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Benzodiazepine Toxicity

  • Author: Chip Gresham, MD, FACEM; Chief Editor: Asim Tarabar, MD  more...
 
Updated: Apr 29, 2016
 

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.

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 Clinical 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 depend on the presentation, as follows:

  • Obtain an arterial blood gas (ABG) if respiratory depression is present
  • Obtain an ECG to evaluate for co-ingestants, particularly cyclic antidepressants
  • Obtain a chest radiograph if respiratory compromise is present
  • Obtain a pregnancy test in women of childbearing age

In patients with an intentional overdose, measure the following:

  • Serum electrolytes
  • Glucose
  • BUN
  • Creatinine clearance
  • Ethanol
  • 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. BZDs are very rarely fatal in overdoses, although the resulting altered mental status greatly increases the risk of aspiration following oral charcoal dose.[1]

Flumazenil (Romazicon) is a specific antidote for BZD poisoning, although its use in acute BZD overdose is controversial and its risks usually outweigh any possible benefit.[2] 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 BZD overdose in BZD-naive patients (eg, during conscious sedation on BZD-naive patient).

See Treatment and Medication for more detail.

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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 resources, see the Poisoning - First Aid and Emergency Center, Mental Health and Behavior Center, and Substance Abuse Center, as well as Benzodiazepine Abuse, Drug Overdose, Activated Charcoal, and Poison Proofing Your Home.

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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.

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Epidemiology

According to the Drug Abuse Warning Network (DAWN) of the US Department of Health and Human Services, total emergency department (ED) visits for nonmedical use of 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[3]

DAWN was discontinued in 2011. ED data from the new data collection system are expected in 2017.[4]

In 2014, a total of 27,060 benzodiazepine (BZD) single-substance exposures were reported to US poison control centers. Of these, 370 (1.4%) resulted in major toxicity and 18 (0.07%) resulted in death.[5] Inclusion of cases involving BZDs in combination with alcohol or other drugs yields much higher numbers. DAWN has 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%).[3]

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.[6]

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.[7]

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 benzodiazepines, and alcohol.[8]

The most reported BZD use is in persons older than 19 years. Elderly individuals and very young persons are more susceptible to the CNS depressant effects of BZDs than people in other age groups.

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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. 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, aprazolam is relatively more toxic than others in overdose.[9]

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Contributor Information and Disclosures
Author

Chip Gresham, MD, FACEM Emergency Medicine Physician and Medical Toxicologist, Department of Emergency Medicine, Clinical Director of Medication Safety, Middlemore Hospital; Senior Lecturer, Auckland University Medical School, New Zealand

Chip Gresham, MD, FACEM is a member of the following medical societies: American College of Emergency Physicians, American College of Medical Toxicology, Society for Academic Emergency Medicine, Emergency Medicine Residents' Association

Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Disclosure: Nothing to disclose.

Acknowledgements

Michael J Burns, MD Instructor, Department of Emergency Medicine, Harvard University Medical School, Beth Israel Deaconess Medical Center

Michael J Burns, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

David C Lee, MD Research Director, Department of Emergency Medicine, Associate Professor, North Shore University Hospital and New York University Medical School

David C Lee, MD is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Robin Mantooth, MD, FACEP Assistant Medical Director, Department of Emergency Medicine, Norman Regional Health System; Adjunct Clinical Assistant Professor of Family Medicine, Oklahoma State University; Consulting Staff, Department of Emergency Medicine, Integris Southwest Medical Center, Oklahoma University Medical Center, Integris Canadian Valley Health Center, Saint Anthony Hospital, Commanche County Medical Center, Claremore Medical Center, and Oklahoma Heart Hospital

Robin Mantooth, MD, FACEP is a member of the following medical societies: American College of Emergency Physicians and Christian Medical & Dental Society

Disclosure: Nothing to disclose.

John T VanDeVoort, PharmD Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals

John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists

Disclosure: Nothing to disclose.

References
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  2. Marraffa JM, Cohen V, Howland MA. Antidotes for toxicological emergencies: a practical review. Am J Health Syst Pharm. 2012 Feb 1. 69(3):199-212. [Medline].

  3. Drug Abuse Warning Network, 2011: National Estimates of Drug-Related Emergency Department Visits. Substance Abuse and Mental Health Services Administration. Available at http://www.samhsa.gov/data/2k13/DAWN2k11ED/DAWN2k11ED.htm. Accessed: September 29, 2014.

  4. Substance Abuse and Mental Health Services Administration. Emergency Department Data. SAMHSA. Available at http://www.samhsa.gov/data/emergency-department-data-dawn. April 4, 2016; Accessed: April 29, 2016.

  5. Mowry JB, Spyker DA, Brooks DE, McMillan N, Schauben JL. 2014 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 32nd Annual Report. Clin Toxicol (Phila). 2015. 53 (10):962-1147. [Medline]. [Full Text].

  6. Shah NA, Abate MA, Smith MJ, Kaplan JA, Kraner JC, Clay DJ. Characteristics of alprazolam-related deaths compiled by a centralized state medical examiner. Am J Addict. 2012 Nov. 21 Suppl 1:S27-34. [Medline].

  7. Jann M, Kennedy WK, Lopez G. Benzodiazepines: a major component in unintentional prescription drug overdoses with opioid analgesics. J Pharm Pract. 2014 Feb. 27(1):5-16. [Medline].

  8. Darke S, Torok M, Duflou J. Circumstances and toxicology of sudden or unnatural deaths involving alprazolam. Drug Alcohol Depend. 2014 May 1. 138:61-6. [Medline].

  9. Isbister GK, O'Regan L, Sibbritt D, Whyte IM. Alprazolam is relatively more toxic than other benzodiazepines in overdose. Br J Clin Pharmacol. 2004 Jul. 58(1):88-95. [Medline]. [Full Text].

  10. [Guideline] Kleber HD, Weiss RD, Anton RF, et al. Treatment of patients with substance use disorders, second edition. American Psychiatric Association. Am J Psychiatry. 2006 Aug. 163(8 Suppl):5-82. [Medline]. [Full Text].

  11. [Guideline] National Collaborating Centre for Mental Health. Self-harm: the short-term physical and psychological management and secondary prevention of self-harm in primary and secondary care. London (UK): National Institute for Clinical Excellence (NICE). 2004. 199. [Full Text].

  12. Penninga EI, Graudal N, Ladekarl MB, Jürgens G. Adverse Events Associated with Flumazenil Treatment for the Management of Suspected Benzodiazepine Intoxication - A Systematic Review with Meta-Analyses of Randomised Trials. Basic Clin Pharmacol Toxicol. 2016 Jan. 118 (1):37-44. [Medline].

  13. The Flumazenil in Benzodiazepine Intoxication Multicenter Study Group. Treatment of benzodiazepine overdose with flumazenil. Clin Ther. 1992 Nov-Dec. 14(6):978-95. [Medline].

  14. Seger DL. Flumazenil--treatment or toxin. J Toxicol Clin Toxicol. 2004. 42(2):209-16. [Medline].

 
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