Clinical trial NCT02405988: Pharmacodynamics and Arteriovenous Differences of Naloxone in Healthy Participants Exposed to an Opioid
Official title: Pharmacodynamics and Arteriovenous Differences of Naloxone in Healthy Participants Exposed to an Opioid
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Drug Overdose
Keywords: Emergency Treatment
Morphine Derivates
Heroin
Antidotes
Administration, Intravenous
Pharmacology
Naloxone
Healthy volunteers
Lead sponsor: Norwegian University of Science and Technology
Sponsor class: OTHER
Collaborators: name: St. Olavs Hospital
First posted: 2015-04-01
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

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.

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.

Eligibility 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.

Primary outcomes:
measure: Serum-effect-site equilibration rate constant
timeFrame: up to 120 minutes
Secondary outcomes:
measure: Pharmacokinetics: Area Under the Curve of IV naloxone in arterial and venous serum
timeFrame: 120 minutes
measure: Pharmacokinetics: maximum concentration (Cmax) of IV naloxone in arterial and venous serum
timeFrame: 120 minutes
measure: Pharmacokinetics: time to maximum concentration (Tmax) of IV naloxone in arterial and venous serum
timeFrame: 120 minutes
measure: Pharmacodynamics: measurement of naloxone antagonism of remifentanil effects, by measuring changes in pupillary size
timeFrame: 120 minutes
measure: Quantitate serum concentrations of remifentanil in arterial and venous blood at specified time points
timeFrame: 120 minutes
measure: the effect site equilibration rate constant (ke0) for remifentanil for arterial sampling with pupillary size
timeFrame: 120 minutes
measure: serum concentration of remifentanil
timeFrame: 120 minutes
Other outcomes:
Locations:
city: Trondheim
country: Norway
facility: Department of Circulation and Medical Imaging
Study officials:
affiliation: Norwegian University of Science and Technology
name: Toril A Nagelhus Hernes, phd prof
role: STUDY_DIRECTOR
References:
citation: 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.