1. Focus on airway and breathing. Patient may require intubation and ventilation, especially given the high likelihood of co-ingestion of contamination of benzodiazepines with opioids.
2. Administer activated charcoal if ingestion is less than one hour.
3. Rule out co-ingestion of other substances.
4. Flumazenil can be considered if known benzodiazepine overdose in the absence of coma NYD, mixed overdoses, and patients with benzodiazepine dependence (controversial).

Benzodiazepines are GABA-potentiating substances that have anxiolytic, sedative, anticonvulsant, and muscle-relaxing effects.

In overdose/toxicity, benzodiazepines cause CNS depression, but death is rare and usually attributed to co-ingestion of other drugs or alcohol. Adulteration of benzodiazepines in British Columbia makes resuscitation complex.

Examples include alprazolam (Xanax®), clobazam, clonazepam, diazepam (Valium®), lorazepam (Ativan®), midazolam, oxazepam, temazepam (Restoril®), and etizolam.

“Z-drugs” (e.g. zopiclone, zolpidem) are structurally unrelated to benzodiazepines, but have similar pharmacological and toxic effects.

Street drugs including benzodiazepines in BC vary significantly from the expected substance.  Data from BCCSU (2022) indicated only 54% of Xanax® samples contained benzodiazepines and between 4% and 22% of benzodiazepine samples contained fentanyl.

Diagnosis is clinical and based on history of benzodiazepine ingestion and the presence of several clinical features:

1. CNS depression (e.g. drowsiness, ataxia, confusion, slurred speech, sedation).
2. Paradoxical agitation, hyperexcitability, hyperactivity, disinhibition, or aggression
3. Coma (uncommon with benzodiazepines alone).
4. Death is rare. Benzodiazepines have a wide therapeutic index. Death usually occurs due to co-ingestion with other drugs or alcohol.

Treatment is largely supportive.  If patients are asymptomatic, they should be observed for several hours.

Symptomatic patients require supportive management and observation until symptoms resolve.

1. Assess airway. Ensure patient is protecting airway.  Intubate and ventilate if required.
2. If ingestion was recent, administer activated charcoal.
3. Monitor vital signs.
4. Consider administration of flumazenil. Do not rely on flumazenil for treatment of respiratory function.  Standard supportive measures should be utilized.
5. Avoid forced diuresis or hemodialysis.

Flumazenil is the antidote for benzodiazepines. It is a competitive antagonist at benzodiazepine receptors in the CNS.

It has action against benzodiazepines and “Z-drugs”.

It reverses sedative, amnestic, anticonvulsant, anxiolytic, and muscle relaxant effects of benzodiazepines. It may reverse paradoxical agitation effects as well. It has a benefit for ventilation, but this is poorly understood.

Flumazenil is controversial in benzodiazepine toxicity as it may increase the risk of ventricular dysrhythmias and seizures, the latter of which may be difficult to treat.

Indications

• Reversal of iatrogenic sedation.
• Severe paradoxical reactions.
• Limited role in benzodiazepine and “Z-drug” toxicity.

Contraindications

• Patients with seizure disorders.
• Coma NYD.
• Mixed overdose (especially with TCAs or substances that may cause seizure or cardiac dysrhythmias).
• Patients with benzodiazepine dependence (controversial).

Not Recommended

• Patients with anticholinergic symptoms (e.g., tachycardia, hypotension, hypoxia, ECG changes, hyperreflexia, increased muscle tone, dyskinesias).

Dosing

• 0.2-0.3mg IV over 30 seconds. Repeat in 60-second intervals until desired effect. Typical response with 1-3mg IV or less. Unlikely to achieve benefit >5mg.
• If initial benefit, maintenance dose may be considered. Continuous IV infusion suggested rate 0.1-0.5mg/hr IV up to 1.5mg/hr IV. Stop infusion and reassess every 6-12 hours.
• Children (limited data) initial loading 0.01mg/kg IV (max 0.2mg) give over 30 seconds. Repeat every minute until target effect achieved. Maximum 1mg total.
• Safe in pregnancy.

Monitoring

• Cardiac monitoring.
• Vital signs.
• Maintain IV access.
• Observe every hour for re-sedation as half-life ~1 hour.

Not well defined in literature.

In cases of isolated benzodiazepine toxicity, management will be primarily supportive, and few patients will require transfer.

Asymptomatic patients will require observation for several hours.  Symptomatic patients will require supportive care and observation until symptoms resolve.

Physicians should contact BC Poison Control Centre for consideration of the use of flumazenil in patients with benzodiazepine toxicity.

Asymptomatic patients may be discharged after a period of observation. Initially symptomatic patients may be discharged after supportive care and resolution of symptoms.

1. Russell R, Buxton J, Godwin J, Moe J. Potent sedatives in opioids in BC: Implications for resuscitation, and benzodiazepine and etizolam withdrawal. BC Med J. 2021;63(4):177-178.

   
   

2. Poison Management Manual.  Flumazenil – Antidote. BC Drug and Poison Information Centre; 2015. Accessed November 29, 2022. http://dpic.org/

   
   

3. Poison Management Manual. Benzodiazepines and Related Drugs. BC Drug and Poison Information Centre; 2015. Accessed November 29, 2022. http://dpic.org/

   
   

4. Knill A, Tobias S, Matthews J, Ti L. A Report on British Columbia’s Unregulated Drug Supply. British Columbia Centre on Substance Use. 2022. Accessed November 29, 2022. https://www.bccsu.ca/