Arne Kristian Skulberg1,2, Ida Tylleskar1, Turid Nilsen1, Sissel Skarra1, Øyvind Salvesen3, Trond Sand4,5, Thorsteinn Loftsson6, Ola Dale7,8. 1. 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. 2. Department of Anaesthesiology and Critical Care, Oslo University Hospital, Oslo, Norway. 3. Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, NTNU-Norwegian University of Science and Technology, Trondheim, Norway. 4. Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, NTNU-Norwegian University of Science and Technology, Trondheim, Norway. 5. Department of Neurology and Clinical Neurophysiology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway. 6. Department of Pharmaceutical Sciences, University of Iceland, Reykjavik, Iceland. 7. 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. ola.dale@ntnu.no. 8. Department of Research, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway. ola.dale@ntnu.no.
Abstract
PURPOSE: 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. METHODS: Two-way crossover in 12 healthy volunteers receivingnaloxone 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. RESULTS: 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. CONCLUSIONS: 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. TRIAL REGISTRATION: clinicaltrials.gov : NCT02307721.
RCT Entities:
PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. TRIAL REGISTRATION: clinicaltrials.gov : NCT02307721.
Entities:
Keywords:
Drug overdose; Intranasal; Naloxone; Pharmacodynamics; Pharmacokinetics; Remifentanil
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