Tylleskar Ida, Skulberg Arne Kristian, Skarra Sissel, Nilsen Turid, Dale Ola
Department of Circulation and Medical Imaging, NTNU - Norwegian University of Science and Technology, Trondheim, Norway.
Clinic of Emergency Medicine and Prehospital Care, St. Olavs hospital, Trondheim University Hospital, Trondheim, Norway.
Eur J Clin Pharmacol. 2018 Dec;74(12):1547-1553. doi: 10.1007/s00228-018-2545-y. Epub 2018 Aug 24.
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.
纳洛酮的药效学研究需要阿片类激动作用。通过瑞芬太尼靶控输注（TCI）可实现稳态。阿片类激动作用可通过瞳孔测量法来测定。目前尚不清楚纳洛酮是否存在动静脉浓度差异。因此，本研究旨在进一步建立一个用于研究纳洛酮药代动力学/药效学方面的模型，并探讨人体中纳洛酮是否存在显著的动静脉浓度差异。
本研究获得了相关部门的批准。通过瑞芬太尼TCI（1.3纳克/毫升）获得稳态阿片类激动作用后，给予12名健康志愿者静脉注射（IV）1.0毫克纳洛酮。通过瞳孔测量法测定阿片类效应。在纳洛酮给药前及给药后2小时同时采集动脉和静脉血样，用于测定纳洛酮和瑞芬太尼的含量。
动脉瑞芬太尼在12分钟时达到稳态。静脉注射1毫克纳洛酮在4分钟内将瑞芬太尼的作用逆转至阿片类药物作用前瞳孔大小的93%。估计拮抗持续时间为118分钟。此时，纳洛酮浓度为0.51纳克/毫升。纳洛酮的动脉和静脉血清浓度随时间变化的过程相似，尽管动脉曲线下面积（AUC）略低于静脉AUC（94%）（p = 0.03）。未发生严重不良事件。
静脉注射纳洛酮的逆转起效迅速，持续118分钟。最低有效浓度为0.5纳克/毫升。使用瑞芬太尼TCI获得稳态阿片类激动作用可能是比较新型纳洛酮产品的有用工具。
