CODA Inc., Research Department, Portland, Oregon (R.T.); Research Service, VA Portland Health Care System, Portland, Oregon (R.T., A.J.); and Department of Psychiatry, Oregon Health & Science University, Portland, Oregon (R.T., A.J.)
CODA Inc., Research Department, Portland, Oregon (R.T.); Research Service, VA Portland Health Care System, Portland, Oregon (R.T., A.J.); and Department of Psychiatry, Oregon Health & Science University, Portland, Oregon (R.T., A.J.).
J Pharmacol Exp Ther. 2019 Nov;371(2):453-475. doi: 10.1124/jpet.119.258566. Epub 2019 Sep 6.
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 -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.
2018 年 12 月，疾病控制中心宣布芬太尼是美国最致命的毒品。阿片类药物过量是美国成年人口（18-50 岁）死亡的首要原因，而芬太尼及其类似物[芬太尼/芬太尼类似物（F/FAs）]目前涉及这些死亡人数的 50%以上。20 世纪 70 年代初，美国麻醉师首次接触芬太尼，它通过将深度镇痛与血流动力学稳定性相结合，彻底改变了手术麻醉。然而，他们很快就必须掌握其独特的副作用。F/FAs 可以在极其狭窄的剂量范围内使膈肌、胸壁和上呼吸道产生深刻的僵硬。这种临床效果被麻醉师称为“木胸综合征（WCS）”，在麻醉学之外，以及成瘾研究/医学的临床医生或研究人员中并不常见。如果没有专家气道管理，WCS 几乎是致命的。这篇综述提供了相关的临床人体药理学和动物数据，表明 F/FA 诱导的死亡人数显著增加可能涉及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，导致迅速出现僵硬和气道关闭。虽然吗啡及其前体药物海洛因在高剂量下会引起腹部肌肉轻度僵硬，但两者都不会出现与 F/FA 诱导的 WCS 相同的明显且快速的呼吸衰竭，这将 F/FA 过量与吗啡衍生的生物碱引起的呼吸抑制的缓慢发作区分开来。这种区别对设计和实施新的药理学策略以有效预防 F/FA 诱导的死亡具有重要意义。意义声明：尽管有纳洛酮这种阿片类药物逆转药物可用且人们也意识到它的存在，但芬太尼和 F/FAs 的死亡人数仍在增加。本文综述了文献，表明纳洛酮可能对 F/FAs 的中枢介导的去甲肾上腺素能和胆碱能作用无效，这些作用在临床上表现为严重的肌肉僵硬和气道阻塞（例如，木胸综合征），与吗啡衍生的生物碱引起的呼吸抑制迅速且明显不同。提出了一个生理模型，并讨论了新药开发和治疗的意义。
