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

Determination of Analgesic Equipotent Doses of Inhaled Metoxyflurane vs. Intravenous Fentanyl Using Cold Pressor Test (CPT) in Volunteers: A Randomized, Double Blind, Placebo-controlled Crossover Study.

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

Study Overview

• Status: Completed
• Conditions: Trauma; Acute Pain; Hypovolemia
• Intervention / Treatment: Drug: Methoxyflurane (M); Drug: NaCl (C); Drug: Fentanyl (F1); Drug: Fentanyl (F2)

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 Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 4

Contacts and Locations

Study Locations

• Norway
  • Oslo, Norway
    • Harald Lenz

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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.	Drug: 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.; Other Names: NaCl; 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.
Active Comparator: 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.	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.; 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.; Other Names: NaCl (C)
Active Comparator: 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.	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.; 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.; Other Names: NaCl (C)
Placebo Comparator: 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.	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	90 seconds

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	90 seconds

Collaborators and Investigators

• Sponsor: Oslo University Hospital
• Investigators: Principal Investigator: Harald Lenz, Phd, Oslo University Hospital

Publications and helpful links

General Publications

• Albrecht E, Taffe P, Yersin B, Schoettker P, Decosterd I, Hugli O. Undertreatment of acute pain (oligoanalgesia) and medical practice variation in prehospital analgesia of adult trauma patients: a 10 yr retrospective study. Br J Anaesth. 2013 Jan;110(1):96-106. doi: 10.1093/bja/aes355. Epub 2012 Oct 11.
• Neighbor ML, Honner S, Kohn MA. Factors affecting emergency department opioid administration to severely injured patients. Acad Emerg Med. 2004 Dec;11(12):1290-6. doi: 10.1197/j.aem.2004.07.014.
• Stephen CR. Clinical applications of methoxyflurane. Acta Anaesthesiol Scand Suppl. 1966;24:215-22. doi: 10.1111/j.1399-6576.1966.tb01127.x. No abstract available.
• Mazze RI. Methoxyflurane revisited: tale of an anesthetic from cradle to grave. Anesthesiology. 2006 Oct;105(4):843-6. doi: 10.1097/00000542-200610000-00031.
• Grindlay J, Babl FE. Review article: Efficacy and safety of methoxyflurane analgesia in the emergency department and prehospital setting. Emerg Med Australas. 2009 Feb;21(1):4-11. doi: 10.1111/j.1742-6723.2009.01153.x.
• Rosen M, Latto P, Asscher AW. Kidney function after methoxyflurane analgesia during labour. Br Med J. 1972 Jan 8;1(5792):81-3. doi: 10.1136/bmj.1.5792.81.
• Clark RB, Beard AG, Thompson DS. Renal function in newborns and mothers exposed to methoxyflurane analgesia for labor and delivery. Anesthesiology. 1979 Nov;51(5):464-6. doi: 10.1097/00000542-197911000-00020. No abstract available.
• Lenz H, Hoiseth LO, Comelon M, Draegni T, Rosseland LA. Determination of equi-analgesic doses of inhaled methoxyflurane versus intravenous fentanyl using the cold pressor test in volunteers: a randomised, double-blinded, placebo-controlled crossover study. Br J Anaesth. 2021 May;126(5):1038-1045. doi: 10.1016/j.bja.2020.12.045. Epub 2021 Mar 4.

Study record dates

Study Major Dates

• Study Start (Actual): April 23, 2019
• Primary Completion (Actual): October 29, 2019
• Study Completion (Actual): October 29, 2019

Study Registration Dates

• First Submitted: March 4, 2019
• First Submitted That Met QC Criteria: March 26, 2019
• First Posted (Actual): March 29, 2019

Study Record Updates

• Last Update Posted (Actual): November 19, 2019
• Last Update Submitted That Met QC Criteria: November 18, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: pain; fentanyl; cold pressor test; metoxyflurane
• Additional Relevant MeSH Terms: Pathologic Processes; Pain; Neurologic Manifestations; Acute Pain; Hypovolemia; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Analgesics, Opioid; Narcotics; Adjuvants, Anesthesia; Anesthetics, Inhalation; Fentanyl; Methoxyflurane
• Other Study ID Numbers: 2018-0910-3; 2018-003939-30 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No