CBRNE - Opioids/Benzodiazepines Poisoning

Updated: Jul 17, 2020
  • Author: Christopher P Holstege, MD; Chief Editor: Zygmunt F Dembek, PhD, MPH, MS, LHD  more...
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Overview

Practice Essentials

Both the military and domestic law enforcement are reported to have a growing desire for non-lethal technologies that would temporarily disable individuals without causing permanent injuries. Incapacitating chemical agents, such as opioids or benzodiazepines, are considered a possible viable tool.

As an example of research into such non-lethal technologies, the Institute for Non-Lethal Defense Technologies (INLDT), part of the Applied Research Laboratory at Pennsylvania State University, was established in 1998. It is comprised of experts in non-lethal technology expertise. [1]  In 2002, Stone reported that "work on the use of drugs as nonlethal agents was being conducted" at Pennsylvania State University. [2]   That reserarch was built on a 2000 review paper that urged the Marine Corps to give "immediate consideration to weaponizing sedatives such as diazepam." [2]

In addition to the INLDT, the University of New Hampshire and the University of Bradford also have programs investigating the development of non-lethal weapons, the Non-lethal Technology Innovation Center and Bradford Non-Lethal Weapons Research Project respectively. The Airforce Research Laboratory has investigated the use of high-powered microwave weapons in non-lethal techniques, as well as developing non-lethal vehicle-halting methods. [3, 4]  Numerous U.S. goverment agencies have expressed interest in non-lethal weapons, including the Department of State, Department of Energy, Department of Homeland Security and Department of Justice. [5]  

Internationally, the government of the United Kingdom has investigated and tested a series of non-lethal techniques. [6]  The Defense Against Terrorism Program of Work, a program developed by NATO, sponsored a Non-Lethal Training Exercise to practice and assess non-lethal weapon use by the military in land operations. [7]

In May of 2005, the 3rd European Symposium on Non-Lethal Weapons met in Stadthalle Ettlingen, Germany.  At that meeting, it emerged that the Czech military were developing biochemical incapacitating weapons when a paper was presented entitled Pharmacological non-lethal weapons. [8]   The paper was authored by Professor Ladislav Hess (Institute for Clinical and Experimental Medicine in Prague), Dr. Jitka Schreiberova (Departmenrt of Anaesthesia, University Hospital-Hradec Kralove; Department of Neurosurgery at Charles University Prague), and Dr. Joseph Fusek (Czech Army's Purkyne Military Medical Academy-Hradec Love).  The work, which began in 2000, was focused on he development of sedative and anaesthetic agent combinations for use as weapons and funded by the Czech Army.   In the introduction of their paper, the authors reportedly proposed that "there is a possibility of pharmacologicl control of an individual beaving aggresvely."   The also reportedly proposed that these new chemical weapons could "possibly find widespread use in police work."   The authors also reportedly disucssed different delivery means, including inhalation and transdermal techniques, suggesting the use of dimethyl sulphoxide (DMSO) to fascilitate absorption through the skin.  The transdermal technique of administration using a "paint-ball gun principle" or anesthetic-containing balls which when breaking on contact with clothing would be absorbed via the skin. [8]   

In 2007, at the 4th European Symposium on Non-Lethal Weapons, researchers presented their studies on macaque monkeys in which they used different drug combinations to halt aggressive behavior, proposing that similar methods could be used on people during terrorist attacks. [9]

In addition to opioids and benzodiazepines, the following potential calmatives have been reportedly investigated as non-lethal weapons [10] :

  • Alpha 2 adrenergic receptor agonists
  • Dopamine D3 receptor agonists
  • Selective serotonin reuptake inhibitors
  • Serotonin 5-HT 1A receptor agonists
  • Neuroleptic anesthetics
  • Corticotropin-releasing factor receptor antagonists
  • Cholecystokinin B receptor antagonists

For patient education resources, see Biological Warfare as well as Chemical Warfare.

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Background

In August 2002, Alexander Stone authored a brief report in Science titled, "U.S. Research on Sedatives in Combat Sets Off Alarms." In this report, Stone highlighted research on the use of non-lethal weapons and discusses how the funding for studies of nonlethal weapons jumped from $14 million in 1997 to $36 million in 2001. [2]

In October 2002, the Russian Military reportedly used "a fentanyl derivative" to neutralize terrorists holding hostages at the Moscow Dubrovka Theater Center. The Russian Health Minister declared that the gas used in that event "cannot by itself be called lethal." [11]  Despite that statement, 127 of the hostages died following the use of that gas in the theater. Military authorities' initially refused to disclose the type of gas that was used in the theater to medical officials, which further complicated medical treatment of those affected. Subsequent analysis suggested that the gas probably consisted of a mixture of carfentanil and remifentanil. [12, 13, 14, 15]

One year later, in October 2003, Coupland reviewed the Moscow theater incident and the issue of physician involvement in the discussion of non-lethal weapon use. [16]

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Pathophysiology

Little has been published regarding the use of aerosolized opioids or benzodiazepines as incapacitating agents. The primary action of benzodiazepines is agonist activity at the γ-aminobutyric acid (GABA)–associated benzodiazepine receptors. This activity produces central nervous system depression, which may initially manifest as slurred speech, ataxia, nystagmus, and incoordination. As toxicity increases, the patient may become comatose and develop respiratory depression with airway compromise.

 Intranasal and buccal aerosolized benzodiazepines have potential clinical benefit for treatment of seizure emergencies and sedation of pediatric dental patients, and water-soluble agents have been developed for those uses. [17, 18, 19]   In a study by Xi in 1994, diazepam was aerosolized and studied in patients with seizures. [20]   In Science, Stone discusses research on the use of diazepam as a weaponized sedative. [2]  

Opioids possess agonist activity at the opioid receptors. The three current major classes of opioid receptors are mu, kappa, and delta; each has multiple subtypes with differing pharmacologic activity. Numerous opioid agonists also exist; each has varying affinity for each receptor. Fentanyl and its derivatives (ie, sufentanil, alfentanil, remifentanil, carfentanil) are the most common opioids described as having potential as aerosolized opioid agents. Alfentanil, remifentanil, fentanyl, and carfentanil are 75, 220, 300, and 10,000 times more potent than morphine, respectively. These fentanyls have a higher lipophilicity than other opioids, making them the most suitable for pulmonary delivery. [21]  In 1990, inhaled fentanyl was studied as a method of analgesia. [22]  In a study in 1995, the pharmacokinetics of liposome-encapsulated fentanyl were studied in ten volunteers, and concluded this method had several advantages over other routes of administration. [23]  

Multiple studies have reported that intranasal delivery of some benzodiazepines and opioids leads to a faster onset of effects in comparison to oral administration. Inhalation of some opioids has been shown to produce a result as rapid as intravenous delivery. [21] In 1998, administration of aerosolized fentanyl was studied in healthy volunteers, demonstrating a bioavailability of around 100% as well as rapid absorption and plasma concentrations similar to intravenous fentanyl use. [24]  A study by Reissig et al. comparing the efficacy of oral versus intranasal delivery of alprazolam concluded that inhalation generally results in a more rapid onset of effects, as well as a shorter time to peak effect. [25]  An initial study on intranasal midazolam evaluated serum concentrations of intranasal and intravenous midazolam in six healthy volunteers and concluded that intranasal midazolam was rapidly absorbed into the systemic circulation. [26]  A later study on intransal midazolam concluded that this formulation was similar to intravenous midazolam in both speed of absorption and serum concentration. [27]  In a review by Veldhorst-Janssen et al., the intranasal administration of opioids and benzodiazepines was deemed a suitable route as well as potentially preferable to other forms of administration in certain situations. [28]

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Epidemiology

No reports describe the use of aerosolized opioids or benzodiazepines as incapacitating agents in the U.S. population.

Few reports exist that describe the use of either benzodiazepines or opioids as incapacitating agents worldwide. In 1997, a modified fentanyl derivative was reportedly used in a failed assassination attempt of Khaled Mashaal, a Palestinian political leader and terrorist. Two Israelis reportedly sprayed the fentanyl derivative in Mashaal’s ear as he left his office in an attempt to kill him as punishment for a series of suicide attacks within Israel. However, Mashaal survived after being given an antidote. [29]

Only one incident has claimed the intentional use of an aerosolized opioid as an incapacitating agent. In the Moscow Dubrovka Theater incident, 50 Chechen rebels stormed the theater and took over 800 hostages on October 23, 2002. On October 26, 2002, a gas was introduced into the theater through the ventilation system just before a rescue attempt by Russian Special Forces. It was reported that as many as 127 of the 800 hostages in the theater died. Subsequent reports indicated that 125 of the 127 deaths were due to complications associated with the gas and inadequate medical treatment. [12]

The Russian Health Minister announced 4 days after the events that "a fentanyl derivative was used to neutralize the terrorists." This was corrobrated by reports that both Moscow and Western Embassy physicians noted signs and symptoms consistent with opioid intoxication. Laboratory confirmation of fentanyl use was not possible in these cases, but blood and urine specimens analyzed from two German survivors showed traces of halothane. It is hypothesized that the aerosol contained a mixture of carfentanil and remifentanil, after both were detected on the clothing of a survivor. Remifentanil was likely used to dilute the more potent carfentanil in an attempt to decrease fatalities of the hostages. [12, 30, 31, 32]

On October 13 of 2005, militants carried out attacks in the Russian town of Nalchik.  Russian Special Forces were deployed to the town, and during the second day of fighting Russian NTV reported that they used a “knockout gas” against militants who were holding hostages in a shop. The use of this “gas” received relatively little media attention and there was no information in the press about the nature of the chemical used.  However, it has been assumed by other reports that it was a similar agent to that used in Moscow in 2002 especially since it was reported that victims of the attack were administered an antidote. [8, 33]   

In 2011, a People’s Liberation Army soldier was photographed holding a narcosis gun. This weapon was developed to inject subjects with a liquid incapacitating agent, such as fentanyl or one of its analogs. [34]

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Prognosis

The prognosis is good for patients exposed to aerosolized benzodiazepines or opioids if no secondary injuries or complications develop. Once patients are removed from the exposure and the absorbed drug is metabolized, they should become less sedate. No long-term effects are expected from these agents themselves, however possible complications include the following.

  • Anoxic brain injury: If an exposed person becomes comatose and loses the ability to maintain ventilatory function, hypoxia may develop and lead to anoxic brain injury.

  • Aspiration pneumonia: The inability of an exposed patient to maintain his or her airway may result in aspiration of gastric contents into the lungs.

  • Rhabdomyolysis: If a person exposed to these agents develops profound somnolence, pressure tissue necrosis leading to rhabdomyolysis may occur. If this remains undiagnosed, myoglobinuric renal failure may develop.

The mortality and morbidity associated with the use of aerosolized benzodiazepines or opioids as incapacitating agents is unknown. Following the reported use of an aerosolized fentanyl derivative during the 2002 raid on Chechen rebels who had taken hostages in the Moscow Dubrovka Theater Center, 127 (16%) of the 800 hostages in the theater died, and 650 of the survivors required hospitalization. Four years after the event, approximately 100 of the survivors were questioned about their overall health before and after the siege. [35]  A third of the participants reported development of kidney or liver issues, and a third complained of ongoing respiratory problems since being exposed to the gas. Whether these complications were the result of the use of an aerosolized fentanyl derivative or due to other complications is unclear.

The use of chemical weapons as incapacitating agents and compliance with the Chemical Weapons Convention is a topic of debate. Any toxic chemical, if administered at a high enough concentration, can be lethal.  The delivery of a set dose of a drug via inhalation is nearly impossible in many settings. If a chemical is released into a large area (e.g., a building), it is inevitable that some people in the space will inhale more drug than others, based in part on their proximity to the point source. Because the difference between an incapacitating dose and a lethal dose is so small for the fentanyl analogues, avoiding fatalities in such incidents would be difficult. Casualties could possibly be reduced if proper post-exposure treatment is administered (e.g., rapid administration of naloxone). However, if the agent used is unknown, such as in the Moscow theater event, determining the proper antidote may be difficult. [36]

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