NCT02307721

Brief Summary

Overdose with potential deadly outcome is a serious problem among opioid abusers, not least in Norway. The annual death toll from overdose is about 250, higher than road traffic accidents. Those who inject heroin or other opioids are considered to have the highest risk for death from overdose. To save lives, immediate treatment with a μ-opioid antidote such as naloxone is required. Usually naloxone is injected into a muscle or a blood vessel. Administration of naloxone via the nose (intranasal) has been suggested as an alternative for use by emergency teams and possibly also bystanders. This is not only an easier way to give naloxone, but would also eliminate the risk for needle stick injuries and blood contamination. In a series of studies on intranasal naloxone at The Norwegian University of Science and Technology, this study explores pharmacokinetics and pharmacodynamics of intranasal and intramuscular naloxone in healthy volunteers under the influence of remifentanil.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
12

participants targeted

Target at below P25 for phase_1

Timeline
Completed

Started Dec 2014

Geographic Reach
1 country

1 active site

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

First Submitted

Initial submission to the registry

November 23, 2014

Completed
8 days until next milestone

Study Start

First participant enrolled

December 1, 2014

Completed
3 days until next milestone

First Posted

Study publicly available on registry

December 4, 2014

Completed
4 months until next milestone

Primary Completion

Last participant's last visit for primary outcome

April 1, 2015

Completed
5 months until next milestone

Study Completion

Last participant's last visit for all outcomes

September 1, 2015

Completed
Last Updated

October 17, 2018

Status Verified

October 1, 2018

Enrollment Period

4 months

First QC Date

November 23, 2014

Last Update Submit

October 16, 2018

Conditions

Drug Overdose

Keywords

Emergency TreatmentMorphine DerivatesHeroinAntidotesAdministration, IntranasalPharmacologyNaloxoneHealthy volunteers

Outcome Measures

Primary Outcomes (2)

  • Pharmacodynamic profile of naloxone- Heat Pain Threshold

    We will measure time to maximum reversal, and duration of reversal of opioid effect on heat pain threshold measured. Heat pain thresholds will be tested using a Somedic MSA Thermotest (Somedic AB, Hørby, Sweden). This apparatus can measure the relationship between the intensity of controlled thermal stimuli and the associated perception. The stimulus (1 degree Celsius per sec rise time) is applied to the intact skin by a hand-held thermode while monitoring the temperature. The thermode (area 25x 50 mm= 12,5 cm2) will be placed over the non-dominant thenar eminence. Once the sensation changes from warm to painful the subject stops the increase in temperature by pressing a button, and the thermode cools down. The heat pain threshold (HPT) is measured in degrees C, and we will calculate the average of three repeated single HPTs.

    120 minutes

  • Pharmacodynamic profile of naloxone. Pupillometry

    Using a Neuroptics VIP 200 Pupillometer (Neuroptics, Irvine, CA, USA) we will measure the size of the pupils as a pharmacodynamic measure. The treatment visits will be conducted in a quiet room, with moderate, stable ambient lighting. Using a luxometer we will ensure similar light conditions in each visit of each participant. We will ask the participant to focus on a distant point in the room. The pupillometer will be placed over the measured eye and its position adjusted until the eye was correctly aligned within the LCD screen of the pupillometer. The reading will be recorded in CRF and/ or local work sheet A measurement of the pupils should take less than 10 seconds, and the result is given in millimetre, with an accuracy of 0.1mm and the results recorded. It is a non-invasive and pain free measurement.

    120 minutes

Secondary Outcomes (6)

  • Adverse Events

    minimum 6 days

  • Quantitate serum concentrations of remifentanil at specified time points

    110 minutes

  • Suitability of spray device in prehospital setting

    100 minutes

  • Pharmacokinetics: Area Under the Curve of IN and IM naloxone

    360 minutes

  • Pharmacokinetics: maximum concentration (Cmax) of IN and IM naloxone

    360 minutes

  • +1 more secondary outcomes

Study Arms (2)

intranasal naloxone

EXPERIMENTAL

8 mg/ml naloxone 0,1 mL IN as one puff in one nostril in supine position

Drug: Intranasal naloxoneDrug: RemifentanilDevice: Aptar Unidose

Intramuscular naloxone

ACTIVE COMPARATOR

0,4 mg/ml Naloxone B Braun 2 ML in deltoid muscle

Drug: Intramuscular naloxoneDrug: Remifentanil

Interventions

Intranasal naloxoneDRUG

Administer 0,1 ml 8 mg/ml naloxone intranasally, dose = 0,8 mg naloxone

intranasal naloxone
Intramuscular naloxoneDRUG

Administer 2 mL, dose intramuscular naloxone 0,8 mg

Also known as: Naloxone B Braun 0,4 mg/ml
Intramuscular naloxone
RemifentanilDRUG

Administer remifentanil intravenously by way of Target Control Infusion, Minto model at a target of 2,5 ng/ml. This to achieve a state of safe and predictable opioid influence to assess pharmacodynamic response to naloxone. After treatment of 4 participants protocol amended 22. january 2015 to reduce remifentanil target to 1,25 ng/ml in the next 4. In the last 4 participants the dose will be decided later, but not exceed 2,5 ng/ml.

Intramuscular naloxoneintranasal naloxone
Aptar UnidoseDEVICE

This is the spray device chosen, and its function in this setting (spray up side down) will be assessed by weighing the device before and after administration.

intranasal naloxone

Eligibility Criteria

Age18 Years - 40 Years
Sexall
Healthy VolunteersYes
Age GroupsAdult (18-64)

You may qualify if:

  • American Society of Anesthesiologists (ASA) class I
  • ECG without pathologic abnormalities
  • BMI range of 18,5 - 24,9 kg/m2.
  • 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

You may not qualify if:

  • 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
  • Having any local nasal disease or nasal surgery for the last 2 months or recent cold for the last week
  • 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 or remifentanil hydrochloride and/or to any of its excipients.
  • Any reason why, in the opinion of the investigator, the patient should not participate.

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Department of Circulation and Medical Imaging

Trondheim, Norway

Location

Related Publications (1)

  • Skulberg AK, Tylleskar I, Nilsen T, Skarra S, Salvesen O, Sand T, Loftsson T, Dale O. Pharmacokinetics and -dynamics of intramuscular and intranasal naloxone: an explorative study in healthy volunteers. Eur J Clin Pharmacol. 2018 Jul;74(7):873-883. doi: 10.1007/s00228-018-2443-3. Epub 2018 Mar 22.

    PMID: 29568976RESULT

MeSH Terms

Conditions

Drug Overdose

Interventions

Remifentanil

Condition Hierarchy (Ancestors)

Prescription Drug MisuseDrug MisuseSubstance-Related DisordersChemically-Induced DisordersMental Disorders

Intervention Hierarchy (Ancestors)

PropionatesAcids, AcyclicCarboxylic AcidsOrganic ChemicalsPiperidinesHeterocyclic Compounds, 1-RingHeterocyclic Compounds

Study Officials

  • Toril A Nagelhus Hernes, phd prof

    Norwegian University of Science and Technology

    STUDY DIRECTOR

Study Design

Study Type
interventional
Phase
phase 1
Allocation
RANDOMIZED
Masking
NONE
Purpose
TREATMENT
Intervention Model
CROSSOVER
Sponsor Type
OTHER
Responsible Party
SPONSOR

Study Record Dates

First Submitted

November 23, 2014

First Posted

December 4, 2014

Study Start

December 1, 2014

Primary Completion

April 1, 2015

Study Completion

September 1, 2015

Last Updated

October 17, 2018

Record last verified: 2018-10

Locations

NO(1)