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Chamoun, K.; Chevillard, L.; Hajj, A.; Callebert, J.; Mégarbane, B. Mechanisms of Neurorespiratory Toxicity Induced by Fentanyl Analogs. Encyclopedia. Available online: https://encyclopedia.pub/entry/43682 (accessed on 02 July 2024).
Chamoun K, Chevillard L, Hajj A, Callebert J, Mégarbane B. Mechanisms of Neurorespiratory Toxicity Induced by Fentanyl Analogs. Encyclopedia. Available at: https://encyclopedia.pub/entry/43682. Accessed July 02, 2024.
Chamoun, Karam, Lucie Chevillard, Aline Hajj, Jacques Callebert, Bruno Mégarbane. "Mechanisms of Neurorespiratory Toxicity Induced by Fentanyl Analogs" Encyclopedia, https://encyclopedia.pub/entry/43682 (accessed July 02, 2024).
Chamoun, K., Chevillard, L., Hajj, A., Callebert, J., & Mégarbane, B. (2023, May 02). Mechanisms of Neurorespiratory Toxicity Induced by Fentanyl Analogs. In Encyclopedia. https://encyclopedia.pub/entry/43682
Chamoun, Karam, et al. "Mechanisms of Neurorespiratory Toxicity Induced by Fentanyl Analogs." Encyclopedia. Web. 02 May, 2023.
Mechanisms of Neurorespiratory Toxicity Induced by Fentanyl Analogs
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This entry is adapted from the peer-reviewed paper 10.3390/ph16030382

In 2020, fentanyl and its analogs contributed to ~65% of drug-attributed fatalities in the USA, with a threatening increasing trend during the last ten years. These synthetic opioids used as potent analgesics in human and veterinary medicine have been diverted to recreational aims, illegally produced and sold. Like all opioids, central nervous system depression resulting from overdose or misuse of fentanyl analogs is characterized clinically by the onset of consciousness impairment, pinpoint miosis and bradypnea. However, contrasting with what observed with most opioids, thoracic rigidity may occur rapidly with fentanyl analogs, contributing to increasing the risk of death in the absence of immediate life support. Various mechanisms have been proposed to explain this particularity associated with fentanyl analogs, including the activation of noradrenergic and glutamatergic coerulospinal neurons and dopaminergic basal ganglia neurons. Due to the high affinities to the mu-opioid receptor, the need for more elevated naloxone doses than usually required in morphine overdose to reverse the neurorespiratory depression induced by fentanyl analogs has been questioned. 

fentanyl naloxone neurorespiratory effect opioid

1. Introduction

According to the American Center for Disease Control and the National Institute of Drug Abuse, opioids represent the major source of drug-attributed fatalities in the USA, with an increasing contribution of fentanyl and fentanyl analogs accounting for more than 65% of the 92,000 fatalities in 1999–2020 [1][2]. A major opioid overdose crisis has been developing in the USA and most occidental countries for 20 years in relation to: (i) an excessive prescription of opioid analgesics without adequate monitoring; (ii) the subsequent development of dependence among opioid-treated patients, leading to abuse or misuse (e.g., crushed-tablet injection and manipulated transdermal patch sniffing); and (iii) more recently, the growing availability of fentanyl, fentanyl analogs and unrelated compounds classified as novel psychoactive substances (NPS), sold on the internet as recreational drugs or pharmaceutical candidates [3].
Fentanyl is a potent synthetic opioid receptor agonist developed in the 1960s. Due to its potency (~50–100 times more potent analgesic activity than morphine), rapid action and short elimination half-life, fentanyl has been used as a step-III pain reliever especially in cancer treatment and palliative and intensive care. More potent synthetic fentanyl analogs such as sufentanil, alfentanil and carfentanil have been also marketed as analgesics or anesthetics for human and/or veterinary medicine. Recently, an extensive number of analogs identified (Figure 1) as designer drugs with or without fentanyl-related chemical structures, such as U-47700, has spread on the recreational scene to bypass toxicological screening tests and laws banning illicit psychoactive substances.
/media/item_content/202305/6451cbbd29bcdpharmaceuticals-16-00382-g001.png
Figure 1. Chemical structure of fentanyl and the main fentanyl analogs.
These opioids exhibit similar or enhanced potencies in comparison to the parent fentanyl but have been associated with increased medical concerns [4]. To identify these derivatives and their metabolites in biological fluids and matrices, sophisticated analytical methods for screening and confirmation were developed. However, to date, only 24% of fentanyl analogs can be detected by the most commonly used gas/liquid chromatography-coupled-to-mass-spectrometry assays, most likely due to the low sensitivity of the assays and/or to the poor volatility of the compounds precluding the use of gas chromatography [5]. The development of ultra/high-performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) assays has thus been encouraged. Among those fentanyl analogs, the World Health Organization (WHO) has requested to focus attention on carfentanil, acetylfentanyl, acryloylfentanyl, butyrylfentanyl, furanylfentanyl and ocfentanil. These molecules are potent synthetic opioids to such an extent that only limited amounts are required to cause severe toxicity.
An overdose of fentanyl and analogs results in the classical opioid toxidrome, combining consciousness impairment, pinpoint miosis and bradypnea. Dose-dependent respiratory depression is the most alarming adverse effect resulting from central nervous system (CNS) depression [6]. The onset of thoracic and diaphragmatic rigidity named “wooden chest syndrome” in addition to the classical opioid-related CNS depression has been suggested to explain the enhanced toxicity attributed to fentanyl and its analogs. As a result, an increased risk of death in the absence of immediate management and the requirement of larger doses of naloxone, the non-specific mu-, kappa- and delta-opioid receptor antagonist used as an antidote to reverse opioid-related toxicity in humans, have been questioned, although remaining still controversial [7][8].

2. Neurorespiratory Effects of Fentanyl and Analogs

2.1. Depression of the Ventilation Command

The fentanyl-related neurorespiratory effects are dose-dependent. Mice exposed to low-dose fentanyl in aerosol (2.7 µg/m3) rapidly recovered with no fatality, while 100% of the mice died at higher doses (23.6 µg/m3) [9]. No sensory/pulmonary irritation or airway restriction was present, and CNS ventilatory depression was assumed as the cause of death. In the rat, intraperitoneal (IP) fentanyl administered at 80% of its lethal dose, 50% (LD50) significantly decreased PaO2, increased PaCO2, decreased blood bicarbonate and increased blood lactate [10]. Fentanyl (0.05–1.35 mg/kg) administered IP depressed the respiratory rate (RR), the tidal volume (VT) and subsequently the minute volume (VE) in a dose-dependent manner [11]. All tested opioids administered at 80% of their LD50 significantly increased the inspiratory time (TI), but fentanyl, similarly to methadone, additionally increased the expiratory time (TE) [10]. Consistent with these observations, another study using a smaller intravenous (IV) fentanyl dose (25 µg/kg) elicited a rise in TI and a reduction in VE by decreasing RR, VT, the end-inspiratory pause (EIP), the peak inspiratory (PIF) and the peak expiratory flows (PEF) [11].
Central mu-opioid receptors, particularly those located in the pre-Bötzinger complex, are fundamental to integrally exhibit the onset of the fentanyl-induced switch of pulmonary rapid shallow breathing mediated by C-fibers into apnea [12][13]. The peripheral μ-opioid receptors also contribute to this switch. Fentanyl-associated deficits in respiratory patterning result from a reduced activity of pontine inspiratory neurons, while apnea is observed after the loss of all phasic pontine activity and sustained tonic expiratory neuron activity. Using in situ rat preparations of the arterially perfused dorsolateral pons, neurons were categorized based on their respiratory-associated discharge pattern after incubation with an apneic fentanyl concentration [14]. When exposed to fentanyl, the inspiratory neurons were silenced or exhibited a reduced firing frequency, while the expiratory neurons only reduced their tonic firing frequency. The alterations were reversed when adding naloxone to the preparation. Pontine late-inspiratory and post-inspiratory neuronal activity were absent from apneustic-like breaths during the transition to fentanyl-induced apnea and naloxone-mediated transition to recovery.

2.2. Chest Wall Rigidity

In humans, chest wall rigidity has been reported as a rare complication resulting from fentanyl or analog administration in the perioperative or critical care setting, decreasing chest wall compliance and resulting in unsuccessful spontaneous ventilation that challenges the withdrawal from mechanical ventilation [15]. Mainly reported with fentanyl, the occurrence of chest wall rigidity appears dependent on the administered dose and the infusion rate [8]. The closure of glottis and supraglottic structures also contributes to respiratory failure resulting from chest wall rigidity, as reported in anesthesia using synthetic opioids [16]. The studies focused on fentanyl analogs are still limited, but caution, at least in the perioperative field, has been recommended in patients at risk of opioid use disorder [17].
The exact underlying mechanisms supporting chest wall rigidity are unclear. While centrally mediated, this phenomenon does not seem related to the CNS-dependent respiratory drive depression [18]. Various pathways including noradrenergic, glutamatergic, dopaminergic and serotonergic neurons have been implicated. The effects of fentanyl microinjection into the rat locus coeruleus, which increased the EMG activity of the caudal lateral extensor and gastrocnemius muscles considered as a correlate of opioid-induced muscular rigidity, were inhibited with the alpha 1-adrenoceptor blocker prazosin pretreatment, supporting the involvement of a coerulospinal noradrenergic pathway in fentanyl-induced muscular rigidity in rats [19]. The activation of the EMG signals recorded from the sacrococcygeus dorsi lateralis muscle following fentanyl microinjection into the locus coeruleus was also inhibited by the intrathecal administration of various N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonists [20]. These observations suggested the involvement in fentanyl-induced muscular rigidity of the coerulospinal glutamatergic pathway and both NMDA and non-NMDA receptors in the spinal cord in addition to the ceorulospinal noradrenergic mechanism. The implication of dopaminergic neurons in the basal ganglia, such as the caudate nucleus and nucleus raphe pontis in the reticular formation, was additionally suggested based on the observation of fentanyl-induced alterations in dopamine metabolism in these CNS areas [21]. 

3. Specificities of the Main Fentanyl Analogs

3.1. Carfentanil

Preclinical investigations with carfentanil are limited. Mice exposed to 0.4 mg/m3 of carfentanil by inhalation during 15 min developed respiratory depression with a marked decrease in VE, which was sustained for 24 h after the exposure [22]. Similarly, mice exposure to 6 or 60 mg/min/m3 of carfentanil yielded a significant decrease in VE [23]. In another study conducted in African green monkeys, the median effective dose (ED50) of SC carfentanil for bradypnea and/or loss of posture was determined at 0.71 μg/kg (95% confidence interval, 0.58–0.87) [24]. This estimate well fitted the experimental data available on carfentanil in other laboratory non-human primate studies. In female rhesus monkeys, respiratory depression was produced at IV doses of 0.6 and 1.0 μg/kg [25]. In Rocky Mountain wapiti (Cervus elaphus nelsoni), a regimen combining IM 10 mg/kg carfentanil and 0.1 mg/kg xylazine (administered for anesthesia) decreased the RR, with complete reversion using naloxone administered 10 min later [26]. Carfentanil was found to be the major cause of hypoxemia, as shown by the significant improvement in PaO2 after naloxone administration.

3.2. Alfentanil

Using microiontophoresis, the alfentanil-induced depressant responses on single rat brain stem respiratory and non-respiratory neurons were shown to be slow, shallow and prolonged, while the responses to the other fentanyl analogs were rapid in onset and short in duration [27]. Using impedance plethysmographic respiratory waveform analysis in the rat, SC 500 µg/kg alfentanil increased the expiratory diaphragm EMG activity while decreasing its inspiratory activity [28]. These modifications in diaphragm function were complemented by a substantial respiratory depression. The effects on EMG activity were greater in the diaphragm than in the intercostal muscles. In rhesus monkeys, alfentanil caused a dose-dependent depression of VE [29]. Quadazocine, a selective mu-opioid receptor antagonist, caused a shift to the right of the dose–effect curves for multiple parameters including RR, VT and VE. An arterial blood gas study using multiple alfentanil doses (3, 30, 60 and 120 µg/kg) in canines found a significant short-term decrease in PaO2 and an increase in PaCO2, most prominently with the 30 and 120 µg/kg doses [30].

3.3. Sufentanil

The specific sufentanil-related effects on ventilation have been poorly investigated. In the dog, sufentanil administration decreased PaO2 to 55.0 mmHg, while PaCO2 rose to 44.7 mmHg [31]. Similarly, sufentanil administration to rats resulted in an early increase in PaCO2 at lower doses and a secondary decrease in PaO2 and SaO2 at higher doses [32]. The epidural injection, in contrast to the SC injection, of equipotent analgesic doses of morphine, meperidine, fentanyl and sufentanil did not produce significant respiratory effects [33][34][35].

4. Reversal of the Neurorespiratory Toxicity Induced by Fentanyl and Analogs

4.1. Effects of Naloxone

Opioid overdose rescue is based on the rapid administration of life support and, if available, of naloxone, the antidote of reference. However, due to the rapid onset of fentanyl-induced respiratory depression, attempts to resuscitate patients poisoned with fentanyl or analogs using naloxone may not be effective [36]. These synthetic opioids may require higher and occasionally reiterated naloxone injections to reverse the respiratory depression successfully [37]. Usually, the naloxone dose suitable to reverse opioid-induced CNS depression depends on several factors such as the potency and the dose of the opioid molecule and the chronicity of opioid exposure that may have resulted in tolerance development. Therefore, taking into consideration the high potency of fentanyl and analogs, larger naloxone doses are expected to be required to reverse the CNS depression [38].
A lack in CNS depression reversal was highlighted in different animal models receiving fentanyl analogs with usual naloxone doses used to reverse morphine-induced toxicity [23]. In a non-sedated rat model using open-flow plethysmography, severe hypoxia resulting from CNS depression following fentanyl overdose was shown to oppose an unprompted breathing rhythm uniquely opposed by the animals to the effects of a second re-administration of fentanyl [39], which seemed lifesaving but could avert the reversal effects of high-dose naloxone. Additionally, naloxone administration was considered non-optimally effective to reverse the “wooden chest syndrome” due to the lack of effects on cholinergic and noradrenergic sites [40].
Reversal may differ from one fentanyl analog to another. In a conscious rabbit model with arterialized venous blood analysis and RR and VE measurements, naloxone was shown to be more effective in reversing alfentanil than fentanyl effects [41]. In a micro-iontophoresis study examining the effects of fentanyl analogs on rat respiratory and non-respiratory brain stem neurons, naloxone reversed or blocked the slow responses produced by fentanyl and three analogs (sufentanil, lofentanil and alfentanil) but was ineffective on most fast responses. With combined responses, the slow component was blocked, leaving the fast response unaffected [27].

4.2. Alternative Targeted Strategies

If used to reverse opioid-induced toxicity in patients admitted with respiratory depression attributed to an opioid analgesic overdose, naloxone may also suppress analgesia, a critical issue in these patients suffering from pain. Moreover, if opioid-related respiratory depression is over-antagonized, acute withdrawal syndrome may occur.
The accentuation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated conductance with an ampakine such as CX717 countered the opioid-attributed depressant effects in the pre-Bötzinger complex, allowing protection against fentanyl-induced ventilatory depression and the risk of fatal apnea [42]. Similarly, selective delta-opioid receptor antagonists appeared highly effective to reverse the respiratory depressant effects of potent opioids, while maintaining analgesia [43]. Other opioid receptor antagonists such as methocinnamox showed a greater duration of action than naloxone (up to 2 weeks when administered SC), useful to prevent the re-emergence of fentanyl overdose-related re-narcotization [44]. 
Addressing muscle rigidity to limit opioid-induced respiratory depression represents another major objective [6]. The α1-adrenoreceptor agonist prazosin was effective to improve rat VT and overall oxygenation [19]. The α4β2 nicotinic acetylcholine receptor activation was also effective in advancing pain control while limiting respiratory depression in the presence of opioid overdose in the rat [45]. Additionally, and despite unclear mechanisms of action, serotoninergic 5-HT1A receptor agonists decreased opioid-attributed ventilatory depression in different models [46][47][48].
Finally, fentanyl vaccines may provide an attractive approach to mitigate fentanyl-attributed adverse effects and toxicity. In the rat, dose–response curves of respiratory effects were shifted to the right with the vaccine, without affecting the ability of naloxone to reverse the respiratory depression [49]. Vaccinated rats showed improved physiological parameters including oxygen saturation and heart rate after exposure to fentanyl compared to unvaccinated rats [50]. 

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Subjects: Pharmacology & Pharmacy
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Karam Chamoun
,
Lucie Chevillard
,
Aline Hajj
,
Jacques Callebert
,
Bruno Mégarbane
View Times: 322
Revisions: 2 times (View History)
Update Date: 03 May 2023
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