Benzodiazepine Toxicity 

Updated: Apr 28, 2022
Author: J Michael Kowalski, DO; Chief Editor: Gil Z Shlamovitz, MD, FACEP 

Overview

Practice Essentials

Overdoses involving oral benzodiazepines (BZDs) alone rarely result in significant morbidity (eg, aspiration pneumonia, rhabdomyolysis) or mortality. Serious adverse effects and emergency department visits related to BZD overdose usually involve concomitant ingestions of other drugs.[1]  In mixed overdoses, BZDs can potentiate the effect of alcohol or other sedative-hypnotics. Intravenous administration of BZDs is associated with greater degrees of respiratory depression.[2]

Prolonged parenteral administration of BZDs places patients at risk for propylene glycol poisoning (the diluent used in parenteral formulations of diazepam and lorazepam). Rapid infusions of propylene glycol can induce hypotension. Accumulated propylene glycol can lead to anion gap metabolic acidosis, lactic acidosis, and hyperosmolarity. Rarely, propylene glycol toxicity may result in cardiac arrhythmias, seizures, or coma.[3, 4]

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.[5]  Alprazolam (Xanax) withdrawal syndrome may be especially severe, with associated delirium, psychosis, and hyperadrenergic states.[6]  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.[6]

In 2020, the US Food and Drug Administration (FDA) updated the required boxed warnings and package inserts for all BZDs to include information on the potential for abuse, addiction, and other serious risks. In the announcement, the FDA concluded that prescribing information did not provide adequate warnings about the serious risks and harms associated with these drugs, thus increasing the risk of adverse effects, especially when BZDs are used with some other medicines and substances.[7]

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 most commonly performed. These tests typically identify BZDs that are metabolized to nordiazepam (desmethyldiazepam) or oxazepam. Many benzodiazepines are metabolized to other BZD urine screen.

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
  • Liver function tests
  • Glucose
  • BUN
  • Creatinine clearance
  • Ethanol level
  • Acetaminophen level

See Workup for more detail.

Management

Death secondary to sedative-hypnotic overdose usually results from cardiorespiratory collapse. Therefore, the first step in management is an assessment of the patient's airway, breathing, and circulation, and those should be addressed rapidly if abnormal. In any patient with an altered mental status, a blood glucose level should be obtained immediately. The cornerstone of treatment in BZD overdoses is supportive care and monitoring. Gastrointestional (GI) decontamination, including single-dose activated charcoal and orogastric lavage, is not routinely recommended, as the risks far outweigh the benefits. BZD overdoses are rarely fatal, and altered mental status, if present, greatly increases the risk of aspiration.[8]

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 benefits.[9] In BZD-dependent patients, flumazenil may precipitate life-threatening withdrawal. Flumazenil use is also associated with seizures in patients with prior seizure history or a mixed overdose.[10] In patients taking BZDs for a medical condition, flumenazil may result in exacerbation of the condition. The ideal indication for flumazenil is in isolated iatrogenic (eg, during conscious sedation) cases or isolated BZD overdose in BZD-naive patients.

See Treatment and Medication for more detail.

Background

Benzodiazepine (BZD) toxicity may result from accidental overdose, intentional overdose, or recreational abuse. Since their introduction in 1960, BZDs have become indicated for a variety of conditions, including seizures, anxiety, alcohol withdrawal, insomnia, agitation, and muscle spasm. In addition, BZDs are used as preanesthetic agents, and are frequently combined with other medications, such as opioids, for procedural sedation. BZD overdose often occurs in association with other substances.[11]

For patient education information, see Benzodiazepine Abuse and Poison Proofing Your Home.

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 GABA receptors within the peripheral nervous system (PNS) may cause decreased cardiac contractility and vasodilation. These changes could be detrimental to adequate 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 also present. Regardless of the specific BZD, most agents will reach peak blood concentrations 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 due to rapid redistribution from the CNS to peripheral sites (eg, adipose tissue); thus, lorazepam has a longer CNS duration of action than diazepam. However, diazepam is metabolized to active intermediates with prolonged half-lives, which extend the parent drug's 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.[12]  

DAWN was discontinued in 2011. In 2018, SAMHSA reinstated DAWN. A preliminary 2020 report is currently available.[13]

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.[14]

From 2010 to 2017, annual BZD-associated deaths in the US increased 8.9-fold to 11,537.[15]  

In 2020, a total of 19,431 single-substance exposures to BZDs were reported to US poison control centers. Of these, 618 (3%) resulted in major toxicity and 16 resulted in death.[16] 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%).[12]

The majority of reported BZD toxicity cases are in persons older than 19 years.[16]  The elderly and the very young are more susceptible to the CNS depressant effects of BZDs compared with people in other age groups.

Prognosis

Oral benzodiazepine (BZD) overdoses, without co-ingestions, rarely result in significant morbidity (eg, aspiration pneumonia, rhabdomyolysis) or mortality. Polypharmacy overdoses involving BZDs and other agents can result in more severe symptoms. Alcohol or other sedative-hypnotics in particular can potentiate the effects of BZDs.

Benzodiazepines are commonly misused by individuals with opioid dependence, with prevalence rates of 45–70% for patients in opioid maintenance treatment programs.[17] Although BZDs taken alone are generally well tolerated in overdose, it has been suggested that the combination of BZDs and opioid analgesics can increase the risk of respiratory depression.[18] 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, but also another BZD in some patients—was identified in 97.5% of the alprazolam cases.[19]  

Overdose of ultrashort-acting BZDs (eg, triazolam [Halcion]) is more likely to result in apnea and death than overdose with longer-acting BZDs. Of individual BZDs, alprazolam is relatively more toxic than others in overdose.[20]  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.[21]

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 or alcohol dependence. 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.[22]

 

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:

  • Respiratory depression
  • 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 most commonly utlized. These tests typically identify BZDs that are metabolized to nordiazepam (desmethyldiazepam) or oxazepam.

Many benzodiazepines are metabolized to other compounds, however, so a negative screening result does not rule out the ingestion of a BZD. For example, alprazolam is not detected by a basic benzodiazepine urine screen.

Qualitative screening of urine or blood may be performed but rarely influences treatment decisions and has no impact on immediate clinical care. A positive test helps to confirm a suspected toxicity but a negative test does not exclude BZD ingestion. Further, a positive test in a patient without any symptoms does not equate to acute toxicity, as the test may be positive from previous use.

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

  • Arterial blood gas (ABG) or venous blood gas (VBG) assay, if respiratory depression is present
  • Electrocardiogram, to evaluate for co-ingestants, particularly cyclic antidepressants
  • Chest radiograph, if respiratory compromise is present
  • Pregnancy test, in women of childbearing age
  • Blood glucose level should be obtained immediately in any patient with an altered mental status

In cases of intentional overdose, measure the following:

  • Serum electrolytes
  • Liver function tests
  • Glucose
  • Blood urea nitrogen (BUN)
  • Creatinine clearance
  • Ethanol level
  • Acetaminophen level
 

Treatment

Approach Considerations

The cornerstone of treatment in benzodiazepine (BZD) overdoses is supportive care and monitoring. Death secondary to sedative-hypnotic overdose usually results from cardiorespiratory collapse. Therefore, the first step in management is an assessment of the patient's airway, breathing, and circulation, and these should be addressed rapidly as needed.

Gastrointestional (GI) decontamination, including single-dose activated charcoal and orogastric lavage, is not routinely recommended, as the risks far outweigh the benefits. BZD overdoses are rarely fatal, and altered mental status greatly increases the risk of aspiration.[8]

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 benefits.[9] In BZD-dependent patients, flumazenil may precipitate life-threatening withdrawal. Flumazenil use is also associated with seizures in patients with prior seizure history or a mixed overdose.[10] In patients taking BZDs for a medical condition, flumenazil may result in exacerbation of the underlying condition. The ideal indication for flumazenil is in isolated iatrogenic (eg, during conscious sedation) cases or BZD overdose in BZD-naive patients.

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.
  • Regional Poison Centers can be helpful in management and disposition of acute cases (1-800-222-1222)

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.[23, 24]

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 50% dextrose solution (D50) if necessary

Naloxone can be administered at a very low dose (0.04 mg IV 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 0.4 mg IV 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.[9] Common adverse events with flumazenil include agitation and gastrointestinal symptoms, while serious adverse events include supraventricular arrhythmia and convulsions.[25]

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.[26]

In benzodiazepine-dependent patients, flumazenil may precipitate life-threatening withdrawal. In patients taking BZDs for a medical condition, flumenazil may result in exacerbation of the condition. 

In addition to those patients with 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.[27]

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 consistently reverse central respiratory depression due to BZDs, and over half the patients in a large multicenter study experienced re-sedation after use.

In benzodiazepine-dependent patients, flumazenil may precipitate life-threatening withdrawal. 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