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

Abstract

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 a-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.

D-Amphetamine Accelerates Recovery of Consciousness and Respiratory Drive After High-Dose Fentanyl in Rats

“…Fentanyl is 50-100 times more potent than morphine (Suzuki and El-Haddad, 2017), and causes respiratory depression, chest wall rigidity, and loss of consciousness which can rapidly lead to hypoxia, hypercarbia, and death if not treated promptly (Henderson et al, 2014;Lalley et al, 2014;Torralva and Janowsky, 2019). Fentanyl is commonly administered as a potent analgesic in a variety of formulations, including intravenous, transdermal, and sublingual.…”

“…Although intravenous fentanyl administration is generally safe in the perioperative setting with appropriate monitoring, opioidinduced respiratory depression is still a common postoperative complication that can affect up to 17% of patients (Cashman and Dolin, 2004). In addition, fentanyl causes approximately 60,000 drug overdose deaths each year in the United States, making it a significant public health problem (Scholl et al, 2018;Torralva and Janowsky, 2019).…”

Commentary: New Complications Make Treatment of “Opioid” Overdose Challenging

“…Opioid-induced chest wall rigidity, also called "WoodenChest Syndrome (WCS)", has been known for decades, although it is usually described in the anesthesiology literature related to surgical procedures [8] [36]. WCS presents as musclewall rigidity, laryngospasm, seizure-like events, cyanosis, and loss of consciousness [37] [38].…”

“…This has been used as support for the argument that WCS is a cause of fentanoid-induced respiratory depression and overdose death. Not only is WCS not reversed by an ORA-an ORA may make it worse [36]. It has been suggested that fentanoid overdose sets up a potential "double-whammy": WCS and respiratory depression [22].…”

“…The mechanism and actual incidence are not known, nor has a clear treatment paradigm been developed [42]. But laryngospasm is almost exclusively reported with lipophilic opio-ids, such as the fentanoids [36]. Fentanoids increase norepinephrine levels, which can worsen both chest wall rigidity and laryngospasm [38].…”