- Email: [email protected]
Potent opioids and implications for national defense
Toxicology Letters 321 (2020) 90–94
Contents lists available at ScienceDirect
Toxicology Letters journal homepage: www.elsevier.com/locate/toxlet
Potent opioids and implications for national defense David D. Gummin
T
Medical College of Wisconsin, United States
ARTICLE INFO
ABSTRACT
Keywords: Fentanyl Fentalogs Chemical defense Environmental toxicity
Potent opioids are increasingly responsible for morbidity and mortality in the Western world. Fentanyl and fentanyl derivatives are increasingly prevalent as adulterants or substitutes for opioid drugs of abuse in Europe and in North America. Trafficking and distribution of these chemicals evolve continuously and are poorly characterized at this time. Rescue and emergency personnel are increasingly concerned with the possibility of unintentional environmental exposures that might occur in the course of their operational duties. There is evidence that opioid agonists have been broadcast or applied directly in an offensive manner as incapacitating agents. Defending against toxicity from such agents requires a thoughtful plan for protection, decontamination, and treatment.
1. Background The opioid crisis in the United States (US) and other Western nations has necessitated increased surveillance, law enforcement interventions, and significant public health concern. North America leads the world in both prescription and non-prescription opioid consumption, but recently, the availability and non-medical consumption of potent synthetic opioids such as fentanyl and its analogs has caused a dramatic increase in opioid overdose deaths. This trend carries on. (World Drug Report, 2019) The potential to weaponize these potent agents is not merely hypothetical, it has occurred on an international scale, and the involvement of these agents must be considered in the setting of any chemical disaster or terror threat. As opioid receptor ligands, fentanyl and other mu agonists are believed to manifest dose-response toxicity, i.e., expected toxicity can be expressed in the ratio of the toxic dose to the therapeutic dose. Toxicity in this realm becomes a function of the specific toxicant, and is therefore dependent upon the unique chemical structure of the substance. Efficacy of a pharmaceutical substance relates exclusively to its intended therapeutic effect. For dose-response agents, tissue (including blood or serum) concentrations typically correlate with the specific degree of response. Potency is a relative pharmacodynamic parameter and affords a mg/kg dose-based comparison between similar agents within a therapeutic class. Potency is purely a function of the specific substance. For example, morphine is roughly 10 times more potent than meperidine (pethidine) while fentanyl is roughly 1000 times more potent than meperidine. When focused upon a specific receptor, doseadjusted therapeutic and toxic effects are often similar but occur at different tissue concentrations for the individual drug. Unfortunately,
neither efficacy nor potency is easily predicted from the molecular configuration of a given substance. Fentanyl was first synthesized in1960 in Beerse, Belgium, by Dr. Paul Janssen in an attempt to create a narcotic analgesic with a higher therapeutic index (TI) than morphine, the clinical standard for strong analgesics up until that time. The first clinical use of fentanyl in the US was in 1968 and shortly thereafter, molecular analogs (now often termed “fentalogs”) of fentanyl were produced, again with the intent to increase the therapeutic index, enhancing safety. These included parafluorofentanyl, α-methylacetylfentanyl, 3-methylfentanyl, β-hydroxyfentanyl, ohmefentanyl, and β-hydroxy-4-methylfentanyl. Unfortunately, many of the fentalogs demonstrated higher potency and also produced more euphoria than did the naturally-occurring morphinans, yet there was not significant improvement in therapeutic index. The diversion, illicit manufacture, and abuse of these substances increased over the next few years. By September 1981 the US Drug Enforcement Agency (DEA) had changed α-methylfentanyl to a Schedule I substance, due to excessive abuse of the drug as well as the lack of a clear therapeutic indication. It should be noted that fentalog toxicity is evaluated with a significant degree of uncertainty, since for most of these specific substances, illicit analog potency has never been evaluated in humans. 2. Scope of the human crisis Drug overdose deaths in the US topped 60,000 by year 2016, including a five-fold increase (over 20,000) in deaths related to synthetic opioids. The vast majority of these deaths involve illicitly manufactured fentanyl, most of which is illegally imported from synthetic laboratories
E-mail address: [email protected]. https://doi.org/10.1016/j.toxlet.2019.12.017 Received 1 September 2019; Received in revised form 9 December 2019; Accepted 13 December 2019 Available online 24 December 2019 0378-4274/ © 2019 Elsevier B.V. All rights reserved.
Toxicology Letters 321 (2020) 90–94
D.D. Gummin
Fig. 1. Some described fentanyl analogs (or fentalogs).
Ilicit opioid trafficking over the previous century was believed to involve principally heroin trafficked from the Golden Crescent of Western, Central, and Southern Asia directly to Europe and to North America. More recently, heroin routes have migrated increasingly through Mexico into North America and beyond, while fentanyl and fentalogs (often adulterating or replacing heroin in seized isolates) come to the US and Canada from synthetic laboratories in China, either directly or by way of South Pacific Islands. (O’Connor, 2019) An essential element in recognition of potent opioid toxicity is to recognize the opioid toxidrome. A toxidrome (contraction of toxic syndrome) comprises a constellation of clinical signs reflecting toxicity that is consequent to exposure to a specific class of pharmacologic or environmental substances. This term was first coined in the literature in 1985 after more than a decade of progressive clinical recognition of class effects. While exposure to (and more specifically toxicity from) mu-opioid agonists doesn’t always produce the classic opioid toxidrome, the constellation of findings is now well-described and classically consists of findings listed in Fig. 2 (Mofenson and Greensher, 1974; Mofenson and Caraccio, 1985). Noncardiogenic pulmonary edema, caused by an as-yet elusive mechanism, is common in fatal opioid overdose, and may externally manifest as a frothy “cone of death” visible about the decedent’s mouth and nose. (Pelletier and Andrew, 2017) Again, all such findings are not universally present in opioid overdose, but their presence comprises the classic toxidrome. While these clinical effects reflect predominantly mu-opioid receptor effects and constitute exaggerated expression of side effects that might be encountered during therapeutic use, in the
Fig. 2. Constellation of Clinical Findings Identified in the Opioid Toxidrome.
in China. One such fentalog is carfentanil, which is used in veterinary (large animal) medicine and has approximately 100 times the potency of fentanyl. Fentanyl was recently detected in at least half of opioid overdose deaths in seven of 10 US states monitored. As many as 57% of fentanyl deaths were also found to be positive for other illicit substances such as heroin and fentanyl analogs, which were present in more than 10% of opioid overdose deaths in 4 states. Of the fentalogs studied, carfentanil, furanylfentanyl, and acetylfentanyl were identified most frequently in decedents. Some additional fentalogs are tabulated in Fig. 1 (Spencer et al., 2019). 91
Toxicology Letters 321 (2020) 90–94
D.D. Gummin
setting of overdose or of intentional or inadvertent exposure to a highly potent agent, these effects are deleterious and potentially fatal. In the specific sense, clinical presentation rarely manifests the complete dimensions of the opioid toxidrome. Manifestations are helpful diagnostically, but should not be considered pathognomonic. More specific to confirmation of the opioid toxidrome is the presence or absence of a positive response to a reversal agent such as naloxone. In the setting of a potent agonist, higher than expected dosing of reversal agent(s) may be required to achieve adequate antagonism and an appropriate clinical response. It should be articulated that signs and symptoms of the classic opioid toxidrome reflect only the mu-agonist effects of the opioids. It has been estimated that at least 1700 analogs of fentanyl could likely produce some degree of mu-opioid receptor agonism. Other (e.g., kappa, delta, sigma, serotonin) receptor or non-receptor-mediated effects are likely and are not yet characterized. This makes confirmatory and forensic testing much more challenging and clinical management precarious. On the topic of potency, it is important to differentiate the degree of receptor binding from clinical effects. Likewise, it is important to differentiate potency and efficacy from the TI of a given substance. Life threatening opioid toxicity is understood to be largely linked to degree of mu opioid receptor agonism. With thousands of potential analog structures that could demonstrate agonist activity at this receptor, it should be expected that toxicokinetic and toxicodynamic properties would differ amongst the agonists. Potency and efficacy do not necessarily correlate with the TI of a given agent. The stereochemistry of the human mu receptor is largely responsible for the ability of mu agonists to bind to and to agonize at the receptor. Until recently, it was widely held that the fentanyl pharmacophore, that portion of the molecule that triggers activity within the mu receptor, was strictly analogous to the mu pharmacophore present in morphinans such as morphine, codeine, oxycodone, etc. This was believed to be comprised of fentanyl’s N-phenyl ring existing in close proximity to a basic nitrogen (in this case, presumably that of the central piperidine ring). While this N-aryl distance appears intuitively to be amenable to binding to the active site of the mu receptor, recent modeling has called this entire paradigm into question. (Ellis et al., 2018) Suffice it to say, at this point, that there is more to be learned about fentanyl and fentalog activity at mu receptors and that the potential for toxicity of novel potent opioids is more challenging to predict than was formerly thought. While agonism requires hydrogen binding at the acidic residue, D149, of the human mu receptor (Cui et al., 2013) the potency of a substance does not appear to correlate with experimental binding affinity and may be better predicted by the average molecular “docking” score (ADS) (Ellis et al., 2018). Until crystallography provide us with more information about the human mu receptor and its configuration during fentanyl or fentalog binding and activation, this issue is likely to remain controversial and incompletely characterized.
Over the next two hours, he is said to have developed a severe headache, vomiting and mental status depression. It is not clear from media reports whether he manifested other findings consistent with the opioid toxidrome. Meshal spent the next four days in a Jordanian hospital, comatose and “deteriorating.” A plea was made by Jordanian officials, via the United States, and ultimately, Israeli Prime Minister Benjamin Netanyahu gave in to political pressure, and an “antidote” was delivered from Israel. Meshal reportedly woke, intact 2 days later, and Isreal officially took responsibility for this attack on September 29, 1997, citing the use of a substance “similar to fentanyl”. During the attack, two Mossad agents were taken into custody, and their release was negotiated in exchange for release of Hamas prisoners. (Crowley, 2014) 3.2. The barricade (Dubrovka) theater incident During a theatrical production of the musical, Nord Ost, in a crowded theater in Moscow, Russia on October 23–26, 2002, some 40–50 Chechen rebels, in a coordinated terror event, captured more than 800 hostages and took possession of the theater and the lives therein. On day 4 of the siege, Russian special forces stormed the theater after releasing a “white cloud” through the theater’s ventilation system. According to hostages interviewed on the morning of October 26, early that morning, some of the hostage-takers pointed to a white aerosol emerging silently from the balcony wall. From hostage reports, the dense, white, cloud spread evenly and descended slowly to the floor of the theater. The aerosol was variably described by hostages as being odorless vs. having an “indescribable odor.” From first spotting the aerosol to being overcome by it and losing consciousness, “10-30 s” transpired according to one casualty or “at least 30 s” according to another. Many of those inside the theater lost consciousness or were otherwise incapacitated, and in the end, more than 125 hostages died by inhalation, including 10 children. Additionally, 33 of the Chechen attackers were killed. The Russian government ultimately issued a statement and acknowledged that the aerosol was comprised of a “mixture based on derivatives of fentanyl,” as well as, “a composite chemical compound of general narcotic action.” This public statement suggests that there was more than one component in the incapacitating agent that was used. A subsequent analysis of this event was performed in the United Kingdom and results of chemical testing were published. Carfentanil and remifentanil were detected by high pressure liquid chromatographytandem mass spectrometry (LC–MS-MS) analysis performed on a shirt that was worn throughout the siege. Additionally, norcarfentanil (a metabolite of carfentanil) was detected by LC–MS-MS in urine provided by a separate hostage. (Krechetnikov, 2012; Riches et al., 2012) 4. Conclusion There is evidence that opioid agonists have been broadcast or directly applied offensively as incapacitating agents. In some cases, this application proved lethal. Defending against toxicity from such agents requires a thoughtful plan for protection, decontamination, and treatment. In response to many alleged exposure incidents involving first responders, cleanup crews, emergency personnel and law enforcement officers over the past 3 years, evidence-based recommendations for appropriate level of personal protective equipment (PPE) are sorely needed. However, in the absence of evidence-based data, consensus documents have proved helpful. The American Academy of Clinical Toxicology (AACT), in association with the American College of Medical Toxicology (ACMT) have issued a consensus document, entitled, “ACMT and AACT Position Statement: Preventing Occupational Fentanyl and Fentanyl Analog Exposure to Emergency Responders”, that is concrete, pragmatic, and very helpful to rescue personnel. (Anon., 2019) The recommendations are summarized at Fig. 3. Additionally, the US National Institute for Occupational Safety and Health (NIOSH)
3. Weaponization of potent opioids 3.1. Mossad v. Meshal In September 1997, Khaled Meshal, the Palestinian leader of Hamas, was living in exile in Amman, Jordan. Immediately in the wake of a series of suicide bombings claimed by Hamas in Jerusalem and Tel Aviv, Israeli Mossad agents intercepted Meshal on the street in Amman and allegedly “blew dust” into Meshal’s outer ear canal. The team of agents had reportedly flown in a week earlier on civilian airlines from Amsterdam, Toronto and Paris, using forged Canadian passports. According to media reports, Meshal later reflected: “I felt a loud noise in my ear,” Mr. Meshal said in an interview at a Hamas house here. ”It was like a boom, like an electric shock. Then I had a shivering sensation in my body like an electric shock.’’ 92
Toxicology Letters 321 (2020) 90–94
D.D. Gummin
Fig. 3. ACMT/AACT Joint Position Statement for PPE Anon., 2019.
Fig. 4. NIOSH recommendations for PPE National Institute for Occupational Safety and Health, 2019.
93
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has issued PPE recommendations for prehospital and other emergency personnel, based upon anticipated or potential level of exposure to these potent, but nonvolatile substances. (National Institute for Occupational Safety and Health, 2019) These recommendations are provided at Fig. 4. Important to both sets of recommendations is the need for appropriate PPE relative to the circumstance, the development and implementation of an approach plan and a treatment plan by rescue personnel, and the ability to provide both reversal agents and airway support to casualties.
Cui, X., Yeliseev, A., Liu, R., 2013. Ligand interaction, binding site and G protein activation of the mu opioid receptor. Eur. J. Pharmacol. 702 (February (1-3)), 309–315. Ellis, C.R., Kruhlak, N.L., Kim, M.T., Hawkins, E.G., Stavitskaya, L., 2018. Predicting opioid receptor binding affinity of pharmacologically unclassified designer substances using molecular docking. PLoS One 13 (May (5)), e0197734. Krechetnikov, A., 2012. Moscow Theatre Siege: Questions Remain Unanswered. BBC News 24 October Accessed December 9, 2019. https://www.bbc.com/news/worldeurope-20067384. Mofenson, H.C., Caraccio, T.R., 1985. Toxidromes. Compr. Ther. 11 (February (2)), 46–52. Mofenson, H.C., Greensher, J., 1974. The unknown poison. Pediatrics 54 (September (3)), 336–342. National Institute for Occupational Safety and Health, 2019. Fentanyl: Preventing Occupational Exposure to Emergency Responders. Accessed December 9. https:// www.cdc.gov/niosh/topics/fentanyl/risk.html. O’Connor, S.O., 2019. Fentanyl Flows From China: an Update Since 2017. November 26, 2018, https://www.uscc.gov/sites/default/files/Research/Fentanyl%20Flows %20from%20China.pdf Accessed December 9. Pelletier, D.E., Andrew, T.A., 2017. Common findings and predictive measures of opioid overdoses. Acad Forensic Pathol 7 (March (1)), 91–98. Riches, J.R., Read, R.W., Black, R.M., Cooper, N.J., Timperley, C.M., 2012. Analysis of clothing and urine from Moscow theatre siege casualties reveals carfentanil and remifentanil use. J. Anal. Toxicol. 36 (November–December (9)), 647–656. Spencer, M.R., Warner, M., Bastian, B.A., Trinidad, J.P., Hedegaard, H., 2019. Drug overdose deaths involving fentanyl, 2011-2016. Vital Stat. Rep. 68 (March (3)), 1–19. World Drug Report, 2019. United Nations Office on Drugs and Crime. Accessed December 9, 2019.
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. References https://www.acmt.net/_Library/Positions/Fentanyl_PPE_Emergency_Responders_.pdf, Accessed December 9, 2019. Crowley, M., 2014. The Man Who Haunts Israel. July 29. Time Accessed December 9, 2019. https://time.com/khaled-mashaal.
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Contents lists available at ScienceDirect
Toxicology Letters journal homepage: www.elsevier.com/locate/toxlet
Potent opioids and implications for national defense David D. Gummin
T
Medical College of Wisconsin, United States
ARTICLE INFO
ABSTRACT
Keywords: Fentanyl Fentalogs Chemical defense Environmental toxicity
Potent opioids are increasingly responsible for morbidity and mortality in the Western world. Fentanyl and fentanyl derivatives are increasingly prevalent as adulterants or substitutes for opioid drugs of abuse in Europe and in North America. Trafficking and distribution of these chemicals evolve continuously and are poorly characterized at this time. Rescue and emergency personnel are increasingly concerned with the possibility of unintentional environmental exposures that might occur in the course of their operational duties. There is evidence that opioid agonists have been broadcast or applied directly in an offensive manner as incapacitating agents. Defending against toxicity from such agents requires a thoughtful plan for protection, decontamination, and treatment.
1. Background The opioid crisis in the United States (US) and other Western nations has necessitated increased surveillance, law enforcement interventions, and significant public health concern. North America leads the world in both prescription and non-prescription opioid consumption, but recently, the availability and non-medical consumption of potent synthetic opioids such as fentanyl and its analogs has caused a dramatic increase in opioid overdose deaths. This trend carries on. (World Drug Report, 2019) The potential to weaponize these potent agents is not merely hypothetical, it has occurred on an international scale, and the involvement of these agents must be considered in the setting of any chemical disaster or terror threat. As opioid receptor ligands, fentanyl and other mu agonists are believed to manifest dose-response toxicity, i.e., expected toxicity can be expressed in the ratio of the toxic dose to the therapeutic dose. Toxicity in this realm becomes a function of the specific toxicant, and is therefore dependent upon the unique chemical structure of the substance. Efficacy of a pharmaceutical substance relates exclusively to its intended therapeutic effect. For dose-response agents, tissue (including blood or serum) concentrations typically correlate with the specific degree of response. Potency is a relative pharmacodynamic parameter and affords a mg/kg dose-based comparison between similar agents within a therapeutic class. Potency is purely a function of the specific substance. For example, morphine is roughly 10 times more potent than meperidine (pethidine) while fentanyl is roughly 1000 times more potent than meperidine. When focused upon a specific receptor, doseadjusted therapeutic and toxic effects are often similar but occur at different tissue concentrations for the individual drug. Unfortunately,
neither efficacy nor potency is easily predicted from the molecular configuration of a given substance. Fentanyl was first synthesized in1960 in Beerse, Belgium, by Dr. Paul Janssen in an attempt to create a narcotic analgesic with a higher therapeutic index (TI) than morphine, the clinical standard for strong analgesics up until that time. The first clinical use of fentanyl in the US was in 1968 and shortly thereafter, molecular analogs (now often termed “fentalogs”) of fentanyl were produced, again with the intent to increase the therapeutic index, enhancing safety. These included parafluorofentanyl, α-methylacetylfentanyl, 3-methylfentanyl, β-hydroxyfentanyl, ohmefentanyl, and β-hydroxy-4-methylfentanyl. Unfortunately, many of the fentalogs demonstrated higher potency and also produced more euphoria than did the naturally-occurring morphinans, yet there was not significant improvement in therapeutic index. The diversion, illicit manufacture, and abuse of these substances increased over the next few years. By September 1981 the US Drug Enforcement Agency (DEA) had changed α-methylfentanyl to a Schedule I substance, due to excessive abuse of the drug as well as the lack of a clear therapeutic indication. It should be noted that fentalog toxicity is evaluated with a significant degree of uncertainty, since for most of these specific substances, illicit analog potency has never been evaluated in humans. 2. Scope of the human crisis Drug overdose deaths in the US topped 60,000 by year 2016, including a five-fold increase (over 20,000) in deaths related to synthetic opioids. The vast majority of these deaths involve illicitly manufactured fentanyl, most of which is illegally imported from synthetic laboratories
E-mail address: [email protected]. https://doi.org/10.1016/j.toxlet.2019.12.017 Received 1 September 2019; Received in revised form 9 December 2019; Accepted 13 December 2019 Available online 24 December 2019 0378-4274/ © 2019 Elsevier B.V. All rights reserved.
Toxicology Letters 321 (2020) 90–94
D.D. Gummin
Fig. 1. Some described fentanyl analogs (or fentalogs).
Ilicit opioid trafficking over the previous century was believed to involve principally heroin trafficked from the Golden Crescent of Western, Central, and Southern Asia directly to Europe and to North America. More recently, heroin routes have migrated increasingly through Mexico into North America and beyond, while fentanyl and fentalogs (often adulterating or replacing heroin in seized isolates) come to the US and Canada from synthetic laboratories in China, either directly or by way of South Pacific Islands. (O’Connor, 2019) An essential element in recognition of potent opioid toxicity is to recognize the opioid toxidrome. A toxidrome (contraction of toxic syndrome) comprises a constellation of clinical signs reflecting toxicity that is consequent to exposure to a specific class of pharmacologic or environmental substances. This term was first coined in the literature in 1985 after more than a decade of progressive clinical recognition of class effects. While exposure to (and more specifically toxicity from) mu-opioid agonists doesn’t always produce the classic opioid toxidrome, the constellation of findings is now well-described and classically consists of findings listed in Fig. 2 (Mofenson and Greensher, 1974; Mofenson and Caraccio, 1985). Noncardiogenic pulmonary edema, caused by an as-yet elusive mechanism, is common in fatal opioid overdose, and may externally manifest as a frothy “cone of death” visible about the decedent’s mouth and nose. (Pelletier and Andrew, 2017) Again, all such findings are not universally present in opioid overdose, but their presence comprises the classic toxidrome. While these clinical effects reflect predominantly mu-opioid receptor effects and constitute exaggerated expression of side effects that might be encountered during therapeutic use, in the
Fig. 2. Constellation of Clinical Findings Identified in the Opioid Toxidrome.
in China. One such fentalog is carfentanil, which is used in veterinary (large animal) medicine and has approximately 100 times the potency of fentanyl. Fentanyl was recently detected in at least half of opioid overdose deaths in seven of 10 US states monitored. As many as 57% of fentanyl deaths were also found to be positive for other illicit substances such as heroin and fentanyl analogs, which were present in more than 10% of opioid overdose deaths in 4 states. Of the fentalogs studied, carfentanil, furanylfentanyl, and acetylfentanyl were identified most frequently in decedents. Some additional fentalogs are tabulated in Fig. 1 (Spencer et al., 2019). 91
Toxicology Letters 321 (2020) 90–94
D.D. Gummin
setting of overdose or of intentional or inadvertent exposure to a highly potent agent, these effects are deleterious and potentially fatal. In the specific sense, clinical presentation rarely manifests the complete dimensions of the opioid toxidrome. Manifestations are helpful diagnostically, but should not be considered pathognomonic. More specific to confirmation of the opioid toxidrome is the presence or absence of a positive response to a reversal agent such as naloxone. In the setting of a potent agonist, higher than expected dosing of reversal agent(s) may be required to achieve adequate antagonism and an appropriate clinical response. It should be articulated that signs and symptoms of the classic opioid toxidrome reflect only the mu-agonist effects of the opioids. It has been estimated that at least 1700 analogs of fentanyl could likely produce some degree of mu-opioid receptor agonism. Other (e.g., kappa, delta, sigma, serotonin) receptor or non-receptor-mediated effects are likely and are not yet characterized. This makes confirmatory and forensic testing much more challenging and clinical management precarious. On the topic of potency, it is important to differentiate the degree of receptor binding from clinical effects. Likewise, it is important to differentiate potency and efficacy from the TI of a given substance. Life threatening opioid toxicity is understood to be largely linked to degree of mu opioid receptor agonism. With thousands of potential analog structures that could demonstrate agonist activity at this receptor, it should be expected that toxicokinetic and toxicodynamic properties would differ amongst the agonists. Potency and efficacy do not necessarily correlate with the TI of a given agent. The stereochemistry of the human mu receptor is largely responsible for the ability of mu agonists to bind to and to agonize at the receptor. Until recently, it was widely held that the fentanyl pharmacophore, that portion of the molecule that triggers activity within the mu receptor, was strictly analogous to the mu pharmacophore present in morphinans such as morphine, codeine, oxycodone, etc. This was believed to be comprised of fentanyl’s N-phenyl ring existing in close proximity to a basic nitrogen (in this case, presumably that of the central piperidine ring). While this N-aryl distance appears intuitively to be amenable to binding to the active site of the mu receptor, recent modeling has called this entire paradigm into question. (Ellis et al., 2018) Suffice it to say, at this point, that there is more to be learned about fentanyl and fentalog activity at mu receptors and that the potential for toxicity of novel potent opioids is more challenging to predict than was formerly thought. While agonism requires hydrogen binding at the acidic residue, D149, of the human mu receptor (Cui et al., 2013) the potency of a substance does not appear to correlate with experimental binding affinity and may be better predicted by the average molecular “docking” score (ADS) (Ellis et al., 2018). Until crystallography provide us with more information about the human mu receptor and its configuration during fentanyl or fentalog binding and activation, this issue is likely to remain controversial and incompletely characterized.
Over the next two hours, he is said to have developed a severe headache, vomiting and mental status depression. It is not clear from media reports whether he manifested other findings consistent with the opioid toxidrome. Meshal spent the next four days in a Jordanian hospital, comatose and “deteriorating.” A plea was made by Jordanian officials, via the United States, and ultimately, Israeli Prime Minister Benjamin Netanyahu gave in to political pressure, and an “antidote” was delivered from Israel. Meshal reportedly woke, intact 2 days later, and Isreal officially took responsibility for this attack on September 29, 1997, citing the use of a substance “similar to fentanyl”. During the attack, two Mossad agents were taken into custody, and their release was negotiated in exchange for release of Hamas prisoners. (Crowley, 2014) 3.2. The barricade (Dubrovka) theater incident During a theatrical production of the musical, Nord Ost, in a crowded theater in Moscow, Russia on October 23–26, 2002, some 40–50 Chechen rebels, in a coordinated terror event, captured more than 800 hostages and took possession of the theater and the lives therein. On day 4 of the siege, Russian special forces stormed the theater after releasing a “white cloud” through the theater’s ventilation system. According to hostages interviewed on the morning of October 26, early that morning, some of the hostage-takers pointed to a white aerosol emerging silently from the balcony wall. From hostage reports, the dense, white, cloud spread evenly and descended slowly to the floor of the theater. The aerosol was variably described by hostages as being odorless vs. having an “indescribable odor.” From first spotting the aerosol to being overcome by it and losing consciousness, “10-30 s” transpired according to one casualty or “at least 30 s” according to another. Many of those inside the theater lost consciousness or were otherwise incapacitated, and in the end, more than 125 hostages died by inhalation, including 10 children. Additionally, 33 of the Chechen attackers were killed. The Russian government ultimately issued a statement and acknowledged that the aerosol was comprised of a “mixture based on derivatives of fentanyl,” as well as, “a composite chemical compound of general narcotic action.” This public statement suggests that there was more than one component in the incapacitating agent that was used. A subsequent analysis of this event was performed in the United Kingdom and results of chemical testing were published. Carfentanil and remifentanil were detected by high pressure liquid chromatographytandem mass spectrometry (LC–MS-MS) analysis performed on a shirt that was worn throughout the siege. Additionally, norcarfentanil (a metabolite of carfentanil) was detected by LC–MS-MS in urine provided by a separate hostage. (Krechetnikov, 2012; Riches et al., 2012) 4. Conclusion There is evidence that opioid agonists have been broadcast or directly applied offensively as incapacitating agents. In some cases, this application proved lethal. Defending against toxicity from such agents requires a thoughtful plan for protection, decontamination, and treatment. In response to many alleged exposure incidents involving first responders, cleanup crews, emergency personnel and law enforcement officers over the past 3 years, evidence-based recommendations for appropriate level of personal protective equipment (PPE) are sorely needed. However, in the absence of evidence-based data, consensus documents have proved helpful. The American Academy of Clinical Toxicology (AACT), in association with the American College of Medical Toxicology (ACMT) have issued a consensus document, entitled, “ACMT and AACT Position Statement: Preventing Occupational Fentanyl and Fentanyl Analog Exposure to Emergency Responders”, that is concrete, pragmatic, and very helpful to rescue personnel. (Anon., 2019) The recommendations are summarized at Fig. 3. Additionally, the US National Institute for Occupational Safety and Health (NIOSH)
3. Weaponization of potent opioids 3.1. Mossad v. Meshal In September 1997, Khaled Meshal, the Palestinian leader of Hamas, was living in exile in Amman, Jordan. Immediately in the wake of a series of suicide bombings claimed by Hamas in Jerusalem and Tel Aviv, Israeli Mossad agents intercepted Meshal on the street in Amman and allegedly “blew dust” into Meshal’s outer ear canal. The team of agents had reportedly flown in a week earlier on civilian airlines from Amsterdam, Toronto and Paris, using forged Canadian passports. According to media reports, Meshal later reflected: “I felt a loud noise in my ear,” Mr. Meshal said in an interview at a Hamas house here. ”It was like a boom, like an electric shock. Then I had a shivering sensation in my body like an electric shock.’’ 92
Toxicology Letters 321 (2020) 90–94
D.D. Gummin
Fig. 3. ACMT/AACT Joint Position Statement for PPE Anon., 2019.
Fig. 4. NIOSH recommendations for PPE National Institute for Occupational Safety and Health, 2019.
93
Toxicology Letters 321 (2020) 90–94
D.D. Gummin
has issued PPE recommendations for prehospital and other emergency personnel, based upon anticipated or potential level of exposure to these potent, but nonvolatile substances. (National Institute for Occupational Safety and Health, 2019) These recommendations are provided at Fig. 4. Important to both sets of recommendations is the need for appropriate PPE relative to the circumstance, the development and implementation of an approach plan and a treatment plan by rescue personnel, and the ability to provide both reversal agents and airway support to casualties.
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Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. References https://www.acmt.net/_Library/Positions/Fentanyl_PPE_Emergency_Responders_.pdf, Accessed December 9, 2019. Crowley, M., 2014. The Man Who Haunts Israel. July 29. Time Accessed December 9, 2019. https://time.com/khaled-mashaal.
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