyflurane (M)

The subjects will undergo CPT (cold pressor test) to determine the analgesic effect of the drugs, in this intervention inhalation of metoxyflurane 3 ml and NaCl i.v. will be administered.(13,14) The CPT will be conducted using a temperature-controlled bath with circulating 3°C water (FP 45-HE Refrigerated/Heating Circulator, Julabo Labortechnic, 77960 Seelback, Germany). The subjects submerge their right hand to the wrist with fingers abducted for up to 90 s. The endpoints are NRS scores every 10 s.This test will be performed 3 times for each session.

Intervention Type DRUG

Fentanyl (F1)

The subjects will undergo CPT (cold pressor test) to determine the analgesic effect of the drugs, in this intervention fentanyl 0.025 mg i.v. and NaCl for inhalation will be administered(13,14) The CPT will be conducted using a temperature-controlled bath with circulating 3°C water (FP 45-HE Refrigerated/Heating Circulator, Julabo Labortechnic, 77960 Seelback, Germany). The subjects submerge their right hand to the wrist with fingers abducted for up to 90 s. The endpoints are NRS scores every 10 s.This test will be performed 3 times for each session.

Intervention Type DRUG

Fentanyl (F2)

The subjects will undergo CPT (cold pressor test) to determine the analgesic effect of the drugs, in this intervention fentanyl 0.05 mg i.v. and NaCl for inhalation will be administered.(13,14) The CPT will be conducted using a temperature-controlled bath with circulating 3°C water (FP 45-HE Refrigerated/Heating Circulator, Julabo Labortechnic, 77960 Seelback, Germany). The subjects submerge their right hand to the wrist with fingers abducted for up to 90 s. The endpoints are NRS scores every 10 s.This test will be performed 3 times for each session.

Intervention Type DRUG

NaCl (C)

The subjects will undergo CPT (cold pressor test) to determine the analgesic effect of the drugs, in this intervention NaCl i.v. and NaCl inhal will be used - placebo(13,14) The CPT will be conducted using a temperature-controlled bath with circulating 3°C water (FP 45-HE Refrigerated/Heating Circulator, Julabo Labortechnic, 77960 Seelback, Germany). The subjects submerge their right hand to the wrist with fingers abducted for up to 90 s. The endpoints are NRS scores every 10 s.This test will be performed 3 times for each session.

Intervention Type DRUG

Other Intervention Names

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NaCl NaCl (C) NaCl (C)

Eligibility Criteria

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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
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
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

Minimum Eligible Age

18 Years

Maximum Eligible Age

64 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes