CBRNE - Opioids/Benzodiazepines Poisoning 

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

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

 

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]

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]

 

Presentation

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 might occur following such an event.
  • In the early phases of an emergency response, the agent would probably be unknown, and the history might be misleading and inaccurate.
  • Physical examination is the key to identifying the causative agent.

Physical

Following exposure to 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 patient may have fixed dilated pupils rather than the miosis that is characteristic of an opioid syndrome.

In opioid intoxication, the following features may be present:

  • Central nervous system depression manifesting as fatigue, somnolence, ataxia, and/or coma

  • Miosis -  Intoxication with the opioids meperidine and propoxyphene (withdrawn from the US market) does not typically cause miosis, and normal pupillary size is regularly maintained; however, neither of these agents has been associated with aerosolization. Miosis may be limited by preexisting medical conditions, such as a history of previous cataract surgery. Mydriasis may occur in patients with severe toxicity because of anoxic brain injury.

  • 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.

In benzodiazepine intoxication, the following features may be present:

  • Respiratory depression manifesting as hypoventilation, apnea, and airway occlusion
  • Central nervous system depression manifesting as drowsiness, somnolence, ataxia, nystagmus, and/or coma
  • Cardiovascular manifestations, including hypotension, tachycardia, bradycardia, and hypoxia-induced cardiac arrhythmias
 

DDx

 

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 incapacitating agent if the specific agent is unknown to the clinicians.

Rapid urine drug screenings (immunoassays) are available and may assist in diagnosis. However, these immunoassays do have a number of limitations. Opioid immunoassays are directed toward morphine, and 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 the following tests is reasonable in any person who has potentially been exposed to an incapacitating agent:

  • Complete blood cell count
  • Electrolytes assay
  • Clotting studies
  • Renal function tests
  • Liver function tests

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.

Electrocardiography

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 electrocardiogram 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.

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 toxicity. 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. To reverse benzodiazepine toxciity, 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.

Care may also include the following:

  • 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 the following 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 Investigation (FBI).

 

Medication

Medication Summary

If patients present after being exposed 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

Class Summary

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.

Benzodiazepine antagonists

Class Summary

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.

 

Follow-up

Further Inpatient 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

See the list below:

  • 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

See the list below:

  • 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 patient education resources, see the Bioterrorism and Warfare Center, as well as Chemical Warfare.