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

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ClinicalTrials.gov Identifier: NCT03894800
Recruitment Status : Recruiting
First Posted : March 29, 2019
Last Update Posted : April 25, 2019
Sponsor:
Information provided by (Responsible Party):
Harald Lenz, Oslo University Hospital

Tracking Information
First Submitted Date  ICMJE March 4, 2019
First Posted Date  ICMJE March 29, 2019
Last Update Posted Date April 25, 2019
Actual Study Start Date  ICMJE April 23, 2019
Estimated Primary Completion Date December 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 26, 2019)
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. [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03894800 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 26, 2019)
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. [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Determination of Analgesic Equipotent Doses of Inhaled Metoxyflurane vs. Intravenous Fentanyl
Official Title  ICMJE 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.
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:
This is a randomized, double blind, placebo-controlled crossover study.
Masking: Double (Participant, Investigator)
Masking Description:
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
Primary Purpose: Treatment
Condition  ICMJE
  • Acute Pain
  • Trauma
  • Hypovolemia
Intervention  ICMJE
  • 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 Name: NaCl
  • 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 Name: NaCl (C)
  • 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 Name: NaCl (C)
  • 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.
Study Arms  ICMJE
  • 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.

    Interventions:
    • Drug: Methoxyflurane (M)
    • Drug: NaCl (C)
  • 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.

    Interventions:
    • Drug: Fentanyl (F1)
    • Drug: 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.

    Interventions:
    • Drug: Fentanyl (F2)
    • Drug: 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.

    Intervention: Drug: NaCl (C)
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 9, 2019)
12
Original Estimated Enrollment  ICMJE
 (submitted: March 26, 2019)
10
Estimated Study Completion Date  ICMJE December 31, 2020
Estimated Primary Completion Date December 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 64 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Harald Lenz, Phd 004790549545 harald.lenz@medisin.uio.no
Contact: Leiv Arne Rosseland, Phd 004792204274 l.a.rosseland@medisin.uio.no
Listed Location Countries  ICMJE Norway
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03894800
Other Study ID Numbers  ICMJE 2018-0910-3
2018-003939-30 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Harald Lenz, Oslo University Hospital
Study Sponsor  ICMJE Oslo University Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Harald Lenz, Phd Oslo University Hospital
PRS Account Oslo University Hospital
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP