CBRNE - Opioids/Benzodiazepines Poisoning

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]

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]

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]

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]

An event involving an opioid or benzodiazepine aerosolized incapacitating agent is likely to 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.

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(s) 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 -  Of note, 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 have 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

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 sedating agents. 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 thus 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.

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.

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 evaluate for these potential problems.

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 in 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.

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 should be 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.  The FDA first approved nasal naloxone in November 2015, with Health Canada following soon after in October 2016. Subsequent studies on the pharmacokinetics (PK) of naloxone have confirmed that intranasal naloxone is absorbed rapidly into the systemic circulation, and reaches plasma concentrations in a similar timeframe to that of the traditional intramuscular (IM) dose. Based on pharmacokinetic data, these studies conclude that intranasal naloxone is an adequate reversal agent for opioid overdoses.[37, 38, 39]

A high-dose (5 mg/0.5 mL) naloxone solution in a prefilled syringe (Zimhi), for IM or subcutaneous injection, was approved by the FDA in October 2021. In pharmacokinetic studies, a single IM dose of 5 mg provided significantly higher peak plasma concentration and area under the curve (AUC) compared with a single 2-mg IM injection.[40]  

To reverse benzodiazepine toxciity, flumazenil may be considered—with caution, because a number of contraindications exist to its use (see Medication).

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.

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.

Any health care facility that is unable to adequately monitor symptomatic patients as detailed above 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.

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).

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.

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 (Zimhi)

Historically, the most commonly used opioid receptor antagonist in the United States. It is used to reverse opioid intoxication or overdose. Prevents or reverses opioid effects (hypotension, respiratory depression, sedation), possibly by displacing opiates from their receptors. Half-life is 1 h. The injectable solution is available as a generic in vials and syringes (0.4 mg/mL, 1 mg/mL) for IV/IM/SC administration. A high-dose (5 mg/0.5 mL; Zimhi) IM/SC injectable solution in a prefilled syringe is also available. In pharmacokinetic studies, a single IM dose of 5-mg provided significantly higher peak plasma concentration and AUC compared with a single 2-mg IM injection.

Naloxone intranasal (Kloxxado, Narcan Nasal Spray)

Competitive opioid antagonist that antagonizes opioid effects by competing for the same receptor sites. The intranasal form is indicated for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression. 

Class Summary

Flumazenil is a competitive benzodiazepine antagonist that reverses the effects of benzodiazepines. However, benzodiazepine antagonists must be used with caution because if given to a patient chronically exposed to benzodiazepines, the antagonist can precipitate benzodiazepine withdrawal. If a patient receives flumazenil and goes into withdrawal, seizures or status epilepticus can occur, necessitating treatment with a non-benzodiazepine agent such as a barbiturate. 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 of flumazenil as a diagnostic and therapeutic agent for unsubstantiated drug-associated coma is controversial. A positive response to small titratable doses of flumazenil or other benzodiazepine antagonist may obviate the need for endotracheal (ET) intubation in the setting of benzodiazepine toxicity.

Flumazenil (Romazicon)

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