Pharmacokinetics and Pharmacodynamics of a New Formulation of Nasal Naloxone for Prehospital Use
Condition: Drug Overdose
MeSH terms: Drug Overdose
Study type: Interventional
Phase: Phase 1/Phase 2

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.
    

Intervention name(s): Intranasal naloxone; Intramuscular naloxone; Remifentanil; Aptar Unidose
Intervention type(s): Drug; Drug; Drug; Device
Intervention description(s): Administer 0,1 ml 8 mg/ml naloxone intranasally, dose = 0,8 mg naloxone; Administer 2 mL, dose intramuscular naloxone 0,8 mg; 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.; 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.
Other intervention name(s): Naloxone B Braun 0,4 mg/ml
Intervention MeSH terms: Remifentanil; Naloxone
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Emergency Treatment; Morphine Derivates; Heroin; Antidotes; Administration, Intranasal; Pharmacology; Naloxone; Healthy volunteers