Opioids/Benzodiazepines Poisoning 

  • Author: Christopher P Holstege, MD; Chief Editor: Robert G Darling, MD, FACEP   more...
 
Updated: Dec 20, 2010
 

Background

Few reports describe the use of either benzodiazepines or opioids as incapacitating agents. 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 highlights the Department of Defense's Joint Non-Lethal Weapons Program and how the funding for studies of nonlethal weapons has jumped from $14 million in 1997 to $36 million in 2001.[1] The Institute of Emerging Defense Technologies at Pennsylvania State University is reportedly conducting research on the use of drugs as nonlethal agents and has reportedly urged the Marine Corps to give immediate consideration to weaponizing sedatives such as diazepam.

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 announcement, 127 of the hostages died following the use of that gas in the theater.

In 2005, the 3rd European Symposium on Non-Lethal Weapons met in Stadthalle Ettlingen, Germany. At this meeting, an abstract was submitted by Hess and colleagues from the Institute for Clinical and Experimental Medicine and the Military Medical Academy, Czech Republic. In this abstract, they referred to their work using numerous potential pharmacological non-lethal weapons.[2]

According to the abstract by 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, they reportedly tested a combination of alfentanil or remifentanil together with a specific 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 very 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.[2]

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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. In a 1994 article published in Epilepsia by Xi et al, aerosolized diazepam was reported to arrest seizure activity within seconds.[3] In Science, Stone reported that diazepam was being given immediate consideration as a weaponized sedative.[1]

Opioids possess agonist activity at the opioid receptor. The 3 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. In Anesthesiology, Hung et al reported a rapid absorption rate following inhaled liposome-encapsulated fentanyl.[4] In Annals of Emergency Medicine, Wax et al provide a comprehensive review of these agents in relation to the Moscow theater event.[5] Alfentanil, remifentanil, fentanyl, and carfentanil are 75, 220, 300, and 10,000 times more potent than morphine, respectively.

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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

Only 1 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 (16%) 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 collaborated 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 2 German survivors showed traces of halothane.

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. Whether these complications were the result of the use of an aerosolized fentanyl derivative or due to other complications is unclear.

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Contributor Information and Disclosures
Author

Christopher P Holstege, MD  Associate Professor of Emergency Medicine and Pediatrics, University of Virginia; Director, Division of Medical Toxicology, Center of Clinical Toxicology; Medical Director, Blue Ridge Poison Ctr, Associate Medical Toxicology Fellowship Director, VA Dept of Health

Christopher P Holstege, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Medical Toxicology, European Association of Poisons Centres and Clinical Toxicologists, Medical Society of Virginia, Society for Academic Emergency Medicine, Society of Toxicology, and Wilderness Medical Society

Disclosure: Nothing to disclose.

Coauthor(s)

Jennifer S Boyle, MD, PharmD  Fellow in Toxicology, University of Virginia Health System

Disclosure: Nothing to disclose.

Specialty Editor Board

Suzanne White, MD  Medical Director, Regional Poison Control Center at Children's Hospital, Program Director of Medical Toxicology, Associate Professor, Departments of Emergency Medicine and Pediatrics, Wayne State University School of Medicine

Suzanne White, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Clinical Toxicology, American College of Epidemiology, American College of Medical Toxicology, American Medical Association, and Michigan State Medical Society

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Senior Pharmacy Editor, eMedicine

Disclosure: eMedicine Salary Employment

Rick Kulkarni, MD 

Rick Kulkarni, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine

Disclosure: WebMD Salary Employment

John D Halamka, MD, MS  Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center

John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Chief Editor

Robert G Darling, MD, FACEP  Adjunct Clinical Assistant Professor of Military and Emergency Medicine, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Associate Director, Center for Disaster and Humanitarian Assistance Medicine

Robert G Darling, MD, FACEP is a member of the following medical societies: American College of Emergency Physicians, American Medical Association, American Telemedicine Association, and Association of Military Surgeons of the US

Disclosure: Nothing to disclose.

References
  1. Stone A. Chemical weapons. U.S. research on sedatives in combat sets off alarms. Science. Aug 2 2002;297(5582):764. [Medline].

  2. Hess L, Schreiberova J, Fusek J. Pharmacological non-lethal weapons. 3rd European Symposium on Non-Lethal Weapons. May 10-12, 2005. Available at http://www.non-lethal-weapons.com/sy03abstracts/V23.pdf. Accessed January 10, 2009.

  3. Xi LY, Zheng WM, Zhen SM, Xian NS. Rapid arrest of seizures with an inhalation aerosol containing diazepam. Epilepsia. Mar-Apr 1994;35(2):356-8. [Medline].

  4. Hung OR, Whynot SC, Varvel JR, et al. Pharmacokinetics of inhaled liposome-encapsulated fentanyl. Anesthesiology. Aug 1995;83(2):277-84. [Medline].

  5. Wax PM, Becker CE, Curry SC. Unexpected "gas" casualties in Moscow: a medical toxicology perspective. Ann Emerg Med. May 2003;41(5):700-5. [Medline].

  6. Booij LH. [The agent used to free the hostages in Moscow and the insufficient Dutch preparations in case of a terrorist chemical disaster]. Ned Tijdschr Geneeskd. Dec 14 2002;146(50):2396-401. [Medline].

  7. Brooks M. Knockout gas: Chemical weapons in disguise?. New Scientist. October 2007;[Full Text].

  8. Coupland RM. Incapacitating chemical weapons: a year after the Moscow theatre siege. Lancet. Oct 25 2003;362(9393):1346. [Medline].

  9. Enserink M, Stone R. Toxicology. Questions swirl over knockout gas used in hostage crisis. Science. Nov 8 2002;298(5596):1150-1. [Medline].

  10. Gudmundsdottir H, Sigurjonsdottir JF, Masson M, et al. Intranasal administration of midazolam in a cyclodextrin based formulation: bioavailability and clinical evaluation in humans. Pharmazie. Dec 2001;56(12):963-6. [Medline].

  11. Ljungman G, Kreuger A, Andreasson S, et al. Midazolam nasal spray reduces procedural anxiety in children. Pediatrics. Jan 2000;105(1 Pt 1):73-8. [Medline].

  12. Loftsson T, Gudmundsdottir H, Sigurjonsdottir JF, et al. Cyclodextrin solubilization of benzodiazepines: formulation of midazolam nasal spray. Int J Pharm. Jan 5 2001;212(1):29-40. [Medline].

  13. Mather LE, Woodhouse A, Ward ME. Pulmonary administration of aerosolised fentanyl: pharmacokinetic analysis of systemic delivery. Br J Clin Pharmacol. Jul 1998;46(1):37-43. [Medline].

  14. Rieder J, Keller C, Hoffmann G. Moscow theatre siege and anaesthetic drugs. Lancet. Mar 29 2003;361(9363):1131. [Medline].

  15. Schiermeier Q. Hostage deaths put gas weapons in spotlight. Nature. Nov 7 2002;420(6911):7. [Medline].

  16. Weinberger S. Czech Research Stirs Chemical Weapons Debate. October 17, 2007. Wired. Available at http://blog.wired.com/defense/2007/10/czech-research-.html. Accessed January 10, 2009.

  17. Worsley MH, MacLeod AD, Brodie MJ, et al. Inhaled fentanyl as a method of analgesia. Anaesthesia. Jun 1990;45(6):449-51. [Medline].

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