■关于标准鼻内纳洛酮给药建议(即,1剂,如果需要,每2-3分钟再给药一次)在非法制造的芬太尼及其衍生物的时代是足够的(以下,芬太尼)。
■比较不同鼻内纳洛酮重复给药策略之间的纳洛酮血浆浓度,并评估其对芬太尼过量的影响。
■这项非盲交叉随机临床试验是在临床药理学单位(SpauldingClinicalResearch,西本德,威斯康星州)2021年3月。纳入标准包括年龄18至55岁,非吸烟状态,以及存在酒精或滥用药物的阴性测试结果。数据分析于2021年10月至2023年5月进行。
■纳洛酮在0、2.5、5和7.5分钟以1剂(4mg/0.1mL)给药(测试),2剂量在0和2.5分钟(测试),和1次剂量在0和2.5分钟(参考)。
■主要结局是纳洛酮血浆浓度较高的第一个预设时间。次要结果是使用生理药代动力学-药效学模型估计芬太尼过量后的脑缺氧时间。使用配对测试在3组的3个预定时间比较纳洛酮浓度。并使用描述性统计对模拟结果进行了总结。
■这项研究包括21名参与者,18人(86%)完成试验。参与者年龄中位数为34岁(IQR,27-50年),略超过一半的参与者是男性(11[52%])。与0和2.5分钟时的1次纳洛酮剂量相比,在0、2.5、5和7.5分钟时1次剂量显着增加了10分钟时的纳洛酮血浆浓度(7.95vs4.42ng/mL;几何平均比,1.95[单边97.8%CI,1.28-∞]),而在0和2.5分钟的2个剂量显着增加了4.5分钟的血浆浓度(2.24vs1.23ng/mL;几何平均比,1.98[单侧97.8%CI,1.03-∞])。未报告与药物相关的严重不良事件。模拟芬太尼2.97mg静脉推注后的中位脑缺氧时间为4.5分钟(IQR,2.1-∞分钟)在0和2.5分钟时使用1次纳洛酮剂量,4.5分钟(IQR,2.1-∞分钟)在0、2.5、5和7.5分钟时使用1次纳洛酮剂量,和3.7分钟(IQR,1.5-∞分钟),在0和2.5分钟时使用2次纳洛酮剂量。
■在这项健康参与者的临床试验中,与在0和2.5分钟给予1次鼻内纳洛酮剂量相比,在0、2.5、5和7.5分钟时1次剂量显着增加了10分钟时的纳洛酮血浆浓度,而2个剂量在0和2.5分钟时显著增加了纳洛酮在4.5分钟时的血浆浓度。需要进一步的研究来确定社区环境中最佳的纳洛酮剂量。
■ClinicalTrials.gov标识符:NCT04764630。
UNASSIGNED: Questions have emerged as to whether standard intranasal naloxone dosing recommendations (ie, 1 dose with readministration every 2-3 minutes if needed) are adequate in the era of illicitly manufactured fentanyl and its derivatives (hereinafter, fentanyl).
UNASSIGNED: To compare naloxone plasma concentrations between different intranasal naloxone repeat dosing strategies and to estimate their effect on fentanyl overdose.
UNASSIGNED: This unblinded crossover randomized clinical trial was conducted with healthy participants in a clinical pharmacology unit (Spaulding Clinical Research, West Bend, Wisconsin) in March 2021. Inclusion criteria included age 18 to 55 years, nonsmoking status, and negative test results for the presence of alcohol or drugs of abuse. Data analysis was performed from October 2021 to May 2023.
UNASSIGNED: Naloxone administered as 1 dose (4 mg/0.1 mL) at 0, 2.5, 5, and 7.5 minutes (test), 2 doses at 0 and 2.5 minutes (test), and 1 dose at 0 and 2.5 minutes (reference).
UNASSIGNED: The primary outcome was the first prespecified time with higher naloxone plasma concentration. The secondary outcome was estimated brain hypoxia time following simulated fentanyl overdoses using a physiologic pharmacokinetic-pharmacodynamic model. Naloxone concentrations were compared using paired tests at 3 prespecified times across the 3 groups, and simulation results were summarized using descriptive statistics.
UNASSIGNED: This study included 21 participants, and 18 (86%) completed the trial. The median participant age was 34 years (IQR, 27-50 years), and slightly more than half of participants were men (11 [52%]). Compared with 1 naloxone dose at 0 and 2.5 minutes, 1 dose at 0, 2.5, 5, and 7.5 minutes significantly increased naloxone plasma concentration at 10 minutes (7.95 vs 4.42 ng/mL; geometric mean ratio, 1.95 [1-sided 97.8% CI, 1.28-∞]), whereas 2 doses at 0 and 2.5 minutes significantly increased the plasma concentration at 4.5 minutes (2.24 vs 1.23 ng/mL; geometric mean ratio, 1.98 [1-sided 97.8% CI, 1.03-∞]). No drug-related serious adverse events were reported. The median brain hypoxia time after a simulated fentanyl 2.97-mg intravenous bolus was 4.5 minutes (IQR, 2.1-∞ minutes) with 1 naloxone dose at 0 and 2.5 minutes, 4.5 minutes (IQR, 2.1-∞ minutes) with 1 naloxone dose at 0, 2.5, 5, and 7.5 minutes, and 3.7 minutes (IQR, 1.5-∞ minutes) with 2 naloxone doses at 0 and 2.5 minutes.
UNASSIGNED: In this clinical trial with healthy participants, compared with 1 intranasal naloxone dose administered at 0 and 2.5 minutes, 1 dose at 0, 2.5, 5, and 7.5 minutes significantly increased naloxone plasma concentration at 10 minutes, whereas 2 doses at 0 and 2.5 minutes significantly increased naloxone plasma concentration at 4.5 minutes. Additional research is needed to determine optimal naloxone dosing in the community setting.
UNASSIGNED: ClinicalTrials.gov Identifier: NCT04764630.