• Arne Kristian Skulberg, Ida Tylleskar, Turid Nilsen, Sissel Skarra, Øyvind Salvesen, Trond Sand, Thorsteinn Loftsson, and Ola Dale.
• Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, NTNU-Norwegian University of Science and Technology, Post-Box 8905, 7491, Trondheim, Norway.
• Eur. J. Clin. Pharmacol. 2018 Jul 1; 74 (7): 873-883.

PurposeThis study aimed to develop a model for pharmacodynamic and pharmacokinetic studies of naloxone antagonism under steady-state opioid agonism and to compare a high-concentration/low-volume intranasal naloxone formulation 8 mg/ml to intramuscular 0.8 mg.MethodsTwo-way crossover in 12 healthy volunteers receiving naloxone while receiving remifentanil by a target-controlled infusion for 102 min. The group were subdivided into three different doses of remifentanil. Blood samples for serum naloxone concentrations, pupillometry and heat pain threshold were measured.ResultsThe relative bioavailability of intranasal to intramuscular naloxone was 0.75. Pupillometry showed difference in antagonism; the effect was significant in the data set as a whole (p < 0.001) and in all three subgroups (p < 0.02-p < 0.001). Heat pain threshold showed no statistical difference.ConclusionsA target-controlled infusion of remifentanil provides good conditions for studying the pharmacodynamics of naloxone, and pupillometry was a better modality than heat pain threshold. Intranasal naloxone 0.8 mg is inferior for a similar dose intramuscular. Our design may help to bridge the gap between studies in healthy volunteers and the patient population in need of naloxone for opioid overdose.Trial Registrationclinicaltrials.gov : NCT02307721.

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