Clinical Trial: Pharmacokinetics and Pharmacodynamics of a New Formulation of Nasal Naloxone for Prehospital Use

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Pharmacokinetics and Pharmacodynamics of a New Formulation of Nasal Naloxone for Prehospital Use

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 Summary:

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 intr
Sponsor: Norwegian University of Science and Technology

Current Primary Outcome:

  • Pharmacodynamic profile of naloxone- Heat Pain Threshold [ Time Frame: 120 minutes ]
    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.
  • Pharmacodynamic profile of naloxone. Pupillometry [ Time Frame: 120 minutes ]
    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

    Original Primary Outcome: Same as current

    Current Secondary Outcome:

    • Adverse Events [ Time Frame: minimum 6 days ]
      will be reported from the start of the first session to the follow-up visit.
    • Quantitate serum concentrations of remifentanil at specified time points [ Time Frame: 110 minutes ]
      Measure serum concentration of remifentanil by Gas Chromatography-Mass Spectrometry (GCMS) at 0,15,30,45, 60 and 90 minutes.
    • Suitability of spray device in prehospital setting [ Time Frame: 100 minutes ]
      By weighting spray device before and after intranasal administration to asses function in the supine patient.
    • Pharmacokinetics: Area Under the Curve of IN and IM naloxone [ Time Frame: 360 minutes ]
      Measurement of serum naloxone at times 2,5,10,15,20,25,30,35,45,60,90,120,240 and 360 minutes after naloxone administration
    • Pharmacokinetics: maximum concentration (Cmax) of IN and IM naloxone [ Time Frame: 360 minutes ]
      Measurement of serum naloxone at times 2, 5, 10, 15, 20, 25, 30, 35, 45, 60, 90, 120, 240 and 360 minutes after naloxone administration
    • Pharmacokinetics: time to maximum concentration (Tmax) of IN and IM naloxone [ Time Frame: 360 minutes ]
      Measurement of serum naloxone at times 2, 5, 10, 15, 20, 25, 30, 35, 45, 60, 90, 120, 240 and 360 minutes after naloxone administration


    Original Secondary Outcome: Same as current

    Information By: Norwegian University of Science and Technology

    Dates:
    Date Received: November 23, 2014
    Date Started: December 2014
    Date Completion:
    Last Updated: October 26, 2015
    Last Verified: October 2015