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

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ClinicalTrials.gov Identifier: NCT02405988
Recruitment Status : Completed
First Posted : April 1, 2015
Last Update Posted : August 29, 2018
Sponsor:
Collaborator:
St. Olavs Hospital
Information provided by (Responsible Party):
Norwegian University of Science and Technology

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.

Condition or disease Intervention/treatment Phase
Drug Overdose Drug: Intravenous naloxone Drug: Remifentanil Not Applicable

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 12 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Pharmacodynamics and Arteriovenous Differences of Naloxone in Healthy Participants Exposed to an Opioid
Study Start Date : April 2015
Actual Primary Completion Date : February 2016
Actual Study Completion Date : February 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Intravenous naloxone
0,4 mg/ml Naloxone B Braun 2,5 ML intravenously
Drug: Intravenous naloxone
Administer 2,5 mL, dose intravenous naloxone 1,0 mg
Other Name: Naloxone B Braun 0,4 mg/ml

Drug: Remifentanil
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 Measures :
  1. Serum-effect-site equilibration rate constant [ Time Frame: up to 120 minutes ]

Secondary Outcome Measures :
  1. Pharmacokinetics: Area Under the Curve of IV naloxone in arterial and venous serum [ Time Frame: 120 minutes ]
    Measurement of serum naloxone at times 2, 5, 10, 15, 20, 25, 30, 35, 45, 60, 90 and 120 minutes after naloxone administration

  2. Pharmacokinetics: maximum concentration (Cmax) of IV naloxone in arterial and venous serum [ Time Frame: 120 minutes ]
    Measurement of serum naloxone at times 2, 5, 10, 15, 20, 25, 30, 35, 45, 60, 90 and 120 minutes after naloxone administration

  3. Pharmacokinetics: time to maximum concentration (Tmax) of IV naloxone in arterial and venous serum [ Time Frame: 120 minutes ]
    Measurement of serum naloxone at times 2, 5, 10, 15, 20, 25, 30, 35, 45, 60, 90 and 120 minutes after naloxone administration

  4. Pharmacodynamics: measurement of naloxone antagonism of remifentanil effects, by measuring changes in pupillary size [ Time Frame: 120 minutes ]
    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

  5. Quantitate serum concentrations of remifentanil in arterial and venous blood at specified time points [ Time Frame: 120 minutes ]
    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

  6. the effect site equilibration rate constant (ke0) for remifentanil for arterial sampling with pupillary size [ Time Frame: 120 minutes ]
    Measure serum concentration of remifentanil at -23, -9.5, -7, -2, 30, 60 and 90 minutes relative to naloxone administration

  7. serum concentration of remifentanil [ Time Frame: 120 minutes ]
    Measure serum concentration of remifentanil at -23, -9.5, -7, -2, 30, 60 and 90 minutes relative to naloxone administration



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Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02405988


Locations
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Norway
Department of Circulation and Medical Imaging
Trondheim, Norway
Sponsors and Collaborators
Norwegian University of Science and Technology
St. Olavs Hospital
Investigators
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Study Director: Toril A Nagelhus Hernes, phd prof Norwegian University of Science and Technology

Publications of Results:
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Responsible Party: Norwegian University of Science and Technology
ClinicalTrials.gov Identifier: NCT02405988     History of Changes
Other Study ID Numbers: OPI-15-001
2014-005348-16 ( EudraCT Number )
First Posted: April 1, 2015    Key Record Dates
Last Update Posted: August 29, 2018
Last Verified: August 2018

Keywords provided by Norwegian University of Science and Technology:
Emergency Treatment
Morphine Derivates
Heroin
Antidotes
Administration, Intravenous
Pharmacology
Naloxone
Healthy volunteers

Additional relevant MeSH terms:
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Drug Overdose
Substance-Related Disorders
Chemically-Induced Disorders
Remifentanil
Naloxone
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Narcotic Antagonists