Pharmacokinetics and -dynamics of intramuscular and intranasal naloxone: an explorative study in healthy volunteers
This 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.
Two-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.
The 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.
A 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.
KeywordsNaloxone Intranasal Pharmacodynamics Pharmacokinetics Drug overdose Remifentanil
The Clinical Research Facility, St. Olavs Hospital, Trondheim University Hospital, conducted the study, and the Unit for Applied Clinical Research, NTNU, assisted with GCP monitoring and provided the Internet-based randomisation. The naloxone analysis were provided by the Proteomics and Metabolomics Core Facility, PROMEC, NTNU. These infrastructures are all funded by the Faculty of Medicine, NTNU, and the Central Norway Regional Health Authority. This study was supported by grants from the Liaison Committee for Education, Research and Innovation in Central Norway and the Joint Research Committee between St. Olavs Hospital, Trondheim University Hospital, and the Faculty of Medicine and Health Sciences, NTNU, Norway. Anders Åsberg, School of Pharmacy, University of Oslo, has given teaching on pharmacokinetics.
OD was principal investigator and contributed to all aspects of this study. AKS and IT has written the manuscript, designed the research protocol, conducted the research and analysed data. ØS has performed the mixed model statistical analysis. TN and SS has analysed serum samples and prepared data for PK analysis. TS has designed the HPT measurement program. TL has been pivotal in the development of the IN naloxone formulation, the fundament of this study. All authors have reviewed the final draft of the text.
Compliance with ethical standards
Conflict of interest
Norwegian University of Science and Technology (NTNU) and its subsidiary Technology Transfer Office (TTO) have a licencing agreement with Den norske Eterfabrikk (DnE) regarding the naloxone formulation studied. DnE has sent an application for marketing authorization for a drug for human consumption. NTNU, TTO and Ola Dale (OD) have financial benefit from these contracts. OD has been engaged by DnE as Principle Investigator in a pharmacokinetic study of naloxone for which OD receives no personal honorarium. DnE has compensated OD for two travels from Trondheim to Oslo.
Arne Kristian Skulberg (AKS) has signed a non-compete contract with DnE lasting the duration of his PhD program (estimated 2018). This does not limit AKS right to publish results and he receives no royalties or other financial benefits from DnE/NTNU. Other authors declare they have no conflicts of interest.
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