Pharmacodynamics and arteriovenous difference of intravenous naloxone in healthy volunteers exposed to remifentanil
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Pharmacodynamic studies of naloxone require opioid agonism. Steady state condition may be achieved by remifentanil TCI (target controlled infusion). Opioid agonism can be measured by pupillometry. It is not known whether there are arteriovenous concentration differences for naloxone. The aim was thus to further develop a model for studying pharmacokinetic/pharmacodynamic aspects of naloxone and to explore whether a significant arteriovenous concentration difference for naloxone in humans was present.
Relevant authorities approved this study. Healthy volunteers (n = 12) were given 1.0 mg intravenous (IV) naloxone after steady state opioid agonism was obtained by TCI of remifentanil (1.3 ng/ml). Opioid effect was measured by pupillometry. Arterial and venous samples were collected simultaneously before and for 2 h after naloxone administration for quantification of naloxone and remifentanil.
Arterial remifentanil was in steady state at 12 min. One milligram IV naloxone reversed the effect of remifentanil to 93% of pre-opioid pupil-size within 4 min. The estimated duration of antagonism was 118 min. At that time, the concentration of naloxone was 0.51 ng/ml. The time course of arterial and venous serum concentrations for naloxone was similar, although arterial AUC (area under the curve) was slightly lower (94%) than the venous AUC (p = 0.03). There were no serious adverse events.
Onset of reversal by IV naloxone was rapid and lasted 118 min. The minimum effective concentration was 0.5 ng/ml. Using TCI remifentanil to obtain a steady-state opioid agonism may be a useful tool to compare new naloxone products.
KeywordsPharmacodynamics Naloxone Remifentanil Pharmacokinetics Arteriovenous difference
The authors wish to thank the Intensive Care Unit, St. Olavs hospital, Trondheim University Hospital, for the use of their facilities for conduction of the study, and the anaesthesiologists Pål Klepstad, Ole Kristian Rolfseng and Johan Arnt Hegvik for their aid with arterial cannulation. We are grateful for the Clinical Research Facility, St. Olavs hospital, Trondheim University Hospital and their nurses for assistance with the study. Thanks to Unit for Applied Clinical Research, NTNU, for assistance with GCP monitoring. The naloxone and remifentanil analyses were provided by the Proteomics and Metabolomics Core Facility, PROMEC, NTNU.
The Clinical Research Facility, the Unit for Applied Clinical Research and PROMEC are funded by the Faculty of Medicine and Health Sciences, NTNU and the Central Norway Regional Health Authority. This study was supported by grants from the Faculty of Medicine and Health Sciences at NTNU, The Research Council of Norway and Felles Forskningsutvalg, NTNU/St. Olavs hospital, Trondheim University Hospital, Norway.
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 a naloxone nasal spray formulation. 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. Farma Industry AS (sister company to dne pharma) has recently gained market approval in 12 european countries for this spray, containing 1.4 mg Naloxone-HCl. 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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