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

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.

Study Overview

• Status: Completed
• Conditions: Drug Overdose
• Intervention / Treatment: Drug: Intravenous naloxone; Drug: Remifentanil

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 Type: Interventional
• Enrollment (Actual): 12
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Norway
  • Trondheim, Norway
    • Department of Circulation and Medical Imaging

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Norwegian University of Science and Technology
• Collaborators: St. Olavs Hospital

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: April 1, 2015
• Primary Completion (Actual): February 1, 2016
• Study Completion (Actual): February 1, 2016

Study Registration Dates

• First Submitted: March 28, 2015
• First Submitted That Met QC Criteria: March 28, 2015
• First Posted (Estimate): April 1, 2015

Study Record Updates

• Last Update Posted (Actual): August 29, 2018
• Last Update Submitted That Met QC Criteria: August 27, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: Healthy volunteers; Naloxone; Pharmacology; Antidotes; Heroin; Emergency Treatment; Morphine Derivates; Administration, Intravenous
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Substance-Related Disorders; Drug Overdose; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Narcotic Antagonists; Remifentanil; Naloxone
• Other Study ID Numbers: OPI-15-001; 2014-005348-16 (EudraCT Number)