芬太尼介导的快速死亡的去甲肾上腺素机制解释了阿片类药物危机中纳洛酮的失败。,Journal of Pharmacology and Experimental Therapeutics

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芬太尼介导的快速死亡的去甲肾上腺素机制解释了阿片类药物危机中纳洛酮的失败。
Journal of Pharmacology and Experimental Therapeutics ( IF 3.1 ) Pub Date : 2019-09-06 , DOI: 10.1124/jpet.119.258566
Randy Torralva ₁ , Aaron Janowsky ₂

Affiliation

2018年12月，疾病控制中心宣布芬太尼为美国最致命的药物。阿片类药物过量是美国成年人口（18至50岁）的最大死亡原因，而芬太尼及其类似物[芬太尼/芬太尼类似物（F / FAs）]目前占这些死亡人数的50％以上。芬太尼于1970年代初引入麻醉药，当时它结合了深刻的止痛和血液动力学稳定性，彻底改变了手术麻醉的方式。但是，他们很快不得不掌握其独特的副作用。F / FA可以在极窄的剂量范围内在隔膜，胸壁和上呼吸道产生极大的刚性。这种临床效应被麻醉学家称为“木箱综合症”（WCS），在麻醉学之外或成瘾研究/医学领域的临床医生或研究人员中并不为人所知。如果没有专业的气道管理，WCS几乎是致命的。这篇综述提供了相关的临床人类药理学和动物数据，表明F / FA致死人数的显着增加可能涉及α和肾上腺素能和胆碱能受体介导的呼吸系统和心血管系统的机械衰竭，以及僵硬和气道的快速发展关闭。尽管吗啡及其前药海洛因在高剂量时可引起腹部肌肉轻度僵硬，但两者均未表现出F / FA诱导的WCS所见的明显而快速的呼吸衰竭，将F / FA过量与吗啡衍生生物碱引起的呼吸抑制较慢发作分开。这种区别对有效预防F / FA致死的新药理学策略的设计和实施具有重大影响。重要声明：尽管可获得并了解阿片类药物逆转药物纳洛酮，但芬太尼和F / FAs导致的死亡人数仍在增加。这篇文章回顾了一些文献，提示纳洛酮可能对F / FAs的中枢介导的去甲肾上腺素能和胆碱能作用无效，临床表现为严重的肌肉僵硬和气道受损（例如，木箱综合症），这种反应迅速且不同于吗啡引起的呼吸抑制衍生的生物碱。

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Noradrenergic Mechanisms in Fentanyl-Mediated Rapid Death Explain Failure of Naloxone in the Opioid Crisis.

In December 2018, the Centers for Disease Control declared fentanyl the deadliest drug in America. Opioid overdose is the single greatest cause of death in the United States adult population (ages 18-50), and fentanyl and its analogs [fentanyl/fentanyl analogs (F/FAs)] are currently involved in >50% of these deaths. Anesthesiologists in the United States were introduced to fentanyl in the early 1970s when it revolutionized surgical anesthesia by combining profound analgesia with hemodynamic stability. However, they quickly had to master its unique side effect. F/FAs can produce profound rigidity in the diaphragm, chest wall and upper airway within an extremely narrow dosing range. This clinical effect was called wooden chest syndrome (WCS) by anesthesiologists and is not commonly known outside of anesthesiology or to clinicians or researchers in addiction research/medicine. WCS is almost routinely fatal without expert airway management. This review provides relevant clinical human pharmacology and animal data demonstrating that the significant increase in the number of F/FA-induced deaths may involve α-adrenergic and cholinergic receptor-mediated mechanical failure of the respiratory and cardiovascular systems with rapid development of rigidity and airway closure. Although morphine and its prodrug, heroin, can cause mild rigidity in abdominal muscles at high doses, neither presents with the distinct and rapid respiratory failure seen with F/FA-induced WCS, separating F/FA overdose from the slower onset of respiratory depression caused by morphine-derived alkaloids. This distinction has significant consequences for the design and implementation of new pharmacologic strategies to effectively prevent F/FA-induced death. SIGNIFICANCE STATEMENT: Deaths from fentanyl and F/FAs are increasing in spite of availability and awareness of the opioid reversal drug naloxone. This article reviews literature suggesting that naloxone may be ineffective against centrally mediated noradrenergic and cholinergic effects of F/FAs, which clinically manifest as severe muscle rigidity and airway compromise (e.g., wooden chest syndrome) that is rapid and distinct from respiratory depression seen with morphine-derived alkaloids. A physiologic model is proposed and implications for new drug development and treatment are discussed.

更新日期：2019-11-01

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