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Unexpected "gas" casualties in Moscow: A medical toxicology perspective

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Abstract

In October 2002, the Russian military used a mysterious "gas" to incapacitate Chechen rebels at a Moscow theater. Despite increased interest in the potential use of lethal chemical weapons in recent years, the medical community has paid little attention to the development of incapacitating, calmative, and "less than lethal" technologies. In this analysis, we review the events surrounding the use of a calmative "gas" during the Russian military action and discuss what is currently known about fentanyl derivatives, their aerosolization, and the rationale for their use as incapacitating agents. Collectively, the available evidence strongly suggests that a combination of a potent aerosolized fentanyl derivative, such as carfentanil, and an inhalational anesthetic, such as halothane, was used. The paper also assesses potential errors leading to the loss of a substantial number of hostages. Several lessons can be learned from this surprising and novel use of an incapacitating gas.

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... During this event, Russian military forces employed an aerosolized cocktail of fentanyls to subdue Chechen rebels causing the death of 170 people in the process, 127 of them hostages. [28][29][30] Although initially carfentanil was suspected as the only opioid employed in aerosolized form in combination with halothane, it was later found by careful analytical work at the Defence Science and Technology Laboratory (DSTL) in the United Kingdom that remifentanil was also a component of the mixture. [31] Even though fentanyl use as a means of incapacitating a threat can have lethal consequences, these cases are sporadic and not often encountered. ...
... Carfentanil Synthesized by Janssen pharmaceuticals in 1976, carfentanil (methyl 1-(2-phenylethyl)-4-(N-propanylanilino)piperidine-4-carboxylate) became an analog that exceeded the power of the parent drug by 200-fold and 1000 times more of that showcased by morphine (Figure 1). [119] Although commonly associated with its usage as a tranquilizer for large wildlife in the veterinary sciences, [120][121][122][123] carfentanil is more infamous for its confirmed use during the Moscow Dubrovka Theater crisis in 2002 [28][29][30] and its growing potential as a weapon of mass destruction. [124] Moreover, this powerful opioid has recently become involved in various lethal overdose cases worldwide indicating it spread into the illicit drug market. ...
... Using GC-MS, scientists at DSTL were able to determine unambiguously that a mixture of carfentanil and remifentanil was employed during the crisis by the Russian special forces that eventually eliminated the threat but unfortunately resulted in the deaths of innocent civilian by-standers. [28] Another paper describing the use of GC-MS for the detection and identification of carfentanil was published by Swanson et al. from the Medical Examiner Department in Tampa, Florida in 2017. [116] The work describes the analysis of tissues collected postmortem from overdosing decedents using GC-MS-SIM. ...
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Article
The rising number of deaths caused by fentanyl overdosing in the US due to the overwhelming illicit use of this synthetic opioid has started a global campaign to develop efficient ways to control its production and distribution as well as discovering efficient antidotes to mitigate its lethal effects. Another important vein of focused research established by various agencies lies in the development of efficient and practical protocols for the detection of this opioid and analogs thereof in various matrices, whether environmental or biological in nature, particularly in the field of gas chromatography-mass spectrometry (GC-MS). The following review will cover the literature dealing with the detection and identification of synthetic opioids belonging to the fentanyl class by GC-MS means and hyphenated versions of the technique. Detailed descriptions will be given for the GC-MS methods employed for the analysis of the opioid, starting with the nature of the extraction protocol employed prior to analysis to the actual findings presented by the cited reports. Great effort has gone into describing the methods involved in each paper in a detailed manner and these have been compiled by year in tables at the end of each section for the reader’s convenience. Lastly, the review will end with concluding remarks about the state of GC-MS analysis with regards to these powerful opioids and what lies ahead for this analytical field.
... On October 26, 2002, Russian military special forces introduced a "poison" gas to incapacitate Chechen rebels who had taken more than 800 people hostage in the Moscow Dubrovka Theater Center (12). The composition of the "poison" gas was not immediately released to first responders, a factor that delayed or prevented accurate treatment and likely played a large role in the death of more than 120 of the hostages. ...
... The composition of the "poison" gas was not immediately released to first responders, a factor that delayed or prevented accurate treatment and likely played a large role in the death of more than 120 of the hostages. However, the Russian health minister announced 4 days after the event that "a fentanyl derivative was used to neutralize the terrorists" (12). Further analysis of the clothing and urine of British nationals who were in the theater at the time of the siege revealed that a mixture of carfentanil and remifentanil was most likely used (13). ...
... As evidenced by the Moscow theater incident (12) and the increasing concern among law enforcement and first responders (11), acute inhalation exposures to carfentanil are a potential danger; ...
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Article
Carfentanil is a powerful synthetic opioid that is approximately 100 times more potent than fentanyl and 10,000 times more potent than morphine. Carfentanil was originally intended to be used as a sedative for big game animals in a veterinary setting, but it is becoming increasingly recognized as a public health concern. We set out to investigate the effectiveness of naloxone against a potentially lethal dose of inhaled carfentanil in male ferrets. Ferrets were implanted with telemetry devices to study cardiac parameters and exposed to aerosolized carfentanil in a whole-body plethysmography chamber to record respiratory parameters. We observed profound respiratory depression in exposed animals, which led to apneic periods constituting 24-31% of the exposure period. Concomitant with these apneic periods, we also observed cardiac abnormalities in the form of premature junctional contractions (PJCs). At our acute exposure dose, lethal in 3% of our animals, naïve ferrets were unresponsive and incapacitated for a total of 126.1 ± 24.6 minutes. When administered intramuscularly at human equivalent doses (HEDs) of either 5 mg or 10 mg, naloxone significantly reduced the time that ferrets were incapacitated following exposure, although we observed no significant difference in the reduction of time that the animals were incapacitated between the treatment groups. Naloxone was able to quickly resolve the respiratory depression, significantly reducing the frequency of apneic periods in carfentanil-exposed ferrets. Our results suggest that naloxone, when administered via intramuscular injection following incapacitation, is a viable treatment against the effects of a potentially lethal dose of inhaled carfentanil.
... An aerosolized mixture containing carfentanil and remifentanil and/or halothane allegedly used by Russian military when ending a Chechen hostage in Moscow led to the death of 127 hostages. This also suggests an effective uptake of carfentanil by inhalation (Riches et al, 2012;Stanley, 2003;Wax et al., 2003). For further details see Section D.1.2. ...
... Besides its use as an immobilising agent in animals, carfentanil is believed to have been used for this purpose in humans. In October 2002, Russian special forces are thought to have used a gas mixture containing carfentanil as part of a counter terrorism operation (Stanley, 2003;Riches et al., 2012;Wax et al., 2003) (see Section D.1.2). ...
... The opioid hypothesis was supported by reports from Russian physicians that naloxone was successful in reversing the effects of the intoxication. The Russian Health Minister announced 4 days after the event that, 'a fentanyl derivative was used to neutralize the terrorists ' (Wax et al., 2003). It was speculated that the fentanyl derivative concerned could have been carfentanil (Stanley, 2003;Wax et al., 2003). ...
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Technical Report
This publication presents the data and findings of the risk assessment on methyl 1-(2-phenylethyl)-4-[phenyl(propanoyl)amino]piperidine-4-carboxylate (carfentanil), carried out by the extended Scientific Committee of the EMCDDA on 7-8 November 2017. In March 2018, at its 61st regular session, the Commission on Narcotic Drugs (CND) decided to place carfentanil in Schedule I and Schedule IV of the Single Convention on Narcotic Drugs of 1961 based on a recommendation by the World Health Organization. This recommendation was substantially supported by European data provided by the EMCDDA.
... 4 Moreover, there is evidence that high potency synthetic opioids have, in fact, been weaponized. 5 In 2002, the Russian military released an aerosolized mixture of carfentanil and remifentanil into a ventilation system to immobilize Chechen terrorists who had stormed the Dubrovka Opera House in Moscow. More than 120 hostages died in the operation, and 650 of the survivors required hospitalization. ...
... It was clear from the meeting that opioids, particularly highly potent fentanyl analogs, such as carfentanil, pose a significant risk to public health not only because of the ongoing opioid epidemic, but also because of the toxicity and potential mass lethality that could occur from nefarious use of these opioids. 5 It is difficult to imagine how the only drug currently available to treat opioid overdose, naloxone, could be deployed effectively in a mass casualty situation, particularly after exposure to large doses of fentanyl or its analogs. 2 A rapid-acting, potent, and safe opioid receptor antagonist that provides extended (hours or days) protection after a single administration could be a much needed medication for defending civilian and military populations. ...
Article
The only medication available currently to prevent and treat opioid overdose (naloxone) was approved by the US Food and Drug Administration (FDA) nearly 50 years ago. Because of its pharmacokinetic and pharmacodynamic properties, naloxone has limited utility under some conditions and would not be effective to counteract mass casualties involving large‐scale deployment of weaponized synthetic opioids. To address shortcomings of current medical countermeasures for opioid toxicity, a trans‐agency scientific meeting was convened by the US National Institute of Allergy and Infectious Diseases/National Institutes of Health (NIAID/NIH) on August 6 and 7, 2019, to explore emerging alternative approaches for treating opioid overdose in the event of weaponization of synthetic opioids. The meeting was initiated by the Chemical Countermeasures Research Program (CCRP), was organized by NIAID, and was a collaboration with the National Institute on Drug Abuse/NIH (NIDA/NIH), the FDA, the Defense Threat Reduction Agency (DTRA), and the Biomedical Advanced Research and Development Authority (BARDA). This paper provides an overview of several presentations at that meeting that discussed emerging new approaches for treating opioid overdose, including the following: (1) intranasal nalmefene, a competitive, reversible opioid receptor antagonist with a longer duration of action than naloxone; (2) methocinnamox, a novel opioid receptor antagonist; (3) covalent naloxone nanoparticles; (4) serotonin (5‐HT)1A receptor agonists; (5) fentanyl‐binding cyclodextrin scaffolds; (6) detoxifying biomimetic “nanosponge” decoy receptors; and (7) antibody‐based strategies. These approaches could also be applied to treat opioid use disorder.
... Despite decontamination with water, within 2 min he became nauseated, sedate, and hypotensive, but became asymptomatic after receiving 100 mg of intramuscular naltrexone (Haymerle et al., 2010). Nearly 800 people taken hostage in a Moscow theater in October 2002 were exposed to aerosolized carfentanil (Riches et al., 2012;Wax et al., 2003). Although nearly all were incapacitated, only 15% died despite the weaponization of carfentanil for maximal absorption and delayed availability of naloxone (Wax et al., 2003). ...
... Nearly 800 people taken hostage in a Moscow theater in October 2002 were exposed to aerosolized carfentanil (Riches et al., 2012;Wax et al., 2003). Although nearly all were incapacitated, only 15% died despite the weaponization of carfentanil for maximal absorption and delayed availability of naloxone (Wax et al., 2003). ...
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Article
There is growing concern regarding potential occupational exposures to the ultra-potent synthetic opioid carfentanil. However, little data are available on the toxicity of carfentanil in humans, particularly for dermal exposures. To begin to address this, permeation of carfentanil formulated in three vehicles, water, ethanol, and hand sanitizer was measured under infinite-dose conditions in an in vitro static diffusion cell system using the EpiDerm™ (EPI-606-X) RhE model. The permeation rate was fastest for carfentanil in water (3.9 × 10-3 cm/h), followed by hand sanitizer (1.2 × 10-3 cm/h), and slowest for carfentanil in ethanol (0.2 × 10-3 cm/h). In both ethanol and hand sanitizer, a lag-time between exposure and permeation of approximately 1.5 h was observed, while lag-time in water was approximately half an hour. Flux at steady-state was greater at 50.6 μg/ml than at 5.3 μg/ml for both water and ethanol; however, the percent of dose absorbed did not differ between doses for either vehicle. Slight differences in percutaneous permeation of carfentanil were observed between two brands of hand sanitizer, likely due to differences in relative proportion of alcohol and skin penetration enhancers. These data indicate that small skin exposures may not result in rapid, significant toxicity as previously reported.
... On October 26, 2002, Russian Special Forces deployed a chemical aerosol against Chechen terrorists to rescue hostages in the Dubrovka theatre. Although the Russian authorities have never admitted it, an aerosol comprised a mixture of two anaesthetics including CaF was certainly used [25][26][27]. ...
... The washing step with 95% of solution B was hold from 10.25 minutes to 12.5 minutes and the initial condition was applied from 12.5 minutes to 15 minutes. Xevo TQ-S tandem mass spectrometer was used for detection after positive electrospray ionization mode in the MRM mode using the following transitions (quantitation): m/z 395. 2 The validation procedure of CaF quantitation complied with both the French Analytical Toxicology Society (SFTA) and international recommendations for the validation of new analytical methods [25,26] including linearity, limit of detection (LOD), limit of quantification (LOQ), accuracy, precision and matrix effects. Calibration curves, estimated using 1/x weighted quadratic regression, were considered acceptable if the coefficient of determination (r 2 ) was at least 0.99. ...
Article
Today, NPS are increasingly being related to post-mortem cases, and this problem drastically intensifies as a result of the New Synthetic Opioids (NSOs) surge. Among NSOs, carfentanil (CaF) is the most potent fentanyl analogue and was central to a large number of NSOs-related fatalities in North America, as well as in UE, since 2016. In this worrisome context, this manuscript reports the first CaF-related fatality occurred in France. A 41-years-old man was found dead with a syringe planted under his tongue. This man has a psychiatric follow-up for opiate addiction and his recent medical history included intoxication with fentanyl derivatives. Toxicological investigations of post-mortem samples (blood, urine and hair), and syringe were requested. CaF (with several other psychoactive drugs at non-toxic level) was detected in biological samples and in syringe residue using LC-HRMS, and quantified using LC-MS/MS in blood, urine and hair (from proximal to distal hair section – 3 cm length each) at 4.20, 0.40 μg/L and 54/114/166 pg/mg, respectively. The relatively high post-mortem CaF blood concentration together with the absence of metabolite (especially NorCaF) suggests a sudden death of the victim immediately following a significant CaF dose intake (presumably injected) that can explain the decease.
... Si se les hubiera avisado, habrían empleado seguramente grandes dosis de naloxona in situ y antagonista de estas sustancias, salvando vidas. Queda por responder la pregunta de si había algo más en el gas 28,29 . ...
Article
Durante la Primera Guerra Mundial, diversas sustancias químicas se utilizaron de forma sistemática como armas. Años después, los nazis descubrieron accidentalmente los agentes neurotóxicos organofosforados (ANOF) del grupo G: tabún, sarín y somán; pero sorprendentemente no los utilizaron pese a que conocían su letalidad. Posteriormente, durante la Guerra Fría, los países de la OTAN (Organización del Tratado del Atlántico Norte) desarrollaron los ANOF del grupo V, entre los que destaca el VX; y la URSS desarrolló los más temibles, los ANOF del grupo A, entre los que destacan los novichoks. Los ANOF cayeron en el olvido hasta que infamemente resurgieron en la matanza de Halabja (guerra Irán-Irak, 1988), en los atentados terroristas del metro de Tokio (1995) y en el bombardeo de Ghouta (guerra de Siria, 2013). Sin embargo, la utilización bélica se ha redirigido en los últimos años a asesinatos selectivos cometidos por servicios secretos, como en los casos Skripal, Gebrev, Kim Jong-nam o Navalny. Además, personas próximas a las víctimas, como el personal sanitario, también puede intoxicarse. Los ANOF inhiben irreversible y rápidamente la acetilcolinesterasa y su letalidad es mucho mayor que la de los organofosforados pesticidas. El cuadro clínico recuerda a una intoxicación aguda por opiáceos, pero con hipersecreción generalizada: hipersialorrea, rinorrea, dacriorrea, diarrea, broncorrea, etc. Por ello, se conoce como «toxíndrome opioide húmedo». Se revisa la historia de la síntesis de los ANOF, la clínica que induce su exposición y su tratamiento: soporte vital, descontaminación, atropinización y antídotos.
... The 3-and 4-positions on the piperidine ring of the fentanyl scaffold have been exploited to develop more potent fentanyl analogs, including carfentanil, 3-methylfentanyl, and lofentanil [2,27] (Fig. S1). In particular, carfentanil (4carbomethoxy fentanyl) has evolved from being used as an animal anesthetic to a deadly abused drug [28], and even has the potential of being used as a chemical weapon [29]. Intriguingly, with the same addition of a 3-methyl moiety, 3-methylfentanyl has much higher potency (as high as $200fold, (3R,4S)-isomer) than fentanyl [30,31], while lofentanil (i.e., 3-methyl carfentanil) only has slightly better affinity at the MOR than carfentanil [32,33]. ...
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Fentanyl and its analogs are selective agonists of the µ-opioid receptor (MOR). Among novel synthetic opioids (NSOs), they dominate the recreational drug market and are the main culprits for the opioid crisis, which has been exacerbated by the COVID-19 pandemic. By taking advantage of the crystal structures of the MOR, several groups have investigated the binding mechanism of fentanyl, but have not reached a consensus, in terms of both the binding orientation and the fentanyl conformation. Thus, the binding mechanism of fentanyl at the MOR remains an unsolved and challenging question. Here, we carried out a systematic computational study to investigate the preferred fentanyl conformations, and how these conformations are being accommodated in the MOR binding pocket. We characterized the free energy landscape of fentanyl conformations with metadynamics simulations, and compared and evaluated several possible fentanyl binding conditions in the MOR with long-timescale molecular dynamics simulations. Our results indicate that the most preferred binding pose in the MOR binding pocket corresponds well with the global minimum on the energy landscape of fentanyl in the absence of the receptor, while the energy landscape can be reconfigured by modifying the fentanyl scaffold. The interactions with the receptor may stabilize a slightly unfavored fentanyl conformation in an alternative binding pose. By extending similar investigations to fentanyl analogs, our findings establish a structure-activity relationship of fentanyl binding at the MOR. In addition to providing a structural basis to understand the potential toxicity of the emerging NSOs, such insights will contribute to developing new, safer analgesics.
... In 2002, a group of Chechen terrorists attacked the Dubrovka theatre in Moscow, Russia, resulting in a hostage standoff [7]. In response, special forces under direction of President Putin instilled a chemical aerosol into the vents of the theater incapacitating those inside. ...
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Article
Department of Psychosocial oncology and Palliative care, Dana Farber cancer institute, Boston, ma, usa; c The Koch institute for integrated cancer Research, massachusetts institute of Technology, cambridge, ma, usa; d The Fenway institute, Boston, ma, usa; e center for global Health, university of illinois college of medicine, chicago, il, usa; f Harvard Humanitarian institute, Boston, ma, usa ABSTRACT the unprovoked invasion of ukraine by the Russian Federation has resulted in the largest humanitarian crisis in Europe since World War ii. as fighting intensifies throughout ukraine, there is an increasing concern that the Russian Federation may consider the direct use of chemical or radiological weapons against military personnel and civilians in ukraine. despite prohibition of chemical weapons from the Chemical Weapons Convention of 1997, recent evidence has demonstrated that state actors will continue to use these agents as weapons of war and terror, despite publicly denying their use. We review chemical weapons produced and used by the Russian Federation (or its allies) to identify plausible risks in the Russian war in ukraine. We also provide rapid assessment and treatment guidelines to recognize and manage these acute exposures.
... The 3-and 4-positions on the piperidine ring of the fentanyl scaffold have been exploited to develop more potent fentanyl analogs, including carfentanil, 3-methylfentanyl, and lofentanil [2,26]. In particular, carfentanil has evolved from being used as an animal anesthetic to a deadly abused drug [27], and even has the potential of being used as a chemical weapon [28]. Intriguingly, with the same addition of a 3-methyl moiety, 3-methylfentanyl has much higher potency (as high as ~200-fold, (3R,4S)-isomer) than fentanyl [29,30], while lofentanil (i.e., 3methylcarfetanil) only has slightly better affinity at the MOR than carfentanil [31,32]. ...
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Preprint
Fentanyl and its analogs are selective agonists of the µ-opioid receptor (MOR). Among novel synthetic opioids (NSOs), they dominate the recreational drug market and are the main culprits for the opioid crisis, which has been exacerbated by the COVID-19 pandemic. By taking advantage of the crystal structures of the MOR, several groups have investigated the binding mechanism of fentanyl, but have not reached a consensus, in terms of both the binding orientation and the fentanyl conformation. Thus, the binding mechanism of fentanyl at the MOR remains an unsolved and challenging question. Here, we carried out a systematic computational study to investigate the preferred fentanyl conformations, and how these conformations are being accommodated in the MOR binding pocket. We characterized the free energy landscape of fentanyl conformations with metadynamics simulations, as well as performed long-timescale molecular dynamics simulations to compare and evaluate several possible fentanyl binding conditions. Our results indicate that the most preferred binding pose in the MOR binding pocket corresponds well with the minima on the energy landscape of fentanyl in the absence of the receptor, while the energy landscape can be reconfigured by modifying the fentanyl scaffold. The interactions with the receptor may stabilize a slightly unfavored fentanyl conformation in an alternative binding pose. By extending similar investigations to fentanyl analogs, our findings establish a structure-activity relationship of fentanyl binding at the MOR. In addition to providing a structural basis to understand the potential toxicity of the emerging NSOs, such insights will contribute to developing new, safer analgesics.
... Given the likelihood of continued misuse of fentanyl and fentanyl analogs, the emergence (Thompson, 2020;Ujvary et al., 2021) of a structurally distinct class of illicit synthetic benzimidazoles which share many of the same characteristics that make fentanyl misuse so dangerous, and the concerns about weaponization of ultra-high affinity synthetics like carfentanil (France et al., 2021;Shafer, 2019;Wax, Becker, & Curry, 2003), the development of more effective overdose reversal agents is one component of a strategy to reduce the impact of opioid misuse, and must be viewed as a public health priority (Christie et al., 2017;Volkow & Collins, 2017). ...
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Article
Overdose deaths are often viewed as the leading edge of the opioid epidemic which has gripped the United States over the past two decades (Skolnick, 2018a). This emphasis is perhaps unsurprising because opioid overdose is both the number-one cause of death for individuals between 25 and 64 years old (Dezfulian et al., 2021) and a significant contributor to the decline in average lifespan (Dowell et al., 2017). Exacerbated by the COVID 19 pandemic, it was estimated there were 93,400 drug overdose deaths in the United States during the 12 months ending December 2020, with more than 69,000 (that is, >74%) of these fatalities attributed to opioid overdose (Ahmad et al., 2021). However, the focus on mortality statistics (Ahmad et al., 2021; Shover et al., 2020) tends to obscure the broader medical impact of nonfatal opioid overdose. Analyses of multiple databases indicate that for each opioid-induced fatality, there are between 6.4 and 8.4 non-fatal overdoses, exacting a significant burden on both the individual and society. Over the past 7-8 years, there has been an alarming increase in the misuse of synthetic opioids ("synthetics"), primarily fentanyl and related piperidine-based analogs. Within the past 2-3 years, a structurally unrelated class of high potency synthetics, benzimidazoles exemplified by etonitazene and isotonitazene ("iso"), have also appeared in illicit drug markets (Thompson, 2020; Ujvary et al. 2021). In 2020, it was estimated that over 80% of fatal opioid overdoses in the United States now involve synthetics (Ahmad et al., 2021). The unique physicochemical and pharmacological properties of synthetics described in this review are responsible for both the morbidity and mortality associated with their misuse as well as their widespread availability. This dramatic increase in the misuse of synthetics is often referred to as the "3rd wave" (Pardo et al., 2019; Volkow and Blanco, 2020) of the opioid epidemic. Among the consequences resulting from misuse of these potent opioids is the need for higher doses of the competitive antagonist, naloxone, to reverse an overdose. The development of more effective reversal agents such as those described in this review is an essential component of a tripartite strategy (Volkow and Collins, 2017) to reduce the biopsychosocial impact of opioid misuse in the "synthetic era".
... The agent, although successful in overwhelming the hostage-takers, also killed 127 hostages. 40 Many disabling agents are weapons of opportunity, easily acquired pharmaceutical agents, or substances of abuse that are added surreptitiously to common sources of food or drink. ...
Article
Children are potential victims of chemical or biological terrorism. In recent years, children have been victims of terrorist acts such as the chemical attacks (2017–2018) in Syria. Consequently, it is necessary to prepare for and respond to the needs of children after a chemical or biological attack. A broad range of public health initiatives have occurred since the terrorist attacks of September 11, 2001. However, in many cases, these initiatives have not ensured the protection of children. Since 2001, public health preparedness has broadened to an all-hazards approach, in which response plans for terrorism are blended with those for unintentional disasters or outbreaks (eg, natural events such as earthquakes or pandemic influenza or man-made catastrophes such as a hazardous-materials spill). In response to new principles and programs that have evolved over the last decade, this technical report supports the accompanying update of the American Academy of Pediatrics 2006 policy statement “Chemical-Biological Terrorism and its Impact on Children.” The roles of the pediatrician and public health agencies continue to evolve, and only their coordinated readiness and response efforts will ensure that the medical and mental health needs of children will be met successfully. In this document, we will address chemical and biological incidents. Radiation disasters are addressed separately.
... Incapacitating agents were studied during the Cold War when it was assumed that incapacitating the enemy would impact them more because these individuals would not only become unavailable for duty but also because they would consume more logistical resources relating to their evacuation [11]. In October 2002, the Russian military used a mysterious "gas" to incapacitate Chechen rebels who had taken 800 hostages at a Moscow theater [12]. Unfortunately, more than 120 of the hostages in the theater died and more than 650 of the survivors required hospitalization. ...
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Article
Background One of the most prominent opioid analgesics in the United States is the high potency agonist fentanyl. It is used in the treatment of acute and chronic pain and as an anesthetic adjuvant. When used inappropriately, however, ingestion of just a few milligrams of fentanyl or other synthetic opioid can cause opioid-induced respiratory depression (OIRD), often leading to death. Currently, the treatment of choice for OIRD is the opioid receptor antagonist naloxone. Recent reports, however, suggest that higher doses or repeated dosing of naloxone (due to recurrence of respiratory depression) may be required to reverse fully fentanyl-induced respiratory depression, rendering this treatment inadequate. To combat this synthetic opioid overdose crisis, this research aims at identifying a novel opioid reversal agent with enhanced efficacy towards fentanyl and other synthetic opioids. Methods A series of naltrexone analogues were characterized for their ability to antagonize the effects of fentanyl in vitro utilizing a modified forskolin-induced cAMP accumulation assay. Lead analogue 29 was chosen to undergo further PK studies, followed by in vivo pharmacological analysis to determine its ability to antagonize opioid-induced antinociception in the hot plate assay. Results A series of potent MOR antagonists were identified, including the highly potent analogue 29 (IC 50 = 2.06 nM). Follow-up PK studies revealed 29 to possess near 100% bioavailability following IP administration. Brain concentrations of 29 surpassed plasma concentrations, with an apparent terminal half-life of ~ 80 min in mice. In the hot plate assay, 29 dose-dependently (0.01–0.1 mg/kg; IP) and fully antagonized the antinociception induced by oxycodone (5.6 mg/kg; IP). Furthermore, the dose of 29 that is fully effective in preventing oxycodone-induced antinociception (0.1 mg/kg) was ineffective against locomotor deficits caused by the KOR agonist U50,488. Conclusions Methods have been developed that have utility to identify enhanced rescue agents for the treatment of OIRD. Analogue 29 , possessing potent MOR antagonist activity in vitro and in vivo, provides a promising lead in our search for an enhanced synthetic opioid rescue agent.
... Nonpharmaceutical carfentanil is present in the illicit drug markets as a mixture in heroin, a recreational drug that poses a public health threat. It is alleged to have been used as a chemical warfare agent in antiterrorist activities [10,11]. Both fentanyl and carfentanil have been classified under the controlled substance act as scheduled I and II drugs, respectively, by the US Drug Enforcement Administration [4]. ...
Article
The geometrical molecular structures, atomic charges, frontier molecular orbitals, and UV–visible electronic data of analgesic drugs carfentanil and acetylfentanyl were computed using quantum chemical code. In addition, NMR (1H and 13C) chemical shifts, harmonic vibrational wavenumbers, and the corresponding vibrational assignments were proposed on the basis of potential energy distribution. The calculations were carried out at Becke-3-Lee–Yang–Parr (B3LYP) functional with density functional theory (DFT) and time-dependent density functional theory (TD-DFT) using the 6–311 + + G(d,p) basis set. The piperidine rings of the two molecules adopt a more stable chair conformation of a six-membered ring structure with slight distortion at the point of substitution. This shows that the piperidine moiety of the carfentanil and acetylfentanyl have similar geometric parameters and thus support the hypothesis that the piperidine ring in these molecules is the primary structural feature that is responsible for their analgesic activities. In addition, the introduction of the carbomethoxy (-COCH3) group into the piperidine ring of fentanyl has little or no effect on the electronic properties of this class of molecules. The theoretical results were successfully compared with similar piperidine-based analgesic drugs fentanyl and available experimental data. This research gives precise and invaluable information that will help in the structural elucidation of analogs of fentanyl that could be used in the development of analytical methods for the accurate and reliable detection and monitoring of these important molecules.
... Śmierć poniosło ponad 120 osób, a pozostali wymagali hospitalizacji ze względu na bardzo silne depresyjne działanie zastosowanego środka. Tak wysoka śmiertelność była związana z zatajeniem przez służby informacji o zawartości uwolnionego gazu i związanym z tym długim czasem poszukiwania przez służby medyczne swoistego antidotum, którym jak się później okazało był nalokson (odwraca depresję układu oddechowego spowodowaną zatruciem fentanylami) [58,59]. W 2012 r. grupa brytyjskich naukowców badając materiał pobrany od ocalałych osób ustaliła, że zastosowany teatrze gaz zawierał niezwykle silnie działający na ośrodkowych układ nerwowy karfentanyl i remifentanyl [11]. ...
... For example, the use of fentanyl drug during 2002 hostage situation in Moscow resulted in 125 deaths. [6][7][8] These opioid threats can be absorbed through the skin and crossdermal membranes to reach body fluids. 9,10 Likewise, dermal exposure of nerve agents will also lead to emergency situations. ...
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Article
There are urgent needs for sensing devices capable of distin-guishing between episodes of opioid overdose and nerve agent poisoning. This work presents a wearable microneedle sensor array for minimally-invasive continuous electrochemical detection of opioid (OPi) and organophosphate (OP) nerve agents on a single patch platform. The new multi-modal microneedle sensor array relies on unmodified and organophosphorus hydrolase (OPH) enzyme-modified carbon paste (CP) microneedle electrodes for square wave voltammetric (SWV) detection of the fentanyl and nerve agent targets, respectively. Such real-time simultaneous sensing provides distinct unique information, along with attractive analytical performance, including high sensitivity, selectivity sand stability, for real-time on-body OPi-OP analysis. The patch represents the first sensing device capable of continuously monitoring fentanyl down to the nanomolar level through a nanomaterial-based multi-layered surface architecture. Applicability of the sensor array towards opioids screening is demonstrated for morphine and norfentanyl. Successful OPi-OP detection con-ducted in a skin-mimicking phantom gel demonstrates the suitability of the device for rapid on-body sensing. Such progress towards continuous minimally-invasive transdermal analysis of drugs of abuse and nerve agents holds promise for rapid countermeasures for protecting soldiers, civil-ians, and healthcare personnel.
... Calculated as the median lethal dose (LD50)/lowest median effective dose (ED50), a high therapeutic index generally implies a wide safety margin between the effective dose and the lethal dose. The reported therapeutic index of carfentanil is 10,600 compared with fentanyl's 300, using morphine as the reference at 70. 34 Nevertheless, this parameter is potentially misleading as it suggests that carfentanil is safer than fentanyl, even though the reported LD50 values in rats are similar (3.39 mgÁkg -1 for carfentanil and 3.05 mgÁkg -1 for fentanyl). 18,35 The discrepancy between analgesic potency and lethality may be related to the fact that these values are derived from animal studies, and may not be generalizable to other species such as humans. ...
Article
Carfentanil is a synthetic fentanyl analogue approved for veterinary use. It is a mu-opioid receptor agonist with an estimated analgesic potency approximately 10,000 times that of morphine and 20-30 times that of fentanyl, based on animal studies. Since 2016, an increasing number of reports describe detection of carfentanil in the illicit drug supply. Little is known about the pharmacology of carfentanil in humans. Its high potency and presumed high lipophilicity, large volume of distribution, and potential active metabolites have raised concerns about the management of people exposed to carfentanil as well as the safety of first responders. Exposed individuals exhibit features of an opioid toxidrome and respond to opioid antagonists such as naloxone, although empiric dose requirements are unknown and very high doses may be required. Rare reports of suspected accidental poisoning of first responders have not been analytically confirmed and are unlikely to represent true poisoning. General occupational hygiene measures, including regular decontamination with soap and water, basic personal protective equipment (nitrile gloves, N95 mask, and eye goggles), and ready access to naloxone are generally sufficient in most circumstances.
... It has recently been identified as having been involved in a significant number of overdose fatalities (3)(4)(5)(6)(7), though survival of carfentanil exposure has been described (8)(9)(10)(11). It is also alleged that carfentanil has been involved in military applications (12,13). Carfentanil is approximately 10,000 times as powerful as morphine. ...
Article
Carfentanil is a synthetic opioid approximately 10,000 times as powerful as morphine. It is not approved for human use. However, cases of death associated with carfentanil have become more frequent in recent years. In this report, the case of a patient with a positive urine test for norcarfentanil (a metabolite of carfentanil) is described. The analytical method leading to the detection is summarized. This is a rarely reported case of survival of carfentanil use. It is unique in the published literature of an account of a norcarfentanil-positive patient concurrently enrolled in a substance use disorder treatment program. To the authors' knowledge, this is the first documented case of a carfentanil exposure in the state of New York.
... The agent, although successful in overwhelming the hostage-takers, also killed 127 hostages. 40 Many disabling agents are weapons of opportunity, easily acquired pharmaceutical agents, or substances of abuse that are added surreptitiously to common sources of food or drink. ...
Article
Children are potential victims of chemical or biological terrorism. In recent years, children have been victims of terrorist acts such as the chemical attacks (2017-2018) in Syria. Consequently, it is necessary to prepare for and respond to the needs of children after a chemical or biological attack. A broad range of public health initiatives have occurred since the terrorist attacks of September 11, 2001. However, in many cases, these initiatives have not ensured the protection of children. Since 2001, public health preparedness has broadened to an all-hazards approach, in which response plans for terrorism are blended with those for unintentional disasters or outbreaks (eg, natural events such as earthquakes or pandemic influenza or man-made catastrophes such as a hazardous-materials spill). In response to new principles and programs that have evolved over the last decade, this technical report supports the accompanying update of the American Academy of Pediatrics 2006 policy statement "Chemical-Biological Terrorism and its Impact on Children." The roles of the pediatrician and public health agencies continue to evolve, and only their coordinated readiness and response efforts will ensure that the medical and mental health needs of children will be met successfully. In this document, we will address chemical and biological incidents. Radiation disasters are addressed separately.
... More specifically, the first response system can be best optimized if the time between an incident [exposure] to recognition of the toxic effect (e.g., toxidrome recognition) and subsequent administration of the ideal MCM is reduced, i.e., "rapid recognition leads to urgent intervention." To illustrate this point, Dr. Kirk very briefly summarized the sequence of events and outcomes associated with the 1995 Tokyo sarin attack [4,5] and the 2002 Moscow theater hostage siege, where synthetic opioids were deployed against civilians [6][7][8]. Dr. Sutter then provided a first-hand case series report of a 2016 opioid-based mass casualty incident that occurred in Sacramento, California involving fentanyladulterated tablets presented as hydrocodone/acetaminophen [9]. This mass casualty public health emergency of exaggerated fentanyl opioid toxicity provided a real-life illustration of where improvements in the current medical response system could be beneficial. ...
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On August 6th, 2019, a two-day trans-agency scientific meeting was convened by the United States (U.S.) National Institute of Allergy and Infectious Diseases (NIAID/NIH) on the research and development of medical countermeasures (MCMs) and treatment strategies to mitigate synthetic opioid-induced toxicities. This trans-agency meeting was an initiative of the Chemical Countermeasures Research Program (CCRP) and organized by the NIAID in collaboration with the National Institute of Drug Abuse (NIDA), the Biomedical Advanced Research and Development Authority (BARDA), the Food and Drug Administration (FDA), and the Defense Threat Reduction Agency (DTRA). The CCRP is part of the larger NIH biodefense research program coordinated by NIAID, which also includes MCM research and development programs against biological, radiological, and nuclear threats. Its overarching goal is to integrate cutting-edge research and technological advances in science and medicine to enhance the nation’s medical response capabilities during and after a public health emergency involving the deliberate or accidental release of toxic chemicals. The potential of a mass casualty public health event involving synthetic opioids is a rapidly growing concern. As such, the overall goals of this trans-agency meeting are to better understand opioid-induced toxicities and advance the development of MCMs to mitigate and reverse opioid-induced respiratory depression (OIRD) to prevent consequential mortality. The primary objectives of the meeting were (1) highlight the latest research on mechanisms of OIRD and related toxicities, animal models, diagnostics, delivery technologies, and emerging new treatment options to prevent lethality; (2) identify current knowledge gaps to advance medical countermeasure development; (3) hear from the U.S. FDA on regulatory considerations to support new technology and treatment approaches; and (4) provide a forum for networking and collaborative partnerships. To accomplish this, a diverse group of almost 200 US domestic and international subject matter experts spanning fundamental and translational research from academia, industry, and government came together in-person to share their collective expertise and experience in this important field. This report briefly summarizes the information presented throughout the meeting, which was also webcast live in its entirety to registered remote attendees.
... In 2016 it was responsible for ∼20,000 overdose deaths in the USA (Jones et al., 2018). Furthermore, it and its analogs carfentanil and remifentanil, are considered weapons of war, as the latter two were used by the Russian military to incapacitate rebels in a Moscow theater (Wax et al., 2003;Riches et al., 2012). In 2016 Canadian authorities seized 1 kg of carfentanil sent from China, equivalent to 50 million lethal doses (Kinetz and Butler, 2016). ...
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During the past decade, the ability of surface-enhanced Raman spectroscopy (SERS) to measure extremely low concentrations, such as mg/L and below, and the availability of hand-held Raman spectrometers, has led to a significant growth in the number and variety of applications of SERS to real-world problems. Most of these applications involve the measurement of drugs, such as quantifying medication in patients, identifying illicit drugs in impaired drivers, and more recently, identifying drugs used as weapons. Similar to Raman spectroscopy, most of the point-of-care and field applications involve the identification of the drug to determine the course of action. However, unlike Raman spectroscopy, spectral libraries are not readily available to perform the necessary identification. In a large part, this is due to the uniqueness of the commercially available SERS substrates, each of which can produce different spectra for the same drug. In an effort to overcome this limitation, we have measured numerous drugs using the most common, and readily available SERS material and hand-held Raman analyzers, specifically gold colloids and analyzers using 785 nm laser excitation. Here we present the spectra of some 39 drugs of current interest, such as buprenorphine, delta-9 tetrahydrocannabinol, and fentanyl, which we hope will aid in the development of current and future SERS drug analysis applications.
... COs now identify fentanyl as the greatest risk to their safety in prisons. 2002 to incapacitate Chechen rebels who had taken more than 800 people hostage-126 of whom died from inhaling the drug (Wax, Becker, & Curry, 2003). ...
Article
Background and aims: Fentanyl and derivatives are lethal components of North America's opioid crisis. Prisons often house a disproportionate number of illicit opiate users. To date, no on-the-ground empirical research exists on how opioids are altering the health and risk profile of prisons. The objectives of this study were to examine (1) how fentanyl and its analogues have shaped the prison experience for prisoners; and (2) how these opioids have altered the occupation of correctional officers (CO's). Methods: We conducted semi-structured interviews with 587 adult prisoners and 131 COs across four provincial prisons in Western Canada. Prisoners were recruited on their housing units and randomly selected. COs were recruited through non-probability, theoretical sampling. We employed a generalized prompt guide and asked a range of questions pertaining to how the presence of fentanyl and its analogues have changed the prison experience for prisoners and have impacted the work routine of COs. Interviews were digitally recorded, transcribed verbatim, thematically coded and analyzed using Nvivo 11. Results: For prisoners, we identified four main results: (1) the presence of fentanyl leads to an increased number of overdoses; (2) prisons are nonetheless perceived as a comparatively safe place to use drugs; (3) fentanyl is often mixed into other drugs, making it hard for drug users to avoid fentanyl; and (4) prisoners fear fentanyl is being weaponized. For officers, we identified: (1) increased fears about inadvertent personal exposure or widespread institutional opioid contamination; (2) fear of targeted poisonings; (3) changing attitudes towards opioid-using prisoners; and (4) a declining commitment to correctional careers. Conclusion: The presence of fentanyl in prisons has significantly influenced how prisoners experience prison and relate to each other and how COs perceive their job. COs now identify fentanyl as the greatest risk to their safety in prisons.
... It is 10 000 times as potent as morphine. 25,26 Unintentional use of illicitly manufactured fentanyls alone, added to heroin, cocaine, or to counterfeit prescription tablets resembling oxycodone or hydrocodone, has been cited as an important driver of the recent increases in opioid overdose deaths. 27,28 There have been many reports detailing symptoms that first responders have developed when responding to drug overdose incidents in environments where multiple types of illicit drugs may be present. ...
Article
Opioids have many beneficial uses in medicine, but, taken inappropriately, they can cause life‐threatening health effects. The increasing use of physician‐prescribed and illicit opioids, including highly potent fentanyl and its analogs, have contributed to a significant increase in opioid‐related drug overdoses in the United States, leading to a public health emergency. There have been a number of reports describing adverse health effects experienced by police officers, fire‐fighter emergency medical services providers, and private sector ambulance personnel when responding to drug overdose incidents. Several sets of exposure prevention recommendations for first responders are available from government and the private sector. Understanding the scientific basis for these recommendations, increasing awareness by responders of the potential risks associated with opioid exposure during a response, and educating responders about safe work practices when exposure to opioids is suspected or confirmed are all critical prevention measures that can keep first responders safe.
... Dehydration, starvation and psycho-logical stress also participated on the critical condition of hostages in enclosed space of the theater. Unauthorized sources indicate that there were probably used derivatives of 3-methylfentanyl, carfentanil or alfentanil [2,3]. Some hypotheses admit the use of remifentanil [4]. ...
... Commercially, it is always sold in combination with the µ-opioid antagonist naloxone due to its extreme toxicity in humans. Carfentanil is used to immobilize large exotic wildlife and has been implicated in the 2002 Moscow theater hostage crisis (Wax et al., 2003;Riches et al., 2012). Recently, carfentanil and other synthetic opioids have been reported as a contaminant in street heroin in the United States and Europe, and have been associated with an increased number of life-threatening emergency department admissions and deaths (EMCDDA and Europol, 2017;Papsun et al., 2017;Shanks and Behonick, 2017;Shulman et al., 2017). ...
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Carfentanil, one of the most potent opioids known, has recently been reported as a contaminant in street heroin in the United States and Europe, and is associated with an increased number of life-threatening emergency department admissions and deaths. Here, we report on the application of a novel in vitro opioid activity reporter assay and a sensitive bioanalytical assay in the context of a fatal carfentanil intoxication, revealing the highest carfentanil concentrations reported until now. A 21-year-old male was found dead at home with a note stating that he had taken carfentanil with suicidal intentions. A foil bag and plastic bag labeled “C.50” were found at the scene. These bags were similar to a sample obtained by the Belgian Early Warning System on Drugs from a German darknet shop and to those found in the context of a fatality in Norway. Blood, urine and vitreous, obtained during autopsy, were screened with a newly developed in vitro opioid activity reporter assay able to detect compounds based on their μ-opioid receptor activity rather than their chemical structure. All extracts showed strong opioid activity. Results were confirmed by a bioanalytical assay, which revealed extremely high concentrations for carfentanil and norcarfentanil. It should be noted that carfentanil concentrations are typically in pg/mL, but here they were 92 ng/mL in blood, 2.8 ng/mL in urine, and 23 ng/mL in vitreous. The blood and vitreous contained 0.532 and 0.300 ng/mL norcarfentanil, respectively. No norcarfentanil was detected in urine. This is the first report where a novel activity-based opioid screening assay was successfully deployed in a forensic case. Confirmation and quantification using a validated bioanalytical procedure revealed the, to our knowledge, highest carfentanil concentrations reported in humans so far.
... In 2002, fentanyls gained notoriety in connection with the Moscow Dubrovka theater siege, when the Russian military used a knockout gas to incapacitate Chechen rebels, leading to the loss of more than 100 rebels and hostages. The available evidence suggests that a combination of an aerosolized fentanyl derivative, such as carfentanil, and an inhalation anesthetic, such as halothane, was used [113], although it seems that remifentanil may also have been present in the aerosol [53]. ...
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Drugs related to morphine represent not only large range of important therapeutic applications for the relief of moderate to severe pain but also give rise to a relatively large series of novel opioids that mimic the action of this naturally occurring analgesic. Most of these are based on fentanyl structures that are much more potent, and dangerous, than fentanyl itself. This publication reviews reports of fatalities attributed to 15 novel opioids with the view to assessing mortality associated with their misuse as well as reviewing published analytical procedures that would be able to detect these and other novel opioids. These drugs include reports of deaths to acetylfentanyl, acrylfentanyl, butr(yl)fentanyl, carfentanil, 2- and 4-fluorofentanyls, 4-fluorobutyrfentanyl, 4-fluoroisobutyrfentanyl, furanylfentanyl, α- and 3-methylfentanyls, 4-methoxyfentanyl, ocfentanil, as well as AH-7921, U-47700 and MT-45. Most of these cases reporting a drug-caused death involved other drugs in addition to the opioid. No obvious minimum fatal concentration was discerned for any of the opioids for which details were provided, however, the more potent members required detection limits well under 1 ng/mL and often even well below 0.1 ng/mL requiring use of the most sensitive mass spectral detection procedures, particularly when screening specimens using a non-targeted mode. Four other novel opioids have been reported in admissions to hospitals include 4-chloroisobutryfentanyl, cyclopentylfentanyl and tetrahydrofuranfentanyl, all of which are likely to have the potential to cause death. It is also likely that other analogues will appear with time.
... 5 The other known human exposure event was the hostage-taking incident in a Moscow theater in 2002 when Russian Special Forces were believed to have used a combination of aerosolized carfentanil and halothane to incapacitate Chechen insurgents. 11 Of the 800 hostages, 81% were hospitalized and 16% died. A subsequent analysis of clothing from a few British survivors of the Russian theater crisis demonstrated the presence of carfentanil and remifentanil. ...
Article
Carfentanil and related fentanyl analogues have been linked to a number of overdose deaths from drug users in several cities across North America. Diagnosis of carfentanil exposure requires a very high index of clinical suspicion, especially because available laboratory narcotic screens do not detect this agent. We describe a 34‐year‐old male admitted with depressed level of consciousness and in respiratory failure after recreational exposure to a white powder later inferred to contain carfentanil. Urine and whole blood samples were obtained for conventional preliminary drug screen immunoassays for unknown exposures; in addition to utilizing high pressure liquid chromatography tandem mass spectrometry assay for quantification of carfentanil and its metabolite. The patient was intubated and required mechanically‐assisted ventilation for 31 hours until he was able to breathe safely on his own. Pharmacokinetic modeling of 3 timed blood samples identified the elimination half‐life as 5.7 hours for carfentanil and 11.8 hours for the norcarfentanil metabolite. Awakening and breathing spontaneously corresponded to an interpolated blood carfentanil concentration of 0.52 ng/ml. This is the first pharmacokinetic and pharmacodynamic case report on the recreational use of carfentanil. Critical care clinicians should anticipate long periods of ventilatory support in the care of patients exposed to carfentanil. This article is protected by copyright. All rights reserved.
Chapter
In recent years our understanding of molecular mechanisms of drug action and interindividual variability in drug response has grown enormously. Meanwhile, the practice of anesthesiology has expanded to the preoperative environment and numerous locations outside the OR. Anesthetic Pharmacology: Basic Principles and Clinical Practice, 2nd edition, is an outstanding therapeutic resource in anesthesia and critical care: Section 1 introduces the principles of drug action, Section 2 presents the molecular, cellular and integrated physiology of the target organ/functional system and Section 3 reviews the pharmacology and toxicology of anesthetic drugs. The new Section 4, Therapeutics of Clinical Practice, provides integrated and comparative pharmacology and the practical application of drugs in daily clinical practice. Edited by three highly acclaimed academic anesthetic pharmacologists, with contributions from an international team of experts, and illustrated in full colour, this is a sophisticated, user-friendly resource for all practitioners providing care in the perioperative period.
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Cobalt(III) and rhodium(III) complexes containing the water-soluble porphyrin ligand meso-tri(4-sulfonatophenyl)mono(4-carboxyphenyl)porphine (C1S3TPP), [Rh(C1S3TPP)]Nax•nH2O (1) and [Co(C1S3TPP)]Nax•nH2O (2) were prepared from the direct reaction of free porphyrin and metal chloride salts in refluxing MeOH/DMF or EtOH/H2O. Compounds 1 and 2 were characterized using UV–vis and ¹H NMR spectroscopies, and high-resolution mass spectrometry. Cell culture based assays of opioid receptor activation showed that while the rhodium complex reduced fentanyl opioid activity 113-fold to an IC50 value of 1.7 μM, the cobalt complex reduced fentanyl activity by 160-fold to an IC50 value of 2.4 μM. An oxidative mechanism for fentanyl breakdown is proposed.
Article
Carfentanil, a µ-opioid receptor (MOR) agonist with an analgesic potency 10,000 times that of morphine, is extensively metabolized to norcarfentanil (M1), 4- Piperidinecarboxylic acid, 1- (2- hydroxy- 2- phenylethyl) - 4- [(1- oxopropyl) phenylamino] -, methyl ester (M0 in this article), and other low abundant metabolites in human hepatocytes and liver/lung microsomes. M0 possessed comparable MOR activity to carfentanil, and accounted for approximately 12% of the total carfentanil metabolite formation in human liver microsomes (HLMs). Little is known about the subsequent elimination of M0. This study investigated its metabolic pathway in HLMs, separation and preliminary identification of metabolites by liquid chromatography-tandem mass spectrometry, and possible involvement of cytochrome P450 enzymes in M0 metabolism with kinetic analysis. M0 produced 9 metabolites via N-dealkylation (M1), oxidation (M3, M6-9), N-dealkylation followed by oxidation (M2 and M4), and glucuronidation (M5). Formation of the major metabolite M1 fitted typical Michaelis-Menten kinetics. Recombinant human CYP3A5 showed the highest activity toward M1 formation followed by CYP3A4 and CYP2C8, while M8 was primarily formed by CYP3A4 followed by CYP2C19 and CYP2C8. These findings reveal the main involvement of CYP3A5 and 3A4 in human hepatic elimination of M0 with a kinetic profile similar to carfentanil which may inform development of treatment protocols for carfentanil exposure.
Chapter
This chapter sets out the general principles of caring for casualties in a CBRN environment, as well as those suffering from the ill effects of CBRN hazards—expressed as intoxication (chemical effect), infection (with biological agents) or irradiation (exposed to ionising radiation).
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Illicit fentanyl is a well known contributor to the ongoing opioid crisis. The ability to take either protective action or administer medical countermeasures can be predicated on the ability to detect even minute concentrations. For this reason, a fast, accurate, and cost effective method for fentanyl detection in the field is necessary. State of the art methods tend to be large and expensive powered electronics that limit their wide dissemination. Alternative methods of detection include laminar flow immunoassays (LFIs) and colorimetric indicators. Many of these tests have been evaluated for potential field use under laboratory conditions. However, none of these studies have evaluated them under environmentally relevant conditions, mainly temperature and humidity, that may be encountered in the field. These environmental conditions may affect the limits of detection or cross reactivity of the test, and ultimately the user’s interpretation of and response to the result. Here we assess the effect of five environmental conditions on the responses of two LFI tests and one colorimetric test to six fentanyl analogues and five cross reactivity standards.
Chapter
Novel synthetic opioids (NSOs), such as fentanyl, fentanyl derivatives and newly emerging analogues, have become increasingly available in the recreational drug market worldwide in recent years. Fentanyl is a synthetic phenylpiperidine with analgesic and anaesthetic properties. It is available as a stand-alone product, as an adulterant in heroin, cocaine and amphetamines or as a constituent of illicit prescription medications. In addition to fentanyl and the fentanyl analogues such as carfentanyl, acetylfentanyl, butyrylfentanyl and furanylfentanyl, numerous other potent NSOs have recently appeared on the illicit drug market; many of these have chemical structures that do not resemble morphine or fentanyl, however, they are active at the μ-opioid receptor. These novel synthetic opioids include the benzamide-based opioids U-47700 and AH-7921, tianeptine and MT-45. Novel synthetic opioids are amongst the most abundant and potentially lethal new psychoactive substance (NPS) chemical subclass. Currently, the true prevalence of use of NSOs is hard to determine as newer modified compounds that circumvent existing drug laws are being synthetized and introduced into the drug market on a regular basis. This necessitates the availability of reference material and rapid analytical method developments to keep track of these emerging opioids. Opioids, whether natural or synthetic, cause respiratory depression leading to acute hypoxia and hypercapnia through central nervous system depression. This chapter will focus on selected synthetic opioids including fentanyl, its NPS derivatives, and other common NSOs. The physical and chemical properties, pharmacology, toxicity and abuse potential of these synthetic opioids are discussed in this chapter.
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This article focuses upon new challenges faced by today's society which electrochemical sensors maybe able to address. Focusing primarily upon two of the major challenges faced at the time of writing; the opioid crisis caused by fentanyl and the deadly Covid-19 pandemic, the employment of electrochemical sensors is assessed to determine the contribution they could make toward tackling these problems. Although only a small scope of the electrochemical research present is covered within this article the principles discussed are directly translated to other fields where electrochemical sensors could be applied. This article to aims to highlight the uses of electrochemical sensors and discusses in detail both their advantages but also where further improvements are required to improve their applications across a range of fields.
Article
Résumé L’accessibilité précaire, la vasoconstriction habituelle en situation critique, la nécessité d’une asepsie parfaite rendent l’abord intraveineux aléatoire alors qu’il est indispensable sur le plan pharmacocinétique d’administrer les médicaments le plus rapidement possible et en toute sécurité. La recherche d’une alternative à la voie veineuse est donc nécessaire. Concernant la voie pulmonaire, malgré une biodisponibilité variable des opioïdes utilisés (morphine et le fentanyl : entre 16 à 100 %), liée notamment au type de dispositif propulseur, cette voie offre une efficacité comparable à celle de la voie IV. Le mélange équimolaire en oxygène et protoxyde d’azote (MEOPA) est encore très utilisé en douleur chronique, pour des accès douloureux dans le cadre de douleurs procédurales, voire même en préhospitalier. Les propriétés analgésiques et anti-hyperalgésiques de ce gaz permettent un soulagement efficace des douleurs modérées à sévères avec un risque d’effets indésirables limité. Un gaz anesthésique possédant des propriétés analgésiques a été proposé depuis quelques années pour soulager des douleurs en situation d’urgence. Il s’agit du méthoxyflurane à 99,9 %. La vapeur de méthoxyflurane inhalée produit un effet antalgique à de faibles concentrations. Le méthoxyflurane est une alternative aux antalgiques disponibles dans la prise en charge en urgence de la douleur modérée à sévère. La voie intranasale offre une cinétique intéressante avec une absorption très rapide des opioïdes administrés permettant un pic d’action adapté à l’urgence. Cette voie est également proposée pour la kétamine. Moyennant quelques effets indésirables tels que la somnolence, les nausées, l’efficacité analgésique semble comparable à celle du fentanyl. Par rapport à la voie parentérale, les voies d’administration alternatives telles que la voie pulmonaire ou intranasale, offrent une efficacité adaptée à l’urgence, à condition de maîtriser les modalités d’administration des agents et les effets indésirables.
Article
Carfentanil is an ultra-potent opioid with an analgesic potency 10,000 times that of morphine but has received little scientific investigation. In the present study, the human cytochrome P450 (CYP) isozymes catalyzing the oxidative metabolism of carfentanil were investigated. Using UHPLC-HRMS, Michaelis-Menten kinetics of formation for three major metabolites norcarfentanil (M1), pharmaceutical active metabolite 4-[(1-oxopropyl)phenylamino]-1-(2-hydroxyl-2-phenylethyl)-4-piperidinecarboxylic acid methyl ester (M11), and 4-[(1-oxopropyl)phenylamino]-1-(2-oxo-2-phenylethyl)-4-piperidinecarboxylic acid methyl ester (M15) were determined. Isozymes catalyzing the formation of the low abundant, highly active metabolite 1-[2-(2-hydroxylphenyl)ethyl]-4-[(1-oxopropyl)phenylamino]-4-piperidinecarboxylic acid methyl ester (M13) were also identified. Selective P450 inhibition studies with pooled human liver microsomes (HLMs) and recombinant CYP isozymes suggested that metabolites M1, M11, and M15 were predominantly formed by isozyme CYP3A5, followed by CYP3A4. Isozymes CYP2C8 and CYP2C9 also made contributions but to a much lesser extent. Highly potent metabolite M13 was predominantly formed by isozyme CYP2C9, followed by CYP2C8. These findings indicate that CYP3A5, CYP3A4, CYP2C8 and CYP2C9 play a major role in the transformation of carfentanil to M1 (norcarfentanil), M11, M13 and M15 through N-dealkylation of piperidine ring, hydroxylation of phenethyl group and ketone formation on phenethyl linker by human liver micrsomes.
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Fentanyl is a potent synthetic opioid pain reliever with a high bioavailability that can be used as prescription anesthetic. Rapid identification via non-contact methods of both known and emerging opioid substances in the fentanyl family help identify the substances and enable rapid medical attention. We apply PBEh-3c method to identify vibrational normal modes from 0.01 to 3 THz in solid fentanyl and its selected analogs. The molecular structure of each fentanyl analog and unique arrangement of H-bonds and dispersion interactions significantly change crystal packing and is subsequently reflected in the THz spectrum. Further, the study of THz spectra of a series of stereoisomers shows that small changes in molecular structure results in distinct crystal packing and significantly alters THz spectra as well. We discuss spectral features of synthetic opioids with higher potency than conventional fentanyl such as ohmefentanyl and sufentanil and discover the pattern of THz spectra of fentanyl analogs.
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The opioid crisis has proliferated at an unprecedented rate worldwide, posing significant public health challenges. This review presents the current state of electrochemical methods to positively identify and quantify fentanyl, a potent and popular opioid, and its analogs in liquid and solid matrices. Specific emphasis is placed on point-of-use sensors, which are urgently needed to provide first responders with tools to identify unknown powders and treat victims of an opioid overdose. Electroanalytical techniques are uniquely poised to generate such sensors based on their portability, low cost, and ease of use. However, significant challenges remain, including enhancing sensor sensitivity for quantification of fentanyl at biologically relevant concentrations (<80 nM), and the extension of electrochemical methods to selectively identify common fentanyl analogs. Critically examining the strengths and weaknesses of electrochemical analysis for fentanyl detection and quantification is paramount for the continued development of deployable sensors to assist first responders in the control of this illicit family of substances.
Article
Because of its remarkable potency and relative ease of synthesis, carfentanil (1) has recently emerged as a problematic contaminant in other drugs of abuse. Carfentanil and its close analogs, currently approved only for large animal veterinary medicine, have found use both as illicit additives to the clandestine manufacture of scheduled drugs and as chemical weapons. In this Review, the background, synthesis, manufacture, metabolism, pharmacology, approved indications, dosage, and adverse effects of carfentanil will be discussed along with its emergence as a key player in the ongoing opioid crisis.
Chapter
Current scenarios reveal new types of ever increasing dynamic and aggressive threats, which lead to a move from a traditional security management to a strategic vision for protecting citizens and assets in a more comprehensive way. In such an environment, the risk related to incidents involving the use of CBRN (Chemical, Biological, Radiological and Nuclear) agents must be considered a cause of potentially devastating consequences. Non-proliferation and disarmament operations can make an essential contribution to combat terrorism by preventing or reducing the access of non-state actors or non-authorised persons to chemicals, biological and nuclear dual-use materials but this could be not enough. Illicit proliferation of chemical weapons, clandestine production of toxins and biological agents, ‘dirty bombs’ and trafficking of fissile material are just some examples of the use of CBRN agents for terrorist purposes. This chapter argues that, in order to address these issues, the integration of human, instrumental, technological and financial resources should be improved and reinforced. For that purpose, an effective strategy to mitigate and reduce the risk of using CBRN materials requires a high level of coordination across national agencies. Further development of interagency CBRN defence capabilities remains a top priority for global security.
Article
Purpose The metabolism of carfentanil was assessed using human, dog, and rat pulmonary microsomes. Mass spectrometry based analysis allowed for metabolite identification and species differentiation. Participation of different metabolic enzymes in carfentanil biotransformation was also assessed. Methods Metabolite profiling was accomplished by incubating 10 µM carfentanil in human, dog, and rat lung microsomes. The metabolites were separated and analyzed by ultra-high performance liquid chromatography/high-resolution mass spectrometry. Results In total, 18 metabolites were detected. Nine metabolites were authentically identified through comparison to synthesized reference standards. In human lung microsomes, nine metabolites were identified. In dog lung microsomes, 15 metabolites were identified with three being dog specific. In rat lung microsomes, 15 metabolites were identified and two were rat specific. Proposed metabolic pathways included N-dealkylation, monohydroxylation, dihydroxylation, N-oxidation of piperidine ring nitrogen, and ketone formation. Participation of enzymes CYP2B6, CYP2E1, CYP2J2, and CYP3A4/5 to carfentanil metabolism was suggested by selective enzymatic inhibition. Conclusions The pulmonary clearance in human lung microsomes was lower than the previously reported hepatic metabolism suggesting organ specific metabolic rates. The contribution of multiple cytochrome P450 enzymes to human, dog, and rat pulmonary microsomal carfentanil biotransformation varied between species. The identified metabolites may provide useful markers for possible forensic and clinical determination of the mode of ingestion but the use of dog and rat animal models was not indicated. To our knowledge, this is the first reported use of chemically synthesized reference standards for the unequivocal identification of lung carfentanil metabolites.
Chapter
Chemical crowd control agents (CCCAs) are used to produce temporary incapacitation of an individual or a group of individuals without the need for physical force. Whilst use of these agents is relatively benign, there are reports of serious toxicity typically when these agents have been used at high concentration, in confined spaces, or through prolonged exposure. A wide variety of physiological effects may result, with the most common clinical findings being pain, burning, and irritation of exposed mucous membranes and skin. More lethal methods of chemical control may be used, with exposure to fentanyl (and derivatives) and nerve agents discussed. Individuals will often present in extremis quickly after exposure to these more potent chemicals, and recognition of signs and symptoms of their toxicity is important to enable timely administration of antidotes. With all these chemicals it is also important to understand the risk they pose to healthcare professionals and the appropriate measures that should be taken to minimise the chance of secondary exposure.
Article
A simple-to-use device to measure drugs in saliva, blood plasma, and whole blood for point-of-care analysis and treatment of overdose patients has been investigated. A rudimentary flow strip has been developed to separate opioids from these biofluids for analysis by surface-enhanced Raman spectroscopy (SERS). The strips are based on lateral flow assays, in which the antibodies have been substituted by SERS-active pads for detection. Samples of codeine and fentanyl, artificially added to these biofluids, were measured using the strips by a field-usable Raman spectrometer. We report measurement of these drugs in saliva, blood plasma, and whole blood at 1, 0.5, and 5 µg/mL, respectively, in 5 minutes. Calculated limits of detection for the spectra suggest that these drugs can be measured at 5 to 20 ng/mL with improvements in the strips’ separation capability.
Article
The abuse of fentanyl and its analogues, which are potent, short-acting, synthetic narcotic analgesics, has become a major issue. Many cases containing fentanyl-analogue and novel synthetic opioids have also been reported. Hence, we report the determination of fentanyl, fentanyl-analogue and novel synthetic opioids in whole blood by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The method is characterized by the use of a simple, fast and inexpensive liquid-liquid extraction (LLE) for sample preparation, a rapid run time (8 min) and a low required volume of whole blood (100 μl). The limits of detection (LODs) ranged from 0.005 to 0.03 ng/ml, and the lower limits of quantitation (LLOQs) ranged from 0.05 to 0.2 ng/ml. The method was shown to be liner over a concentration range of 0.2-40 ng/ml for fentanyl, norfentanyl and norcarfentanil and 0.05-40 ng/ml for all other target analytes. Recoveries were within the range of 72.09%-103.22%, and the matrix effects were in the 67.95%-113.32% range. Moreover, the method was applied to the detection and quantification of fentanyl and its analogues in whole blood from real forensic cases. This methodology has great potential for use in the determination of fentanyl and its analogues in forensic cases.
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Article
One hundred fifteen Americans die every day from opioid overdose. These overdose fatalities have been augmented by the increased availability of potent synthetic opioids, such as fentanyl and its derivatives. The death rate of synthetic opioids, other than methadone, increased by 72.2% from 2014 to 2015, and doubled from 2015 to 2016, situating the USA in the midst of an opioid overdose epidemic. The analytical identification of these opioids in postmortem samples and the correct toxicological data interpretation is critical to identify and implement preventive strategies. This article reviews the current knowledge of postmortem toxicology of synthetic opioids and the chemical and pharmacological factors that may affect drug concentrations in the different postmortem matrices and therefore, their interpretation. These factors include key chemical properties, essential pharmacokinetics parameters (metabolism), postmortem redistribution and stability data in postmortem samples. Range and ratios of concentrations reported in traditional and non-traditional postmortem specimens, blood, urine, vitreous humor, liver and brain, are summarized in tables. The review is focused on fentanyl and derivatives (e.g., acetyl fentanyl, butyryl fentanyl, carfentanil, furanyl fentanyl, 4-methoxybutyrylfentanyl, 4-fluorobutyrylfentanyl, ocfentanil) and non-traditional opioid agonists (e.g., AH-7921, MT-45, U-47700). All of these data are critically compared to postmortem data, and chemical and pharmacological properties of natural opioids (morphine), semi-synthetic (oxycodone, hydrocodone, hydromorphone, and oxymorphone), and synthetic opioids (methadone and buprenorphine). The interpretation of drug intoxication in death investigation is based on the available published literature. This review serves to facilitate the evaluation of cases where synthetic opioids may be implicated in a fatality through the critical review of peer reviewed published case reports and research articles.
Article
Despite the recent epidemic of fentanyl abuse, there are few validated assays capable of rapidly detecting these compounds. In order to improve the ability to detect carfentanil at physiologically relevant concentrations, we developed a systems biology approach to discover host-based markers which are specifically amplified upon exposure in a rabbit model. For this work, two 'omics' pipelines utilizing mass spectrometry were developed and leveraged. First, a proteomics pipeline was developed to interrogate the blood plasma for protein-based biomarkers. Due to the incredible dynamic range of the plasma protein content, a multi-dimensional fractionation technique was used to partition and more accurately investigate the circulating plasma proteome. Isobaric tandem mass tags were integrated into the workflow to make quantitative assessments across all animals for an extended time course post exposure. In addition to the proteomics efforts, blood plasma was also processed through an untargeted metabolomics pipeline. This approach allows for the identification of > 800 small molecule features. By processing and analyzing datasets in parallel, we were able to identify a unique fingerprint of protein and metabolite perturbations that manifest following exposure to carfentanil.
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Article
Purpose Opioid use, misuse, and abuse are now a rapidly evolving epidemic in the USA. This review aims to update changes in the dosing of naloxone, describe new strategies in prehospital management, and examine in more detail the diverse pathophysiology of opioids beyond respiratory depression. Recent findings There are no comparative studies of old or new antidotes or procedures elucidating the superiority of one therapy. Abuse and misuse of over-the-counter loperamide and non-FDA approved tianeptine, using the herbal product kratom, and gambling with powerful fentanyl analogues are recent trends that will impact clinical care. The response to these new threats has resulted in excellent reviews, epidemiology, and case series which are commonly the only data available in the discipline of medical toxicology. Summary The antidote naloxone is still first-line therapy to reverse respiratory depression from opioids. Larger and more frequent doses of naloxone may be necessary in the presence of potent fentanyl derivatives. In the hospital, other toxicities may need to be managed such as acute lung injury, seizures, cardiotoxicity, or serotonin toxicity. Therapy for each of these is dependent on attentive supportive care and a variety of antidotes.
Article
Carfentanil is a mu (μ) opioid receptor agonist and is estimated to be ~10,000 times more potent than morphine in animal (non-human) models. It is not approved for human use and is only used to immobilize large exotic animals in veterinary medicine. In mid-2016, carfentanil emerged as a contaminant in street heroin in the USA and was central to a large number of emergency department visits and deaths. We describe an analytical method for the detection and quantification of carfentanil in whole blood specimens via a protein precipitation extraction with acetonitrile and liquid chromatography with triple quadrupole mass spectrometry. From 1 September 2016 to 1 January 2017, carfentanil was identified in 262 postmortem blood specimens. Blood concentrations ranged from 10.2 to 2,000 ng/L, with a mean concentration equal to 193 ng/L and a median concentration equal to 98.4 ng/L. We describe 13 fatalities from the Midwest region (Indiana, Kentucky, Michigan and Ohio) of the USA in which our laboratory performed comprehensive toxicology and in which carfentanil was detected and associated with cause of death. We recommend that any analytical method applied to the detection of this substance in human whole blood specimens be sufficiently sensitive to detect sub-100 ng/L concentrations and preferably utilize a 10-50 ng/L reporting limit.
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Article
We evaluated efficacy and safety of naltrexone for antagonizing carfentanil immobilization in 12 captive Rocky Mountain elk (Cervus elaphus nelsoni) using a randomized incomplete block experiment. In three replicate trials, elk were hand-injected with 10 micrograms carfentanil citrate/kg body weight intramuscularly. Fifteen min after each elk became recumbent, we administered naltrexone HCl (25% of dose intravenously, 75% subcutaneously) dosed at 0 (control), 25, 50, or 100 mg/mg carfentanil; after an additional 15 min of immobilization, controls received 500 mg naltrexone HCl/mg carfentanil. Elk were immobilized in 34 of 36 attempts; the mean (+/-SE) induction time was 3.1 +/- 0.2 min. Regardless of dose, all elk stood < 9 min after receiving naltrexone; controls remained immobilized until they received antagonist. Mean recovery times did not differ with increasing naltrexone dose (P = 0.31) or among individuals (P = 0.16). None of the elk receiving 100 or 500 mg naltrexone/mg carfentanil renarcotized, but three of eight and seven of nine elk receiving 50 and 25 mg naltrexone/mg carfentanil, respectively, showed signs of mild renarcotization 8 to 24 hr later (P = 0.0002). We observed no adverse clinical effects in elk receiving < or = 500 mg naltrexone/mg carfentanil. Based on these data, we recommend 100 mg/mg carfentanil as a minimum effective dose for rapidly antagonizing immobilization and preventing renarcotization.
Article
The intravenous analgesic activity and toxicity of a novel series of N-[4-substituted 1-(2-arylethyl)-4-piperidinyl]-N-phenylpropanamides was studied in rats. Onset, potency and duration of analgesic action were assessed in the tail withdrawal test and compared with the activity of fentanyl, (+)-cis-3-methylfentanyl (R 26 800), morphine, and pethidine. All compounds studied were found to be extremely potent analgesics characterized by an unusually high safety margin. Methyl 4-[N-(1-oxopropyl)-N-phenyl-amino]-1-(2-phenylethyl)-4-piperidinecarboxylate (R 31 833; lowest ED50 = 0.00032 mg/kg) is the most potent compound (10 031 times morphine). cis-Methyl 3-methyl-4-[N-(1-oxopropyl)-N-phenylamino]-1-(2-phenylethyl)-4-piperidine carboxylate (R 32 792) is the longest acting compound (more than 8 h at 4 times the lowest ED50) and N-[4-(1-oxopropyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylpropanamide (R 33 352) is the shortest acting compound (0.74 h at 4 times the lowest ED50) of the 4-substituted fentanyl derivatives. N-[4-(Methoxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylpropanamide (R 30 730) was selected for further investigation. R 30 730 has a rapid onset of action and is 4521 times more potent than morphine at the time of peak effect; it has a relatively short duration of action comparable to that of fentanyl and its safety margin (LD50/lowest ED50 = 25 211) is unusually high.
Article
The effects of three concentrations of inhaled nebulised fentanyl citrate solution given for postoperative pain relief were studied. Each of 30 patients inhaled one dose of 3 ml of solution nebulised over 9 min. A combined analysis of pain relief, time to further analgesia and effect on respiratory frequency showed the highest concentration (318 micrograms/ml fentanyl base) to be more effective (p less than 0.01) than the two lower concentrations (159 micrograms/ml and 64 micrograms/ml) which were indistinguishable from each other. There were no major side effects. This study provides evidence for the efficacy and safety of inhaled fentanyl for postoperative analgesia. Estimation of the delivered doses did not support the hypothesis that fentanyl is more effective by this route compared with other parenteral routes. Further studies are required to improve the method of delivery and investigate the pharmacodynamic features of this technique.
Article
Gray wolves (Canis lupus) were immobilized with 0.5 mg/kg xylazine plus 7.5 micrograms/kg of either sufentanil (n = 8), etorphine (n = 8), or carfentanil (n = 2). Drug doses used in this study were selected to provide consistency for comparison and are not recommended doses for effective immobilization of wolves. Induction times were similar among groups (11.9 +/- 1.0 min). Thirty min after induction, wolves were given either 0.5 mg/kg naloxone hydrochloride plus 0.15 mg/kg yohimbine hydrochloride or saline only intravenously. Arousal times for wolves given naloxone and yohimbine (1.2 +/- 0.1 min) were shorter than wolves given saline (35.5 +/- 6.4 min). Respiratory rates were similar among the three drug groups (6.9 +/- 1.0 breaths/min). One animal given sufentanil then saline was found dead 108 min after induction. Presumptive diagnosis was renarcotization and hypothermia. Results indicated that sufentanil is an effective opioid immobilizing agent for gray wolves.
Article
A study was undertaken to investigate the use of fentanyl by aerosol for postoperative analgesia. Seven patients had placebo, six received fentanyl 100 micrograms and seven were given fentanyl 300 micrograms. A significant improvement in postoperative pain, as assessed by linear visual analogue scale, was achieved in the higher dose group, and in both fentanyl groups the time to alternative analgesia was significantly longer than in the control group. Serum fentanyl levels after inhalation of 100 micrograms reached a plateau around 0.04 ng/ml and after 300 micrograms at around 0.1 ng/ml after 15 minutes. Inhaled fentanyl may have a useful analgesic effect despite these low serum levels; this supports the hypothesis that the mode of analgesia from inhaled opioids may be different from that after other routes of administration. There were no adverse effects such as respiratory depression, bronchospasm, nausea or drowsiness.
Article
An ultrasonic nebulizer was used to create a drug vapor to develop an animal model for the self-administration of inhaled nonvolatile psychoactive drugs. An aerosol mist of a sufentanil citrate solution (10, 25, 50, or 75 micrograms/ml) was delivered to rats in response to lever presses on an FR 5 schedule of reinforcement. The speed of acquisition of the operant response and the selectivity of the drug effect were examined. Rats given access to sufentanil vapor (50 or 75 micrograms/ml) in 13-15 h overnight training sessions reached an average of one reinforcement per hour on an FR 5 schedule of reinforcement significantly sooner than did rats given access to water vapor. Responding maintained by sufentanil during 2-h daily testing sessions was dose dependent at 25, 50, and 75 micrograms/ml. Substituting water vapor for each of the four sufentanil concentrations significantly reduced responding within 5-20 sessions. Naloxone (1 mg/kg, IP) decreased responding for sufentanil to the level attained under water vapor. Presentation of drugs in aerosol form thus provides reasonable means of demonstrating in animals the reinforcing properties of non-volatile drugs by the pulmonary or intranasal route.
Article
Sufentanil as a supplement to halothane/N2O anaesthesia was evaluated in 32 unpremedicated infants and children age 6 months to 9 yr undergoing elective orthopaedic surgery. Patients were randomly assigned in a double-blind manner to receive one of four intravenous supplements: placebo, sufentanil 0.5, 1.0 or 1.5 micrograms.kg-1. Systolic arterial pressure (SAP), heart rate (HR) and end-tidal halothane concentration were recorded before and after induction, supplement administration, tracheal intubation, incision and every 15 min during the procedure. Venous catecholamine samples were obtained before and after incision. A pain score was assigned to the patients in the postanaesthesia care unit (PACU). Sufentanil at all three doses prevented increases in SAP and HR with intubation and incision, provided superior pain relief in the PACU and did not prolong wake-up time. Sufentanil 1.0 and 1.5 micrograms.kg-1 allowed for a reduction in the halothane requirements. Sufentanil 1.5 micrograms.kg-1 was associated with lower catecholamine levels than in the placebo group following incision. Sufentanil supplementation at 1.0 and 1.5 micrograms.kg-1 was associated with bradycardia and/or hypotension during induction and an increased incidence of vomiting during the first 24 hours postoperatively. One patient in the sufentanil 1.0 micrograms.kg-1 group whose surgical time was less than 45 min exhibited respiratory depression in the PACU requiring narcotic reversal. In conclusion, sufentanil 0.5 micrograms.kg-1 improved immediate postoperative pain relief and is acceptable as a supplement during halothane anasethesia in infants and children. The associated side effects of larger doses of sufentanil (1.0 and 1.5 micrograms.kg-1) make their use as a supplement to halothane anaesthesia unacceptable.
Article
High-dose fentanyl anesthesia is widely used in cardiac surgery. Its immediate side-effects are well known. However, its late adverse effect manifested by extreme truncal rigidity, decreased chest wall compliance, hypoventilation, respiratory acidosis and hemodynamic instability is not sufficiently appreciated. Of 380 patients who underwent aortocoronary artery bypass under high-dose (100 micrograms/kg) fentanyl anesthesia, 29 (7.6%) developed the sudden onset of extreme thoracic and abdominal rigidity, leading to respiratory depression 2 to 6 h postoperative, after an apparently normal recovery from the anesthesia. In 15 patients, a high plasma level of fentanyl (5.2 to 7.8 ng/ml) correlated with the clinical events. Administration of naloxone or a muscle relaxant rapidly reversed this late complication of fentanyl, thought to be due to re-entry of fentanyl into plasma from deposits in adipose tissue, muscle and the GI tract, leading to a secondary peak in plasma fentanyl. It is more likely to be encountered when hypothermia, rewarming, and acidosis occur in the postoperative period. Awareness of this life-threatening complication is critical in patients undergoing surgery with fentanyl anesthesia.
Article
Carfentanil was used to anaesthetise 46 adult grey seals (Halichoerus grypus) on 78 occasions during two breeding seasons. The mean dose was 9.92 micrograms/kg bodyweight during the first season and 10.22 micrograms/kg during the second. Naloxone hydrochloride was used as the antagonist, averaging 0.53 mg/kg and 1.73 mg/kg over the two periods although the latter is probably unnecessarily high. Ketamine and xylazine at a ratio of 5:1 were also used during the same two seasons, 57 seals being anaesthetised on 104 occasions. The average dose of ketamine was 4.96 mg/kg and 5.15 mg/kg with xylazine in proportion. Complications arose on a number of occasions and these are discussed.
Article
The aim of the study was to quantitate the degree of respiratory depression when tolerance of superficial nociception and of an endotracheal tube was achieved by supplementing N2O + O2 anaesthesia either with halothane alone or with halothane in combination with fentanyl. Eighty-four patients, matched into seven groups, were studied after induction of anaesthesia with thiopental (4 mg/kg) and suxamethonium (3 mg/kg) using the following supplementation: 0.8, 0.6, 0.4% halothane alone or 0.4, 0.2, 0% halothane with 0.5-2 micrograms/kg fentanyl. After 10 min administration of the anaesthetic mixture using manual intermittent positive pressure ventilation (IPPV) (end-tidal CO2 c. 5.5%), IPPV was discontinued and spontaneous respiration allowed to return. When the end-tidal CO2 had stabilized, samples for blood gas analysis were taken and superficial antinociception was tested by pinching an inguinal skin fold. Supplementation of an N2O + O2 mixture with 0.8% halothane without fentanyl or with 0.4% halothane with 0.5 microgram/kg fentanyl seemed to come closest to the optimum in producing tolerance of an endotracheal tube and of superficial nociception (in about 85% of cases with an increase in PCO2 to only 7 kPa.
Article
Sixty-four free-ranging polar bears (Ursus maritimus) were immobilized using carfentanil at doses ranging from 1.0-38.0 sag/kg (mean 20 ± 8 gsg/kg). Induction was rapid (5.0 mm) (n = 46) and the bears showed good muscle relaxation. Respiratory rate was depressed (mean 3.8 bpm). The mean arousal after the administration of narcotic antagonists was longer than 5 mm. Recurrence of narcotic effects-so called recycling-was seen in some bears and in a separate black bear trial was consistently observed in animals given doses of 10 pg/kg or more of carfentanil. The rapid induction, low drug volume and excellent muscle relaxation related to carfentanil immobilization make this a potentially useful drug for polar bear immobilization.
Article
Between 1986 and 1991, 155 wood bison (Bison bison athabascae) (33 adult females, 92 adult males, twelve 6 mo-old calves, eighteen 1 to 2 mo-old calves) in the Mackenzie Bison Sanctuary, Northwest Territories, Canada, and adjacent area were captured by dart immobilization. Initial trials with carfentanil, xylazine and R51163 as immobilizing agents were conducted. Subsequently, carfentanil alone, or in combination with xylazine, was used. Small doses of xylazine were used when required to control head and hind limb movement of recumbent bison. The mean dose of carfentanil used was 7.0 micrograms/kg. Narcotic antagonists used were naltrexone, naloxone and M5050. Narcotic recycling was seen in animals treated with naloxone and low doses of naltrexone. Furthermore recycling was suspected in the deaths of several animals treated with these antagonist regimes. No recycling was seen when doses of naltrexone in excess of 90:1 naltrexone:carfentanil were used. We recommend using a naltrexone:carfentanil dose in excess of 125:1 to ensure uneventful recovery.
Article
Carfentanil citrate, the only opioid approved in the United States for immobilizing large exotic animals, increasingly has been used to chemically restrain exotic horses, such as Prezwalski's horses (Equus przewalskii) and wild horses (E caballus). Because carfentanil's duration of action is long and renarcotization may develop 2 to 24 hours after administration of antagonists, a study was designed to compare the physiologic effects of opioid antagonists, using domestic horses chemically restrained with xylazine hydrochloride and carfentanil. The study was terminated after the initial 3 horses developed severe tachycardia and hypertension, which resulted in the death of 1 horse from pulmonary edema. Although it was possible that the clinical findings in these horses may have resulted from use of an inadequate dosage of carfentanil or xylazine, or both, analysis of the results more likely indicated that domestic and exotic horses may respond differently to carfentanil, and domestic horses may not be a good model for use in studies of carfentanil.
Article
Pulmonary drug delivery is a promising noninvasive method of systemic administration. Our aim was to determine whether a novel breath-actuated, microprocessor-controlled metered dose oral inhaler (SmartMist, Aradigm Corporation) could deliver fentanyl in a way suitable for control of severe pain. Aersolised pulmonary fentanyl base 100-300 microg was administered to healthy volunteers using SmartMist and the resultant plasma concentration-time data were compared with those from the same doses administered by intravenous (i.v.) injection in the same subjects. Plasma concentrations from SmartMist were similar to those from i.v. injection. Time-averaged bioavailability based upon nominal doses averaged approximately 100%, and was > 50% within 5 min of delivery. Fentanyl systemic pharmacokinetics were similar to those previously reported with no trends to dose-dependence from either route. Side-effects (e.g. sedation, lightheadedness) were the same from both routes. Fentanyl delivery using SmartMist can provide analgetically relevant plasma drug concentrations. This, combined with its ease of noninvasive use and transportability, suggests a strong potential for field and domicilliary use, and for patient controlled analgesia without the need for i.v. cannulae.
Article
A captive 590-kg (1,298-lb) 22-year-old castrated male Kodiak brown bear was evaluated because of a soft tissue mass in the right carpal and antebrachial regions. General anesthesia was deemed necessary on 3 occasions for various procedures including radiographic evaluation and biopsy, excision, and radiation treatment. The bear was given carfentanil orally to induce sedation, followed by i.m. administration of tiletamine-zolazepam (on 1 occasion) and atropine. Anesthesia was maintained by administration of isoflurane in oxygen. After each procedure, effects of carfentanil were reversed by administration of naltrexone. Although there was some variability, blood pressure, nasal temperature, heart rate, respiratory rate, oxygen saturation, PO2, and PCO2 remained within a clinically acceptable ranges.
Article
Five chimpanzees (Pan troglodytes) initially received oral droperidol sedation (1.25 mg for a juvenile chimpanzee, body wt = 18.5 kg, and 2.5 mg for adults, body wt >20 kg, range: 18.5-71 kg) followed by transmucosal carfentanil administration at 2.0 microg/kg. This preinduction regimen was developed to produce heavy sedation or even light anesthesia in order to eliminate the need for or at least minimize the stress of darting with tiletamine/zolazepam at 3 mg/kg i.m. This study was designed to assess the safety and efficacy of transmucosal carfentanil. Once each animal was unresponsive to external stimuli, or at approximately 25 min (range 24-34 min) after carfentanil administration, naltrexone and tiletamine/zolazepam (N/T/Z) were combined into one intramuscular injection for anesthetic induction. Naltrexone was administered at 100 times the carfentanil dose in milligrams. For comparison, two chimpanzees received only droperidol, 2.5 mg p.o., followed by tiletamine/zolazepam, 3 mg/kg i.m. The preinduction period for all animals receiving carfentanil was characterized as smooth, with chimpanzees becoming gradually less active and less responsive to external stimuli. Two animals became very heavily sedated at 24 and 35 min, respectively, and were hand injected with N/T/Z. The other three chimpanzees became sternally recumbent but retained some response to stimuli, and N/T/Z was administered by remote injection with minimal response. Rectal body temperatures, pulse and respiratory rates, arterial oxygen hemoglobin saturation, and arterial blood gases were measured at initial contact (t = 0 min) and at 10-min intervals thereafter. Respiratory depression was present in all chimpanzees, regardless of protocol. Mean hemoglobin saturation was 91% for both groups. Mean partial pressure of oxygen, arterial values for carfentanil-treated and control animals were 64.4 +/- 7.6 and 63.5 +/- 6.0 at t = 0, respectively. Only the partial pressure of carbon dioxide, arterial (Paco2) and pH showed significant differences between treated and control animals. Mean Paco2 was greater and mean pH lower for the carfentanil-treated group compared with the controls at t = 0 (58.9 +/- 3.7 and 50.3 +/- 3.1 for Paco2 and 7.33 +/- 0.02 and 7.40 +/- 0.30 for pH, respectively). The results of this study suggest that oral droperidol followed by transmucosal carfentanil can be used effectively as a premedication regimen to produce profound sedation, which limits the stress of darting during parenteral anesthetic induction with tiletamine/zolazepam in chimpanzees. The main side effect of respiratory depression appears to be adequately managed by reversing the carfentanil at the time of induction.
Article
TOXICOLOGYCAMBRIDGE, U.K., AND WASHINGTON, D.C.-- Scientists are still speculating about the exact nature of the gas that subdued the Chechen terrorists but also killed 118 hostages in a Moscow theater on 26 October. Experts are doubtful about the official Russian explanation, which is that the gas was a derivative of fentanyl, an opiate. Hopes for a clearer picture are now riding on toxicological analyses on Western hostages.
More than two days later, gas still a mystery Radio Free Europe Web site
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Russia: More than two days later, gas still a mystery. Radio Free Europe Web site. October 28, 2002. Available at: http://www.rferl.org/nca/features/2002/10/28102002161259. asp. Accessed January 3, 2003.
The advantages and limitations of calmatives for use as a non-lethal technique. The Sunshine Project Web site Available at: http://www.sunshine-project.org
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Lakoski JM, Murray WB, Kenny JM. The advantages and limitations of calmatives for use as a non-lethal technique. The Sunshine Project Web site. Available at: http://www.sunshine-project.org. Accessed January 3, 2003.
Moscow gas likely a potent narcotic: drug normally used to subdue big game
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Brown D, Baker P. Moscow gas likely a potent narcotic: drug normally used to subdue big game. Washington Post. November 9, 2002:A12.
Officials raise hostage death toll. NTI Global Security Newswire
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Russia: Officials raise hostage death toll. NTI Global Security Newswire. November 8, 2002. Available at: http://www.nti.org/d_newswire/issues/thisweek/2002_11_11_ chmw.html. Accessed January 3, 2003.
Experts differ on whether Russian hostage rescue violated treaty. Global Security Newswire
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Ruppe D. CWC: Experts differ on whether Russian hostage rescue violated treaty. Global Security Newswire. October 30, 2002. Available at: http://www.nti.org/ d_newswire/issues/thisweek/2002_11_1_chmw.html. Accessed January 3, 2003.
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From anxiety, fear and hope, the deadly rescue in Moscow
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Pulmonary administration of aerosolized fentanyl: pharmacokinetic analysis of systemic delivery
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Delayed respiratory depression following fentanyl anesthesia for cardiac surgery
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