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

Drug Overdose Clinical Trial

— OPI-15-001  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02405988
• Other study ID #: OPI-15-001
• Secondary ID: 2014-005348-16
• Status: Completed
• Phase: N/A
• Start date: April 2015
• Est. completion date: February 2016

Study information

• Verified date: August 2018
• Source: Norwegian University of Science and Technology
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: February 2016
• Est. primary completion date: February 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 40 Years

Eligibility

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.

Related Conditions & MeSH terms

• Drug Overdose

Intervention

Drug:
• Intravenous naloxone
Administer 2,5 mL, dose intravenous naloxone 1,0 mg
• 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.

Locations

Country	Name	City	State
Norway	Department of Circulation and Medical Imaging	Trondheim

Sponsors (2)

Lead Sponsor	Collaborator
Norwegian University of Science and Technology	St. Olavs Hospital

Country where clinical trial is conducted

Norway, 

References & Publications (1)

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 Aug 24. doi: 10.1007/s00228-018-2545-y. [Epub ahead of pr — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Serum-effect-site equilibration rate constant		up to 120 minutes
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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