Clinical trial NCT02307721: Pharmacokinetics and Pharmacodynamics of a New Formulation of Nasal Naloxone for Prehospital Use
Official title: Pharmacokinetics and Pharmacodynamics of a New Formulation of Nasal Naloxone for Prehospital Use
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Drug Overdose
Keywords: Emergency Treatment
Morphine Derivates
Heroin
Antidotes
Administration, Intranasal
Pharmacology
Naloxone
Healthy volunteers
Lead sponsor: Norwegian University of Science and Technology
Sponsor class: OTHER
Collaborators: name: St. Olavs Hospital
First posted: 2014-12-04
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

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.

Naloxone is a well-known, well-tolerated drug with an excellent safety profile over many decades of use. The current formulation has proven safe and without local or systemic side effects in the studies conducted so far. The excipients in the present nasal formulation are all well known.

This study has two aims. Firstly to investigate what naloxone does to the body under opioid influence, applying a well-tested model with infusion of the potent opioid remifentanil (Target Control Infusion). This will create a state of strong opioid effect for a short time and in a highly controlled fashion, inducing a state of miosis, reduced respiratory rate and reduced sensation to pain, all three strong indicators of opiates. Naloxone will antagonise these effects, and this change can be measured. Choosing intramuscular 0.8 mg naloxone for comparison means that the novel intranasal naloxone formulation will be compared with the well-established and described treatment protocol for opioid overdose in Norway used today.

Secondly the pharmacokinetic profile of intranasal and intramuscular naloxone will be studied. The same measurements as in preparative studies (OPI 12-001 and OPI 13-001) will be taken: Serum naloxone concentration over time to calculate maximum concentration, Time to maximum concentration, Area Under the Curve and Relative bioavailability. There are two main reasons to repeat these measurements. In contrast to the previous studies under the current protocol the participants will be under the influence by strong opioids. This may have significant physiologic effects, and it will be explored whether the pharmacokinetics of the intranasal formulation are changed. The other reason is that in this study pharmacokinetics of naloxone will be compared with the actual dosage and administration routes of naloxone as used by doctors and paramedics in the pre-hospital setting. This has not been done before, in spite of the widespread use of this treatment, The measurements of remifentanil in serum open the possibility to relate pharmacodynamic data directly to an actual serum concentration of the opioid at the same time.

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.

Safety of the formulation will also be studied by measuring vital signs and for the patient to report any nasal discomfort or potential adverse reactions during the study.

By weighing spray device, and intramuscular 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 - 24,9 kg/m2.
* 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
* Having any local nasal disease or nasal surgery for the last 2 months or recent cold for the last week
* 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 or remifentanil hydrochloride and/or to any of its excipients.
* Any reason why, in the opinion of the investigator, the patient should not participate.

Primary outcomes:
measure: Pharmacodynamic profile of naloxone- Heat Pain Threshold
timeFrame: 120 minutes
measure: Pharmacodynamic profile of naloxone. Pupillometry
timeFrame: 120 minutes
Secondary outcomes:
measure: Adverse Events
timeFrame: minimum 6 days
measure: Quantitate serum concentrations of remifentanil at specified time points
timeFrame: 110 minutes
measure: Suitability of spray device in prehospital setting
timeFrame: 100 minutes
measure: Pharmacokinetics: Area Under the Curve of IN and IM naloxone
timeFrame: 360 minutes
measure: Pharmacokinetics: maximum concentration (Cmax) of IN and IM naloxone
timeFrame: 360 minutes
measure: Pharmacokinetics: time to maximum concentration (Tmax) of IN and IM naloxone
timeFrame: 360 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: 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.