Benzodiazepine Toxicity 

Updated: Jan 23, 2020
Author: Chip Gresham, MD, FACEM; Chief Editor: Gil Z Shlamovitz, MD, FACEP 

Overview

Practice Essentials

Oral benzodiazepine (BZD) overdoses, without co-ingestions, rarely result in significant morbidity (eg, aspiration pneumonia, rhabdomyolysis) or mortality. In mixed overdoses, they can potentiate the effect of alcohol or other sedative-hypnotics. Acute intravenous administration of BZDs is associated with greater degrees of respiratory depression.

Patients receiving prolonged parenteral administration of BZDs are at risk for propylene glycol poisoning (the diluent used in parenteral formulations of diazepam and lorazepam). Although rare, this may result in hypotension, cardiac dysrhythmias, lactic acidosis, seizures, or coma.

In long-term users who have developed dependence, cessation of BZDs can result in a withdrawal syndrome, with manifestations including anxiety, irritability, confusion, seizures, and sleep disorders.[1]  Alprazolam withdrawal syndrome may be especially severe, with associated delirium, psychosis, and hyperadrenergic states.[2]  Treatment of BZD withdrawal is typically with a long-acting BZD (eg, clonazepam), but sucessful use of antiseizure drugs (eg, valproate, carbamazepine) has also been reported.[2]

Signs and symptoms

Symptoms of BZD overdose may include the following:

  • Dizziness
  • Confusion
  • Drowsiness
  • Blurred vision
  • Unresponsiveness
  • Anxiety
  • Agitation

Findings on physical examination may include the following:

  • Nystagmus
  • Hallucinations
  • Slurred speech
  • Ataxia
  • Coma
  • Hypotonia
  • Weakness
  • Altered mental status, impairment of cognition
  • Amnesia
  • Paradoxical agitation
  • Respiratory depression
  • Hypotension

See Presentation for more detail.

Diagnosis

Immunoassay screening techniques are performed most commonly. These tests typically detect BZDs that are metabolized to desmethyldiazepam or oxazepam; thus, a negative screening result does not rule out the presence of a BZD.

Tests and procedures to obtain depend on the presentation, as follows:

  • Arterial blood gas (ABG) assay, if respiratory depression is present
  • ECG, to evaluate for co-ingestants, particularly cyclic antidepressants
  • Chest radiograph, if respiratory compromise is present
  • Pregnancy test, in women of childbearing age

In cases of intentional overdose, measure the following:

  • Serum electrolytes
  • Glucose
  • BUN
  • Creatinine clearance
  • Ethanol level
  • Acetaminophen level

See Workup for more detail.

Management

As with any overdose, the first step is an assessment of the patient's airway, breathing, and circulation, and these should be addressed rapidly as needed. In any patient with an altered mental status, a blood glucose level should be obtained immediately. The cornerstone of treatment in BZD overdoses is good supportive care and monitoring. Single-dose activated charcoal is not routinely recommended, as the risks far outweigh the benefit; BZD overdoses are very rarely fatal, and the resulting altered mental status greatly increases the risk of aspiration following oral charcoal dose.[3]

Flumazenil (Romazicon) is a specific antidote for BZD poisoning, but its use in acute BZD overdose is controversial and its risks usually outweigh any possible benefit.[4] In long-term BZD users, flumazenil may precipitate withdrawal and seizures; in patients taking BZDs for a medical condition, flumenazil may result in exacerbation of the condition. The ideal indication for flumazenil is isolated iatrogenic (eg, during conscious sedation) BZD overdose in BZD-naive patients.

See Treatment and Medication for more detail.

Background

Benzodiazepine (BZD) toxicity may result from overdose or from abuse. Since their introduction in 1960, BZDs have come to be widely used for a variety of indications, including seizures, anxiety, alcohol withdrawal, insomnia, drug-associated agitation, and muscle spasm. In addition, BZDs are used as preanesthetic agents, and are frequently combined with other medications for procedural sedation. BZD overdose often occurs in association with other substances.

For patient education information, see Benzodiazepine Abuse, First Aid for Poisoning in Children, and Child Safety Proofing.

Pathophysiology

Benzodiazepines (BZDs) act by potentiating the activity of gamma-aminobutyric acid (GABA), which is the major inhibitory neurotransmitter in the central nervous system (CNS). BZDs bind to a specific receptor on the GABA A receptor complex and thereby facilitate the binding of GABA to its specific receptor site. BZD binding causes increased frequency of opening of the chloride channel complexed with the GABA A receptor. Chloride channel opening results in membrane hyperpolarization, which inhibits cellular excitation.

Enhanced GABA neurotransmission results in sedation, striated muscle relaxation, anxiolysis, and anticonvulsant effects. Stimulation of peripheral nervous system (PNS) GABA receptors may cause decreased cardiac contractility and vasodilation. These changes could have the potential to alter tissue perfusion.

The rate of BZD onset of action is determined by its ability to cross the blood-brain barrier. The relatively lipophilic BZDs (eg, diazepam) usually have a faster onset of effect than the relatively water-soluble BZDs (eg, lorazepam). BZD effects can be potentiated when ethanol is present as a coingestant. Peak blood concentrations of most agents occur within 1-3 hours.

After a single dose, the lipophilic agents can have a shorter duration of action (shorter CNS effect) than water-soluble agents because rapid redistribution from the CNS to peripheral sites (eg, adipose tissue); thus, lorazepam has a longer CNS duration of action than diazepam. However, diazepam metabolizes to active intermediates with prolonged half-lives, which extend its therapeutic effects.

BZDs are metabolized predominantly in the liver by oxidation and/or conjugation. Most BZDs are broken down into pharmacologically active metabolites, which may have longer half-lives than the parent compounds.

Epidemiology

According to the Drug Abuse Warning Network (DAWN) of the Substance Abuse and Mental Health Services Administration (SAMHSA), total emergency department (ED) visits for nonmedical use of benzodiazepines (BZDs) rose 149% from 2004 to 2011. However, no short-term increases were noted between 2009 and 2011. Records did not always specify the BZD involved, but alprazolam was indicated in about a third of these ED visits, and in approximately a third of BZD-related suicide attempts.[5]

DAWN was discontinued in 2011. SAMHSA plans to combine DAWN into a new data collection, the Emergency Department Surveillance System (SEDSS).[6]

From 1996 to 2013, the percentage of US adults filling a BZD prescription increased 67%, from 8.1 million to 13.5 million, and the median cumulative quantity of BZDs filled over the year increased by 140%. The overdose death rate increased from 0.58 to 3.07 per 100,000 adults, with a plateau seen after 2010, although deaths continued to increase in the elderly and in blacks and Hispanics. In 2013, BZDs accounted for approximately 31% of fatal overdoses involving prescription drugs in the US. However, the danger of BZDs may be obscured by the fact that an estimated 75% of deaths involving benzodiazepines also involve an opioid.[7]

In 2018, a total of 22,995 single-substance exposures to BZDs were reported to US poison control centers. Of these, 469 (2%) resulted in major toxicity and 19 resulted in death.[8] Inclusion of cases involving BZDs in combination with alcohol or other drugs yields much higher numbers. DAWN reported that BZDs were involved in 123,572 of the 606,653 ED visits in 2011 that involved drugs and alcohol taken together (20.4%).[5]

The most reported cases of BZD toxicity are in persons older than 19 years.[8]  The elderly and the very young are more susceptible to the CNS depressant effects of BZDs than people in other age groups.

Prognosis

Oral benzodiazepine (BZD) overdoses, without co-ingestions, rarely result in significant morbidity (eg, aspiration pneumonia, rhabdomyolysis) or mortality, although in mixed overdoses they can potentiate the effect of alcohol or other sedative-hypnotics.

Benzodiazepines are commonly misused by individuals with opioid dependence, with prevalence rates of 45–70% for patients in opioid maintenance treatment.[9]  ​ Although BZDs taken alone are relatively safe in overdose, the combination of BZDs and opioid analgesics can produce significant respiratory depression. In particular, the combination of alprazolam with opioids may be fatal. Analysis of a West Virginia forensic database showed that alprazolam contributed to 17% of drug-related deaths; at least one other drug, typically an opioid, was identified in 97.5% of the alprazolam cases, with concurrent BZDs also found.[10]  

Overdose of ultrashort-acting BZDs (eg, triazolam [Halcion]) is also more likely to result in apnea and death than overdose with longer-acting BZDs. Of individual BZDs, alprazolam (Xanax) is relatively more toxic than others in overdose.[11]  Deaths attributed to BZDs increased fivefold from 1999 to 2009. During 2003 to 2009, death rates from alprazolam increased 233.8%; alprazolam was second only to oxycodone among prescription drugs with the highest increase in death rates.[12]

Similarly, an Australian study reported that alprazolam-positive cases of sudden or unnatural death increased from three cases in 1997 to 86 cases in 2012. The increase was driven mostly by accidental toxicity in people with known drug and alcohol problems. Drugs other than alprazolam and its metabolites were present in 94.9% of cases. The most commonly detected drugs, in order of decreasing frequency, were opioids, other BZDs, and alcohol.[13]

 

 

Presentation

History

Information to elicit when taking the history in cases of possible benzodiazepine (BZD) overdose includes the following:

  • Time of ingestion
  • Dose
  • Co-ingestants, if any
  • Whether the overdose was accidental or intentional
  • In patients prescribed BZDs, the duration of BZD use

Symptoms of BZD overdose may include the following:

  • Dizziness
  • Confusion
  • Drowsiness
  • Blurred vision
  • Unresponsiveness
  • Anxiety
  • Agitation

Physical Examination

Focus the physical examination on the patient's vital signs and cardiorespiratory and neurologic function. "Classic" isolated benzodiazepine overdose presents as coma with normal vital signs.

Findings on physical examination may include the following:

  • Nystagmus
  • Hallucinations
  • Slurred speech
  • Ataxia
  • Coma
  • Hypotonia
  • Weakness
  • Altered mental status, impairment of cognition
  • Amnesia
  • Paradoxical agitation
  • Respiratory depression
  • Hypotension
 

DDx

 

Workup

Approach Considerations

Overall, the laboratory detection of benzodiazepines (BZDs) depends upon the screening method used. Immunoassay screening techniques are performed most commonly and typically detect BZDs that are metabolized to desmethyldiazepam or oxazepam; thus, a negative screening result does not rule out the presence of a BZD. Qualitative screening of urine or blood may be performed but rarely influences treatment decisions and has no impact on immediate clinical care.

Tests and procedures to obtain depend on the presentation, as follows:

  • Arterial blood gas (ABG) assay, if respiratory depression is present
  • ECG, to evaluate for co-ingestants, particularly cyclic antidepressants
  • Chest radiograph, if respiratory compromise is present
  • Pregnancy test, in women of childbearing age

In cases of intentional overdose, measure the following:

  • Serum electrolytes
  • Glucose
  • BUN
  • Creatinine clearance
  • Ethanol level
  • Acetaminophen level
 

Treatment

Approach Considerations

As with any overdose, the first step is to assess the patient's airway, breathing, and circulation and to address those rapidly as needed. The cornerstone of treatment in benzodiazepine (BZD) overdoses is good supportive care and monitoring.

Single-dose activated charcoal is not routinely recommended, as the risks far outweigh the benefit. BZD are very rarely fatal in overdoses, and the altered mental status from BZD overdose greatly increases the risk of aspiration following oral charcoal dosing.[3]

Flumazenil (Romazicon) is a specific antidote for BZDs, but its use in acute BZD overdose is controversial and its risks usually outweigh any possible benefit.[4] In long-term BZD users, flumazenil may precipitate withdrawal and seizures; in patients taking BZDs for a medical condition, flumenazil may result in exacerbation of the condition.

Disposition of patients is as follows:

  • Patients may be discharged if they remain asymptomatic at least 6 hours post ingestion.
  • Patients with mild toxicity may be observed in the emergency department until they recover.
  • Patients with intentional overdoses require psychiatric evaluation before discharge.
  • Admit patients with hemodynamic instability, coma, or respiratory depression to the intensive care unit (ICU). Respiratory depression may be treated with assisted ventilation.

The American Psychiatric Association and the National Institute of Clinical Excellence have treatment and diagnostic guidelines available for cases of substance abuse and self-harm.[14, 15]

Prehospital Care

Prehospital care for patients who have overdosed on benzodiazepines (BZDs) includes the following:

  • Cardiac monitoring

  • Supplemental oxygen and airway support

  • Intravenous (IV) access

  • Rapid glucose determination (finger stick) and administration of D50 if necessary

Naloxone can be administered at a very low dose (0.05 mg with a gradual increase if needed) if the diagnosis is unclear and an opioid co-ingestion is suspected (eg, if the patient has severe respiratory depression).

An important caveat is that although the administration of 0.4 mg of naloxone will reverse respiratory depression in most patients with opioid overdoses, it will also cause severe withdrawal symptoms (nausea, vomiting) in those who are opioid dependent. This can result in aspiration of gastric contents in patients who are unable to protect their airway because of sedation from the BZD.

Flumazenil

Flumazenil is a competitive BZD receptor antagonist and is the only available specific antidote for BZDs. Its use in acute BZD is controversial, however, and its risks usually outweigh any benefit.[4] Common adverse events with flumazenil include agitation and gastrointestinal symptoms, while serious adverse events include supraventricular arrhythmia and convulsions.[16]

Flumazenil does not consistently reverse central respiratory depression due to BZDs, and over half the patients in a large multicenter study experienced re-sedation after use.[17]

In long-term BZD users, flumazenil may precipitate withdrawal and seizures; in patients taking BZDs for a medical condition, flumenazil may result in exacerbation of the condition.

In addition to those patients on long-term BZD use, flumazenil should not be used in any patient at an increased risk of having a seizure, including those with a seizure history, head injury, co-ingestion of BZD and tricyclic antidepressant or other proconvulsant, or even a possible ingestion of a proconvulsant.[18]

The ideal consideration for flumazenil use is for isolated iatrogenic BZD overdose in BZD-naive patients (eg, during conscious sedation of a BZD-naive patient).

 

Medication

Medication Summary

Flumazenil is a selective competitive antagonist of the gamma-aminobutyric acid (GABA) receptor and is the only available specific antidote for benzodiazepine (BZD) toxicity; it will reverse the effects of BZDs but must be used with caution.

Antidotes, Other

Flumazenil

Flumazenil is a competitive BZD receptor antagonist and is the only available specific antidote for BZDs, although its use in acute BZD is controversial and its risks usually outweighs any benefit.

Flumazenil does not consitantly reverse central respiratory depression due to BZDs, and over half the patients in a large multicenter study experienced re-sedation after use.

In long-term BZD users, flumazenil may precipitate withdrawal and seizures; in patients taking BZDs for a medical condition, flumenazil may result in exacerbation of the condition.

In addition to those patients on long-term BZD use, flumazenil should not be used in any patient at an increased risk of having a seizure, including those with a seizure history, head injury, coingestion of BZD and a tricyclic antidepressant or other proconvulsant, or even a possibly ingestion of a proconvulsant.

The ideal consideration for flumazenil use is isolated iatrogenic BZD overdose in BZD-naive patients (eg, during conscious sedation on BZD-naive patient).

 

Questions & Answers