Pharmacokinetics and Pharmacodynamics of a New Formulation of Nasal Naloxone for Prehospital Use
Pharmacokinetics and Pharmacodynamics of a New Formulation of Nasal Naloxone for Prehospital Use
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.
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.
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.