The in situ isolated larynx for evaluating peripheral opiate receptor antagonists

Willette, Robert N.; Evans, Deborah Y.; Doorley, Brian M.

doi:10.1016/0160-5402(87)90033-7

Cited by 13 publications

(21 citation statements)

References 7 publications

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“…As such, the increase in A-a gradient elicited by fentanyl is also likely to involve increases in upper and/or lower airways resistance thereby diminishing O 2 delivery to alveoli. Indeed, fentanyl increases airway resistance in rats (Willette et al, 1982, 1983, 1987; Bennett et al, 1997) and in rabbits (Taguchi et al, 1986). In humans, fentanyl and sufentanil increase overall airway resistance (Cohendy et al, 1992; Ruiz Neto and Auler Júnior, 1992) via tracheal constriction (Yasuda et al, 1978) and bronchoconstriction (Ruiz Neto and Auler Júnior, 1992).…”

Section: Discussionmentioning

confidence: 99%

Role of central and peripheral opiate receptors in the effects of fentanyl on analgesia, ventilation and arterial blood-gas chemistry in conscious rats

Henderson

May

Gruber³

et al. 2014

Respiratory Physiology & Neurobiology

112

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This study determined the effects of the peripherally restricted µ-opiate receptor (µ-OR) antagonist, naloxone methiodide (NLXmi) on fentanyl (25 µg/kg, i.v.)-induced changes in (1) analgesia, (2) arterial blood gas chemistry (ABG) and alveolar-arterial gradient (A-a gradient), and (3) ventilatory parameters, in conscious rats. The fentanyl-induced increase in analgesia was minimally affected by a 1.5 mg/kg of NLXmi but was attenuated by a 5.0 mg/kg dose. Fentanyl decreased arterial blood pH, pO2 and sO2 and increased pCO2 and A-a gradient. These responses were markedly diminished in NLXmi (1.5 mg/kg)-pretreated rats. Fentanyl caused ventilatory depression (e.g., decreases in tidal volume and peak inspiratory flow). Pretreatment with NLXmi (1.5 mg/kg, i.v.) antagonized the fentanyl decrease in tidal volume but minimally affected the other responses. These findings suggest that (1) the analgesia and ventilatory depression caused by fentanyl involve peripheral µ-ORs and (2) NLXmi prevents the fentanyl effects on ABG by blocking the negative actions of the opioid on tidal volume and A-a gradient.

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Section: Discussionmentioning

confidence: 99%

Role of central and peripheral opiate receptors in the effects of fentanyl on analgesia, ventilation and arterial blood-gas chemistry in conscious rats

Henderson

May

Gruber³

et al. 2014

Respiratory Physiology & Neurobiology

112

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“…Generally, the adductor muscles of the vocal cords (e.g., lateral cricoarytenoid and transverse arytenoid muscles) are relaxed during breathing at rest, allowing the sole abductor muscle of the vocal folds (e.g., posterior cricoarytenoid) to keep vocal cords and vocal folds open. Fentanyl activation of cholinergic and/or sympathetic innervation to these intrinsic laryngeal muscles may result in subsequent vocal cord closure (laryngospasm) (Willette et al, 1987;Lui et al, 1989;Lalley, 2003). Laryngospasm is generally managed in the operating or emergency room with the administration of muscle paralytics (succinylcholine).…”

Section: Wooden Chest Syndromementioning

confidence: 99%

“…This has significant implications for how first responders and EMS/paramedics can best manage the presentation of muscle rigidity and airway compromise with F/FAs. Whereas naloxone is an appropriate treatment to address respiratory depression, animal models studying the laryngeal effects of high-dose fentanyl fail to demonstrate a significant impact on acute vocal cord closure in dose ranges relevant to humans (Willette et al, , 1987Janssen Pharmaceutica, 2017). In an in situ model of the larynx, Willette et al (1987) demonstrated that upper airway effects of opioids are mediated by peripheral and central mechanisms and can be blocked by 100 mcg/kg doses of naloxone for morphine, but require doses of 0.8 mg to 1.6 mg/kg of naloxone to effectively inhibit the centrally mediated airway effects of fentanyl (Willette et al, , 1987.…”

Section: Wooden Chest Syndromementioning

confidence: 99%

“…When considering these data, it is apparent that the ongoing increases in F/FA-related deaths may be a direct result of the lack of public and medical community awareness of F/FAs' lethal side-effect profile and a false sense of security provided by naloxone's past successes against conventional morphine-derived opioids (Baumann et al, 2018). However, conventional m-receptor antagonist therapies (e.g., naloxone, nalmefene, and naltrexone) have little effect on the cholinergic or noradrenergic off-target sites that may be responsible for the rapid lethality of F/FAs (Daskalopoulos et al, 1975;Willette et al, , 1987. Pharmacologic interventions that target these receptors (e.g., a 1 -adrenergic receptor antagonists and cholinergic agents) in combination with m-opioid antagonists must be further explored to develop more effective F/FA reversal and prophylaxis agents.…”

Section: Introductionmentioning

confidence: 99%

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

Torralva

Janowsky

2019

J Pharmacol Exp Ther

114

112

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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.

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“…Systemic opioids also depress ventilation in animals by mechanisms, including central- (Campbell et al, 1995) and vagal afferent-mediated (Kaczy ska and Szereda-Przestaszewska, 2005) depression of ventilatory drive; skeletal muscle rigidity in the chest-wall and abdomen (Seamman, 1983; Niedhart et al, 1989; Bowdle, 1998); increases in pulmonary airway resistance (Willette et al, 1983); and increases in upper airway resistance via closure of the larynx (Willette et al, 1982, 1987; Bennett et al, 1997). Moreover, agonist-induced activation of central and peripheral opioid receptors blunt the hypoxic ventilatory response (see Zhang et al, 2009), and opioids such morphine and fentanyl inhibit carotid body chemoafferent activity and depress the responses of these afferents to hypoxic and hypercapnic challenges (McQueen and Rubeiro, 1980, 1981; Zimpfer et al, 1983; Kirby and McQueen, 1986; Mayer et al, 1989).…”

Section: Introductionmentioning

confidence: 99%

l-Cysteine ethyl ester reverses the deleterious effects of morphine on, arterial blood–gas chemistry in tracheotomized rats

Mendoza

Passafaro

Baby³

et al. 2013

Respiratory Physiology & Neurobiology

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Summary This study determined whether the membrane-permeable ventilatory stimulant, L-cysteine ethylester (L-CYSee), reversed the deleterious actions of morphine on arterial blood-gas chemistry in isoflurane-anesthetized rats. Morphine (2 mg/kg, i.v.) elicited sustained decreases in arterial blood pH, pO2 and sO2, and increases in pCO2 (all responses indicative of hypoventilation) and Alveolar-arterial gradient (indicative of ventilation-perfusion mismatch). Injections of L-CYSee (100 μmol/kg, i.v.) reversed the effects of morphine in tracheotomized rats but were minimally active in non-tracheotomized rats. L-cysteine or L-serine ethylester (100 μmol/kg, i.v.) were without effect. It is evident that L-CYSee can reverse the negative effects of morphine on arterial blood-gas chemistry and Alveolar-arterial gradient but that this positive activity is negated by increases in upper-airway resistance. Since L-cysteine and L-serine ethylester were ineffective, it is evident that cell penetrability and the sulfur moiety of L-CYSee are essential for activity. Due to its ready penetrability into the lungs, chest wall muscle and brain, the effects of L-CYSee on morphine-induced changes in arterial blood-gas chemistry are likely to involve both central and peripheral sites of action.

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The in situ isolated larynx for evaluating peripheral opiate receptor antagonists

Cited by 13 publications

References 7 publications

Role of central and peripheral opiate receptors in the effects of fentanyl on analgesia, ventilation and arterial blood-gas chemistry in conscious rats

Role of central and peripheral opiate receptors in the effects of fentanyl on analgesia, ventilation and arterial blood-gas chemistry in conscious rats

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

l-Cysteine ethyl ester reverses the deleterious effects of morphine on, arterial blood–gas chemistry in tracheotomized rats

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