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Pharmacodynamics and Arteriovenous Differences of Naloxone in Healthy Participants Exposed to an Opioid (OPI-15-001)

Primary Purpose

Drug Overdose

Status
Completed
Phase
Not Applicable
Locations
Norway
Study Type
Interventional
Intervention
Intravenous naloxone
Remifentanil
Sponsored by
Norwegian University of Science and Technology
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Drug Overdose focused on measuring Emergency Treatment, Morphine Derivates, Heroin, Antidotes, Administration, Intravenous, Pharmacology, Naloxone, Healthy volunteers

Eligibility Criteria

18 Years - 40 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • American Society of Anesthesiologists (ASA) class I
  • ECG without pathologic abnormalities
  • BMI range of 18,5 - 26 kg/m2
  • pass the modified allens test to determine collateral circulation of the hand

  • lab values within reference values at St Olav's Hospital for the relevant haematological and biochemical test for inclusion:

    • Haemoglobin (male: 13.4-17.0 g/dL, female 11.7 - 15.3 g/dL)
    • Creatinine (male: 60-105 micromole/L, female 45 - 90 micromole/L)
    • Aspartate aminotransferases (ASAT) (male: 15-45 U/L, female: 15-35 U/L)
    • Alanine transaminase (ALAT) (male: 10-70 U/L, female: 10-45 U/L)
    • Gamma glutamyl transpeptidase (GT) (male: 10-80 U/L, female: 10-45 U/L)
    • For women in reproductive age: serum HCG (normal under 3 ye/L)
  • Signed informed consent and expected cooperation of the subjects for the treatment

Exclusion Criteria:

  • Taking any medications including herbal medicines the last week prior to treatment visits
  • Current or history of drug and/or alcohol abuse (To assess problematic drug or alcohol use we use the CAGE AID screening tool)
  • History of contact with police or authorities in relation to alcohol or drug offences
  • History of prolonged use of opioid analgesics
  • History of prior drug allergy
  • Pregnant women (HCG over 3 ye/L at inclusion)
  • Women in reproductive age not using high efficacy contraceptives (Oral contraceptives, Patch (Evra), Implants, Vaginal ring, Hormonal IUD, Copper intra-uterine device (IUD), Sterilization) throughout the study period until their last visit.
  • Breastfeeding women
  • Participants with access to remifentanil or other potent opioids in their daily workplace.
  • Hypersensitivity to naloxone, remifentanil hydrochloride or lidocaine and/or to any of its excipients.
  • Participants that have participated in previous trials where they have received remifentanil or other opioids.
  • Participants who have donated 450 ml or more blood within 6 weeks prior to visit 2, or who plan to donate blood within 6 weeks after visit 2
  • Any reason why, in the opinion of the investigator, the patient should not participate.

Sites / Locations

  • Department of Circulation and Medical Imaging

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Intravenous naloxone

Arm Description

0,4 mg/ml Naloxone B Braun 2,5 ML intravenously

Outcomes

Primary Outcome Measures

Serum-effect-site equilibration rate constant

Secondary Outcome Measures

Pharmacokinetics: Area Under the Curve of IV naloxone in arterial and venous serum
Measurement of serum naloxone at times 2, 5, 10, 15, 20, 25, 30, 35, 45, 60, 90 and 120 minutes after naloxone administration
Pharmacokinetics: maximum concentration (Cmax) of IV naloxone in arterial and venous serum
Measurement of serum naloxone at times 2, 5, 10, 15, 20, 25, 30, 35, 45, 60, 90 and 120 minutes after naloxone administration
Pharmacokinetics: time to maximum concentration (Tmax) of IV naloxone in arterial and venous serum
Measurement of serum naloxone at times 2, 5, 10, 15, 20, 25, 30, 35, 45, 60, 90 and 120 minutes after naloxone administration
Pharmacodynamics: measurement of naloxone antagonism of remifentanil effects, by measuring changes in pupillary size
Measurement of pupillary size at times -20, -17, -14, -3, -1, 1, 4, 7, 9, 12, 14, 17, 19, 24, 29, 34, 39, 44, 49, 59, 69, 79, 89, 99, 109 and 119 minutes after naloxone administration
Quantitate serum concentrations of remifentanil in arterial and venous blood at specified time points
Measure serum concentration of remifentanil by Gas Chromatography-Mass Spectrometry (GCMS) at -23, -9.5, -7, -2, 30, 60 and 90 minutes relative to naloxone administration
the effect site equilibration rate constant (ke0) for remifentanil for arterial sampling with pupillary size
Measure serum concentration of remifentanil at -23, -9.5, -7, -2, 30, 60 and 90 minutes relative to naloxone administration
serum concentration of remifentanil
Measure serum concentration of remifentanil at -23, -9.5, -7, -2, 30, 60 and 90 minutes relative to naloxone administration

Full Information

First Posted
March 28, 2015
Last Updated
August 27, 2018
Sponsor
Norwegian University of Science and Technology
Collaborators
St. Olavs Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT02405988
Brief Title
Pharmacodynamics and Arteriovenous Differences of Naloxone in Healthy Participants Exposed to an Opioid
Acronym
OPI-15-001
Official Title
Pharmacodynamics and Arteriovenous Differences of Naloxone in Healthy Participants Exposed to an Opioid
Study Type
Interventional

2. Study Status

Record Verification Date
August 2018
Overall Recruitment Status
Completed
Study Start Date
April 2015 (undefined)
Primary Completion Date
February 2016 (Actual)
Study Completion Date
February 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Norwegian University of Science and Technology
Collaborators
St. Olavs Hospital

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Overdose with potential deadly outcome is a serious problem among opioid abusers, not least in Norway. To save lives, immediate treatment with a μ-opioid antidote such as naloxone is required. The purpose of this study is to explore the pharmacokinetics and pharmacodynamics of naloxone in healthy volunteers under opioid influence.
Detailed Description
Healthy volunteers will be brought into a state of opioid influence in a well-known, short acting, controlled and safe manner using remifentanil. This will create a strong opioid effect inducing a miosis, reduced respiration and reduced sensation to pain, all three strong indicators of opiates. Naloxone will counteract these effects, which can be measured as a change in pupillary size. Blood samples for both naloxone and remifentanil will be also be taken. Naloxone is a well-known, well-tolerated drug with an excellent safety profile over many decades of use. The formulation used in this trial holds market authorization. Care will be taken not to include opioid users in this study as naloxone would precipitate acute withdrawal. Also possible drug misusers will be excluded as well as people who have access to remifentanil and infusion equipment in their daily work, although the abuse potential of this highly specialised drug is minimal. By weighing syringes before and after discharge the reliability of the dose delivered will be confirmed.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Drug Overdose
Keywords
Emergency Treatment, Morphine Derivates, Heroin, Antidotes, Administration, Intravenous, Pharmacology, Naloxone, Healthy volunteers

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
12 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Intravenous naloxone
Arm Type
Experimental
Arm Description
0,4 mg/ml Naloxone B Braun 2,5 ML intravenously
Intervention Type
Drug
Intervention Name(s)
Intravenous naloxone
Other Intervention Name(s)
Naloxone B Braun 0,4 mg/ml
Intervention Description
Administer 2,5 mL, dose intravenous naloxone 1,0 mg
Intervention Type
Drug
Intervention Name(s)
Remifentanil
Intervention Description
Administer remifentanil intravenously by way of Target Control Infusion, Minto's model at a target of 1,3 ng/ml. This to achieve a state of safe and predictable opioid influence to assess pharmacodynamic response to naloxone.
Primary Outcome Measure Information:
Title
Serum-effect-site equilibration rate constant
Time Frame
up to 120 minutes
Secondary Outcome Measure Information:
Title
Pharmacokinetics: Area Under the Curve of IV naloxone in arterial and venous serum
Description
Measurement of serum naloxone at times 2, 5, 10, 15, 20, 25, 30, 35, 45, 60, 90 and 120 minutes after naloxone administration
Time Frame
120 minutes
Title
Pharmacokinetics: maximum concentration (Cmax) of IV naloxone in arterial and venous serum
Description
Measurement of serum naloxone at times 2, 5, 10, 15, 20, 25, 30, 35, 45, 60, 90 and 120 minutes after naloxone administration
Time Frame
120 minutes
Title
Pharmacokinetics: time to maximum concentration (Tmax) of IV naloxone in arterial and venous serum
Description
Measurement of serum naloxone at times 2, 5, 10, 15, 20, 25, 30, 35, 45, 60, 90 and 120 minutes after naloxone administration
Time Frame
120 minutes
Title
Pharmacodynamics: measurement of naloxone antagonism of remifentanil effects, by measuring changes in pupillary size
Description
Measurement of pupillary size at times -20, -17, -14, -3, -1, 1, 4, 7, 9, 12, 14, 17, 19, 24, 29, 34, 39, 44, 49, 59, 69, 79, 89, 99, 109 and 119 minutes after naloxone administration
Time Frame
120 minutes
Title
Quantitate serum concentrations of remifentanil in arterial and venous blood at specified time points
Description
Measure serum concentration of remifentanil by Gas Chromatography-Mass Spectrometry (GCMS) at -23, -9.5, -7, -2, 30, 60 and 90 minutes relative to naloxone administration
Time Frame
120 minutes
Title
the effect site equilibration rate constant (ke0) for remifentanil for arterial sampling with pupillary size
Description
Measure serum concentration of remifentanil at -23, -9.5, -7, -2, 30, 60 and 90 minutes relative to naloxone administration
Time Frame
120 minutes
Title
serum concentration of remifentanil
Description
Measure serum concentration of remifentanil at -23, -9.5, -7, -2, 30, 60 and 90 minutes relative to naloxone administration
Time Frame
120 minutes

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: American Society of Anesthesiologists (ASA) class I ECG without pathologic abnormalities BMI range of 18,5 - 26 kg/m2 pass the modified allens test to determine collateral circulation of the hand lab values within reference values at St Olav's Hospital for the relevant haematological and biochemical test for inclusion: Haemoglobin (male: 13.4-17.0 g/dL, female 11.7 - 15.3 g/dL) Creatinine (male: 60-105 micromole/L, female 45 - 90 micromole/L) Aspartate aminotransferases (ASAT) (male: 15-45 U/L, female: 15-35 U/L) Alanine transaminase (ALAT) (male: 10-70 U/L, female: 10-45 U/L) Gamma glutamyl transpeptidase (GT) (male: 10-80 U/L, female: 10-45 U/L) For women in reproductive age: serum HCG (normal under 3 ye/L) Signed informed consent and expected cooperation of the subjects for the treatment Exclusion Criteria: Taking any medications including herbal medicines the last week prior to treatment visits Current or history of drug and/or alcohol abuse (To assess problematic drug or alcohol use we use the CAGE AID screening tool) History of contact with police or authorities in relation to alcohol or drug offences History of prolonged use of opioid analgesics History of prior drug allergy Pregnant women (HCG over 3 ye/L at inclusion) Women in reproductive age not using high efficacy contraceptives (Oral contraceptives, Patch (Evra), Implants, Vaginal ring, Hormonal IUD, Copper intra-uterine device (IUD), Sterilization) throughout the study period until their last visit. Breastfeeding women Participants with access to remifentanil or other potent opioids in their daily workplace. Hypersensitivity to naloxone, remifentanil hydrochloride or lidocaine and/or to any of its excipients. Participants that have participated in previous trials where they have received remifentanil or other opioids. Participants who have donated 450 ml or more blood within 6 weeks prior to visit 2, or who plan to donate blood within 6 weeks after visit 2 Any reason why, in the opinion of the investigator, the patient should not participate.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Toril A Nagelhus Hernes, phd prof
Organizational Affiliation
Norwegian University of Science and Technology
Official's Role
Study Director
Facility Information:
Facility Name
Department of Circulation and Medical Imaging
City
Trondheim
Country
Norway

12. IPD Sharing Statement

Citations:
PubMed Identifier
30143830
Citation
Tylleskar I, Skulberg AK, Skarra S, Nilsen T, Dale O. Pharmacodynamics and arteriovenous difference of intravenous naloxone in healthy volunteers exposed to remifentanil. Eur J Clin Pharmacol. 2018 Dec;74(12):1547-1553. doi: 10.1007/s00228-018-2545-y. Epub 2018 Aug 24.
Results Reference
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Pharmacodynamics and Arteriovenous Differences of Naloxone in Healthy Participants Exposed to an Opioid

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