CBRNE - Opioids/Benzodiazepines Poisoning

Updated: Jul 17, 2017
  • Author: Christopher P Holstege, MD; Chief Editor: Zygmunt F Dembek, PhD, MPH, MS, LHD  more...
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Overview

Background

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." Despite that statement, 127 of the hostages died following the use of that gas in the theater. Subsequent analysis suggested that the gas probably consisted of a mixture of carfentanil and remifentanil. [1]  It is likely that casualties in this event were increased by the military authorities' failure to notify medical officials of the type of gas that was used in the Theater. [2]  

In August 2002, Alexander Stone authored a brief report in Science titled, "Chemical weapons, US Research on Sedatives in Combat Sets Off Alarms." In this report, Stone highlighted the Department of Defense's Joint Non-Lethal Weapons Program and how the funding for studies of nonlethal weapons jumped from $14 million in 1997 to $36 million in 2001. [3]   The Institute for Non-lethal Defense Technologies (INLDT), part of the Applied Research Laboratory at Pennsylvania State University, reportedly conducted research on the use of drugs as nonlethal agents and urged the Marine Corps to give immediate consideration to weaponizing sedatives such as diazepam.

Both the military and domestic law enforcement are reported to have a growing desire for non-lethal technologies. [4] Incapacitating chemical agents, such as opioids or benzodiazepines, are considered a possible viable tool. The INLDT published that the development of incapacitating agents is “both achievable and desirable.” However, as of this writing the only chemical agent on the Department of Defense’s list of current nonlethal weapons is oleoresin capsicum. [5]   

In addition to the INLDT, the University of New Hampshire and the University of Bradford both have programs investigating the development of non-lethal weapons, the Non-lethal Technology Innovation Center and Bradford Non-Lethal Weapons Research Project respectively. [6, 7]  The Airforce Research Laboratory has investigated the use of high-powered microwave weapons in non-lethal techniques, as well as developing nonlethal vehicle-halting methods. [8, 9] The Marine Corps system Command has explored similar tools. [10]  

Internationally, the government of the United Kingdom has investigated and tested a series of nonlethal techniques. [11] The Defense Against Terrorism Program of Work, a program developed by NATO, has an initiative focused on developing non-lethal capabilities, led by Germany, Belgium, and France. [12]

In 2005, the 3rd European Symposium on Non-Lethal Weapons met in Stadthalle Ettlingen, Germany. At this meeting, an abstract submitted by Hess and colleagues from the Institute for Clinical and Experimental Medicine and the Military Medical Academy, Czech Republic, referred to their research on numerous potential pharmacological non-lethal weapons. [13] According to Hess et al, a major drawback of opioid use is the development of respiratory depression, particularly if administered at higher doses inducing immobilization.

In experiments with rabbits, Hess et al reportedly tested a combination of alfentanil or remifentanil together with the opioid antagonist naloxone, seeking to identify the optimal agonist/antagonist ratio while maintaining immobilization and markedly reducing respiratory depression. Inhaled administration of opioids was reported to be associated with a  rapid onset of effect. The ultrapotent opioid etorphine, when combined with dimethylsulfoxide, was capable of crossing normal skin and inducing immobilization within 3-8 minutes. [13]

In addition to opioids and benzodiazepines, the INLDT suggested the following potential calmatives for investigation as nonlethal weapons [14] :

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

 

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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 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. [15, 16, 17]   In Science, Stone reported that diazepam was being given immediate consideration as a weaponized sedative. [3]

Opioids possess agonist activity at the opioid receptor. The three current major classes of opioid receptors are m, k, and d; 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 only opioids that have been described as potential 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. [18]

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. [18] 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. [19]   

Both diazepam and midazolam are also effective when administered intranasally. In general, opioids tend to have a faster onset of action than benzodiazepines. [20]

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Epidemiology

Frequency

United States

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

International

Few reports exist that describe the use of either benzodiazepines or opioids as incapacitating agents.

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. [21]

Only one report describes 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 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. Reportedly, 127 of the 800 hostages in the theater died. Subsequent reports indicated that all had died from complications associated with the gas.

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 opiate 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. Remifentanil was likely used to dilute the more potent carfentanil in an attempt to decrease fatalities of the hostages. [1]

The most recent instance of weaponization of opioids or benzodiazepines occurred in 2011, when a People’s Liberation Army soldier was photographed holding a narcosis gun. This weapon was developed to inject subjects with a liquid incapacitating agent, likely fentanyl or one of its analogs. [22]

Fentanyl has received attention previously, during the Cold War, as a possible incapacitating agent. Its rapid onset time and short duration of effect made it an optimal candidate. However, fentanyl, like many other opioids, can cause severe respiratory depression. Consequently, the United States and United Kingdom did not consider it a viable option. Based on the 2002 event, Russia clearly continued investigation into its use as a nonlethal weapon. [23]

Mortality/Morbidity

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. [24] 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. [23] The delivery of a drug in set dose via inhalation is nearly impossible in such settings. If a chemical is released into a large area (eg, 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 (eg, rapid administration of naloxone). This is likely an additional factor that caused many of the deaths in the Moscow theater event. [25]

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