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

Sponsor

Norwegian University of Science and Technology (Other)

Overall Status

Completed

CT.gov ID

NCT02405988

Collaborator

St. Olavs Hospital (Other)

Enrollment

Location

Arm

10.1

Duration (Months)

1.2

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Drug Overdose	Drug: Intravenous naloxone Drug: Remifentanil	N/A

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

12 participants

Allocation:

N/A

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 :

Apr 1, 2015

Actual Primary Completion Date :

Feb 1, 2016

Actual Study Completion Date :

Feb 1, 2016

Arms and Interventions

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 Names: 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.

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 Names:

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.

Outcome Measures

Primary Outcome Measures

Serum-effect-site equilibration rate constant [up to 120 minutes]

Secondary Outcome Measures

Pharmacokinetics: Area Under the Curve of IV naloxone in arterial and venous serum [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
Pharmacokinetics: maximum concentration (Cmax) of IV naloxone in arterial and venous serum [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
Pharmacokinetics: time to maximum concentration (Tmax) of IV naloxone in arterial and venous serum [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
Pharmacodynamics: measurement of naloxone antagonism of remifentanil effects, by measuring changes in pupillary size [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
Quantitate serum concentrations of remifentanil in arterial and venous blood at specified time points [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
the effect site equilibration rate constant (ke0) for remifentanil for arterial sampling with pupillary size [120 minutes]
Measure serum concentration of remifentanil at -23, -9.5, -7, -2, 30, 60 and 90 minutes relative to naloxone administration
serum concentration of remifentanil [120 minutes]
Measure serum concentration of remifentanil at -23, -9.5, -7, -2, 30, 60 and 90 minutes relative to naloxone administration

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 40 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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.