Pharmacodynamics and Arteriovenous Differences of Naloxone in Healthy Participants Exposed to an Opioid

Study Overview
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Brief Summary
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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
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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.

Official Title
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Pharmacodynamics and Arteriovenous Differences of Naloxone in Healthy Participants Exposed to an Opioid

Conditions
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Drug Overdose

Intervention / Treatment
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* Drug: Intravenous naloxone
* Drug: Remifentanil


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intravenous naloxone<br>0,4 mg/ml Naloxone B Braun 2,5 ML intravenously | Drug: Intravenous naloxone<br>* Administer 2,5 mL, dose intravenous naloxone 1,0 mg<br>* Other names: Naloxone B Braun 0,4 mg/ml;Drug: Remifentanil<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum-effect-site equilibration rate constant |  | up to 120 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 120 minutes | 
| 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 | 120 minutes | 
| 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 | 120 minutes | 
| 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 | 120 minutes | 
| 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 | 120 minutes | 
| 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 | 120 minutes | 
| serum concentration of remifentanil | Measure serum concentration of remifentanil at -23, -9.5, -7, -2, 30, 60 and 90 minutes relative to naloxone administration | 120 minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Emergency Treatment, Morphine Derivates, Heroin, Antidotes, Administration, Intravenous, Pharmacology, Naloxone, Healthy volunteers