eMedicine Specialties > Emergency Medicine > Warfare - Chemical, Biological, Radiological, Nuclear and Explosives

CBRNE - Incapacitating Agents, Opioids/Benzodiazepines

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

Updated: Feb 5, 2009

Introduction

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, the3^rd 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    

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 g -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.

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 in 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.

Clinical

History

An event involving an opioid or benzodiazepine aerosolized incapacitating agent would probably create confusion and panic; cause multiple serious injuries or fatalities; and necessitate a major emergency medical service, police, and/or military response.

• Large numbers of casualties could overwhelm any community's emergency response services.
• Chaos may occur following such an event.
• In the early phases of an emergency response, the agent would probably be unknown, and the history may be misleading and inaccurate.
• Physical examination is the key to identifying the causative agent.

Physical

Following exposure to either an aerosolized opioid or benzodiazepine incapacitating agent, the presentation would be a syndrome consistent with opioid or benzodiazepine toxicity, respectively. These syndromes can vary, depending on the opioid or benzodiazepine agent used. In addition, findings may vary, depending on the patient's preexisting medical problems, the treatment provided by first responders, and the potential complications of the intoxication. For example, if hypoxic brain injury occurs, the characteristic miosis seen in an opioid syndrome may be replaced by fixed dilated pupils.

• Opioid intoxication
  • Respiratory depression manifesting as hypoventilation, apnea, and airway occlusion may be present.
  • Central nervous system depression manifesting as fatigue, somnolence, ataxia, and/or coma may be present.
  • Miosis may be present. Intoxication with the opioids meperidine and propoxyphene does not typically cause miosis, and normal pupillary size is regularly maintained; however, neither of these agents has been associated with aerosolization. Mydriasis may occur in patients with severe toxicity because of anoxic brain injury. Miosis may be limited by preexisting medical conditions, such as a history of previous cataract surgery.
  • Cardiovascular manifestations of opioid toxicity may include hypotension secondary to arteriolar and venous dilation. Both tachycardia secondary to hypotension or hypoxia and bradycardia secondary to a reduction of direct central nervous system stimulation may be observed. If hypoventilation becomes prominent, hypoxia-induced cardiac arrhythmias may occur.
• Benzodiazepine intoxication
  • Respiratory depression manifesting as hypoventilation, apnea, and airway occlusion may be present.
  • Central nervous system depression manifesting as drowsiness, somnolence, ataxia, nystagmus, and/or coma may be present.
  • Cardiovascular manifestations of benzodiazepines may include hypotension, tachycardia, and bradycardia. Hypoxia-induced cardiac arrhythmias may occur.

Differential Diagnoses

Workup

Laboratory Studies

• The use of laboratory studies in the treatment of patients potentially exposed to opioid or benzodiazepine incapacitating agents should initially focus on the potential complications associated with those sedatives. Additional laboratory tests can also be conducted in an attempt to identify the diagnosis of the incapacitating agent if the specific agent is unknown to the clinicians.
• Rapid urine drug screenings (immunoassays) are available and may assist health care professionals in making a diagnosis. However, these immunoassays do have a number of limitations. Opioid immunoassays are directed toward morphine. Many synthetic opioids, such as fentanyl, show no cross-reactivity with these assays. Testing for benzodiazepines is complicated because numerous benzodiazepines have substantially different structures. Results may be positive for diazepam, but negative for other benzodiazepines (eg, clonazepam).
• Performing a complete blood count, electrolyte tests, clotting studies, and renal and liver function tests is reasonable in any person who has potentially been exposed to an incapacitating agent.
• If the patient is comatose, performing a urine myoglobin and/or creatine phosphokinase test is warranted to exclude rhabdomyolysis. Hyperkalemia, hyperphosphatemia, and hypocalcemia may occur in association with rhabdomyolysis. The lactate level may also be elevated in these patients.
• If the incapacitating agent is unknown, obtain extra blood and urine samples. Subsequent testing can be performed to confirm the causative agent.

Imaging Studies

• A patient who has potentially been exposed to an opioid or a benzodiazepine incapacitating agent and who is comatose may be at risk for aspiration pneumonia. Obtain a chest radiograph.
• If the etiology of a patient's altered mental status is uncertain, performing a head CT scan to exclude other intracranial processes is reasonable.

Other Tests

• Both opioids and benzodiazepines may be associated with bradycardia. However, stress occurring in response to a situation associated with an exposure to aerosolized opioids or benzodiazepines may lead to tachycardia. Patients who are exposed to these agents and have preexisting cardiac disease may be at risk for cardiac ischemia. Perform an ECG to exclude these potential problems.

Treatment

Prehospital Care

Prehospital care providers must place their personal safety before the treatment of patients who may be contaminated with an incapacitating agent. Emergency responders should not enter a contaminated location that has not been secured. Little is known regarding the risk of secondary contamination in health care providers exposed to patients with contamination from opioid or benzodiazepine aerosolized agents.

• For civilian paramedics, exposed patients must be decontaminated prior to transfer. Absorption and subsequent toxicity is a risk from contact with patients who have been contaminated. Paramedics are at increased risk for toxicity in the closed confines of an ambulance. Caution must be exercised, especially for flight crews, because toxicity of the pilot during flight can lead to impaired judgment and subsequent risk of crashing the aircraft.
• Initiation of intravenous access and the infusion of intravenous fluids should be considered. Before intubation, naloxone may be administered intravenously to patients with respiratory compromise and suspected opioid. Aggressive airway control must take precedence over pharmacologic reversal because the vast majority of morbidity and mortality results from respiratory depression.

Emergency Department Care

Once decontamination has occurred, the primary emphasis is simply supportive care of exposed patients. Emergency department staff must be certain that proper decontamination has occurred. Aerosolization of the agents from contaminated patients may occur and can pose a risk to hospital personnel.

• Airway protection is paramount. In patients who present with coma, aspiration is a risk if adequate airway protection is not achieved. Hypoglycemia should be considered in all patients presenting with altered mental status and glucose administered when necessary. Naloxone may be infused in an attempt to reverse opioid activity (see Medication). Naloxone has an excellent safety record and is standard therapy in many institutions as part of the so-called coma cocktail. Flumazenil may be considered with caution because a number of contraindications exist in its use (see Medication). Thiamine administration should be considered in patients presenting with altered mental status.
• Intravenous hydration may be necessary; maintain adequate urinary output. Consider placement of a Foley catheter to monitor the patient's urine output.
• Include continuous cardiac monitoring in patients who are symptomatic.

Consultations

If an exposure to aerosolized benzodiazepines or opioids occurs, consider a number of consultations.

• Medical toxicologists: Consider consulting these physicians early to assist in the diagnosis and appropriate treatment of patients with possible exposure to these aerosolized agents.
• Critical care specialists: For patients requiring intensive care monitoring, consider early consultation with a physician trained in critical care medicine.
• Law enforcement: If the cause of the exposure is a terrorist act against civilians, immediately contact the local law enforcement agency, health department, and poison control center. Also, contact federal agencies, such as the US Federal Bureau of Investigations (FBI).

Medication

If patients present following exposure to aerosolized opioids or benzodiazepines, administration of the competitive antagonists naloxone and flumazenil, respectively, may be considered to reverse respiratory depression and coma.

Opioid antagonists

Opioid antagonists competitively inhibit the binding of opioid agonists to the opioid receptors. The goal of this therapy is reinstitution of adequate spontaneous ventilation. In patients presenting with sedation of unknown etiology, the cautious administration of naloxone may be both diagnostic and therapeutic. Even in high doses, naloxone has an excellent safety profile.

Naloxone (Narcan)

DOC of opioid antagonists because of relatively short half-life, safety record, and availability.

Dosing

Adult

0.4-2 mg IV/IM/SC q2-3min prn; use increments of 0.1-0.2 mg in opioid dependency; may need to repeat dose q20-60min
Question diagnosis if no response seen after administering 10 mg

Pediatric

0.1 mg/kg IV/IM/SC; repeat q2-3min prn

Interactions

Decreases analgesic effects of narcotics

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May precipitate withdrawal symptoms in opiate addiction

Benzodiazepine antagonists

Flumazenil is a competitive benzodiazepine antagonist that reverses the effects of benzodiazepines. However, benzodiazepine agonists must be used with caution because, when used to treat a potentially life-threatening condition (eg, seizure disorder), they may exacerbate the underlying disorder. If a patient ingests a drug that lowers the seizure threshold, such as a cyclic antidepressant, reversal may result in seizure or status epilepticus. Flumazenil is not recommended for indiscriminate use before a complete evaluation. If patients present with coma following aerosolized benzodiazepines exposure, flumazenil may be considered if the patient has respiratory depression and no history of long-term benzodiazepine use or seizure disorder. Use as a diagnostic and therapeutic agent for unsubstantiated drug-associated coma is controversial. A positive response to small titratable doses may obviate the need for endotracheal (ET) intubation.

Flumazenil (Romazicon)

Reverses effects of benzodiazepines in overdose by selectively antagonizing benzodiazepine receptor at GABA-A complex.

Dosing

Adult

0.2 mg IV initially over 30 s; repeat at 1-min intervals with 0.5 mg over 30 s until satisfactory response attained or 3 mg given
Dose may require additional titration

Pediatric

0.01 mg/kg IV initially over 15 s; repeat at 1-min intervals with 0.005-0.01 mg/kg

Interactions

Caution in cases of mixed drug overdose; concurrent use with other drugs taken in overdose (eg, cyclic antidepressants) may cause toxic effects

Contraindications

Documented hypersensitivity; overdosage of potential seizure-producing drugs; long-term benzodiazepine use (may cause potentially life-threatening withdrawal); seizures

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Seizures may occur in patients with history of prolonged benzodiazepine use (benzodiazepine-dependent) or in setting of mixed substance exposure, where effects of benzodiazepines are abruptly reversed
Resedation may occur

Follow-up

Further Inpatient Care

• See Emergency Department Care. Keep symptomatic patients who were exposed to the aerosolized agents in a monitored setting until their symptoms completely resolve. Use of maintenance intravenous fluids may be necessary. Prolonged intoxication may occur depending on the dose of the agent absorbed.

Transfer

• Any health care facility that is unable to adequately monitor a patient intoxicated with the agents should consider transfer to a facility that can care for such patients.
• Smaller health care facilities may be overwhelmed if a large-scale exposure occurs. Disaster-plan implementation and appropriate transfer of patients to less-stressed facilities may be necessary.

Complications

• Anoxic brain injury: If an exposed person becomes comatose and loses his or her 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 may occur, and rhabdomyolysis may develop. If this remains undiagnosed, myoglobinuric renal failure may develop.

Prognosis

• The prognosis is good for patients exposed to aerosolized benzodiazepines or opioids if no secondary injuries, such as the complications noted above, develop. Once patients are removed from the exposure and the absorbed drug is metabolized, they should become more lucid. No long-term effects are expected from these agents themselves.

Patient Education

• For excellent patient education resources, visit eMedicine's Bioterrorism and Warfare Center. Also, see eMedicine's patient education article Chemical Warfare.

Miscellaneous

Medicolegal Pitfalls

• Few pitfalls exist from a medicolegal standpoint. Decontaminating patients and avoiding secondary contamination of health care workers is paramount. If a physician demonstrates good supportive care as discussed in this article, the risk of litigation against the caregivers should be minimal.

Special Concerns

• Patients at the extremes of age may be more susceptible to toxicity from these agents. Other factors expected to predispose a patient to toxicity and complications include preexisting health problems (eg, chronic obstructive pulmonary disease [COPD]), volume depletion, and concurrent use of medications with sedative properties.

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].

Keywords

incapacitating agent, opioid, benzodiazepine, fentanyl, carfentanil, alfentanil, sufentanil, diazepam, chemical warfare agents, chemical threat agents, biological threat agents, radiological threat agents, nuclear threat agents, explosive threat agents, chemical weapons, benzodiazepine toxicity, opioid toxicity

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 Association for the Advancement of Science, American College of Emergency Physicians, American College of Medical Toxicology, American Medical Association, 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.

Medical Editor

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.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Rick Kulkarni, MD, Medical Director, Assistant Professor of Surgery, Section of Emergency Medicine, Yale-New Haven Hospital
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

CME Editor

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, 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, and Association of Military Surgeons of the US
Disclosure: Nothing to disclose.

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