AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Sedative-hypnotics are a group of drugs that cause CNS depression. Benzodiazepines and barbiturates are the most commonly used agents in this class. Other agents include the nonbarbiturate nonbenzodiazepine sedative-hypnotics, such as buspirone, zolpidem, ethchlorvynol, glutethimide, chloral hydrate, meprobamate, methaqualone, methyprylon, carisoprodol, and gamma-hydroxybutyrate (GHB) and its analog gamma-butyrolactone (GBL). Most severe sedative-hypnotic poisonings are deliberate (suicidal). These agents are also commonly abused as recreational drugs.

Barbiturates

• Ultrashort acting - Methohexital (Brevital) and thiopental (Pentothal)
• Short and intermediate acting - Amobarbital (Amytal), pentobarbital (Nembutal), secobarbital (Seconal), and butalbital (Fioricet, Fiorinal)
• Long acting - Phenobarbital (Luminal)

Nonbarbiturates

• Benzodiazepines
• Carbamates - Meprobamate (Miltown)
• Chloral Derivatives - Chloral hydrate (Noctec)
• Ethchlorvynol (Placidyl)
• Piperidines - Glutethimide (Doriden) and methyprylon (Noludar)
• Quinazolinone - Methaqualone (Quaalude)
• Imidazopyridine - Zolpidem (Ambien), zaleplon (Sonata), eszopiclone (Lunesta) and alpidem
• Antihistamines (over-the-counter sleep aids) - Diphenhydramine and doxylamine
• GHB- Gamma-hydroxybutyrate

Pathophysiology

All the sedative-hypnotics are general CNS depressants. Most stimulate the activity of GABA, the principal inhibitory neurotransmitter in the CNS. GHB is a sedative-hypnotic recently banned for sale to the public because of frequent abuse and serious toxic adverse effects. GHB is a neuroinhibitory neurotransmitter or neuromodulator in the CNS. It also appears to increase GABA B receptor activity and dopamine levels in the CNS. Benzodiazepines are one of the most frequently prescribed medications in the world.

Frequency

United States

In 1998, a total of 70,982 sedative-hypnotic exposures were reported to US poison control centers, of which 2310 (3.2%) resulted in major toxicity and 89 (0.1%) resulted in death.

Mortality/Morbidity

• Most of the serious ingestions are suicide-related. These drugs are also used with other drugs of abuse (eg, amphetamines, hallucinogens) to offset stimulatory effects.
• Barbiturates have the highest morbidity and mortality of the sedative-hypnotics.
• Pure benzodiazepine ingestion usually causes little more than sedation and ataxia; it very rarely results in death. Death from sedative-hypnotics is caused by respiratory arrest. Alprazolam (Xanax) is relatively more toxic than other benzodiazepines in overdose.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

The history should include the following information:

• Agents ingested
• Amount of ingestion
• Time of ingestion
• Cause and/or reason for ingestion (eg, accidental, intentional, suicide attempt, recreational)
• Whether ingestion is acute or chronic
• Past medical history and history of drug abuse
• Circumstances surrounding the overdose

Physical

Focus the physical examination on vital signs and neurologic and cardiopulmonary status.

• General
• • Mild toxicity resembles ethanol intoxication. Severe respiratory depression is more likely to occur when the sedative-hypnotic is ingested with other CNS depressants.
  • Flexor or extensor posturing can be present in coma resulting from sedative drug ingestion. It does not imply structural damage in this setting.
• Barbiturates
• • Mild intoxication is characterized by ataxia, incoordination, nystagmus, slurred speech, and altered level of consciousness.
  • Moderate poisoning leads to respiratory depression and hyporeflexia.
  • Severe poisoning leads to flaccid areflexic coma, apnea, and hypotension.
  • Generally, 10 times the hypnotic dose produces severe toxicity.
  • Occasionally, hyperreflexia, rigidity, clonus, and Babinski signs are present.
  • Miosis is common, but mydriasis may be present with certain agents.
  • The nonbarbiturates, such as methyprylon and glutethimide, more commonly present with mydriasis.
  • Hypotension is usually secondary to vasodilation and negative cardiac inotropic effects.
  • Complications
    • Noncardiogenic pulmonary edema
    • Hypothermia
    • Delayed gastric emptying (therefore, late lavage and multiple charcoal is effective)
    • Skin lesions (clear vesicles and bullae on an erythematous base at contact surfaces) occur in 6% of ingestions and in approximately 50% of lethal ingestions.
• Methaqualone (Quaalude)
• • Resembles barbiturate poisoning
  • Has more pronounced motor problems (eg, ataxia) and is known as wallbanger because of this phenomenon
  • Can lead to severe muscular hypertonicity and seizures
• Glutethimide (Doriden)
• • Loss of brainstem reflexes
  • Flaccidity
  • Anticholinergic effects
  • Delayed gastric emptying
  • May cause hyperthermia or heatstroke
• Ethchlorvynol (Placidyl)
• • Pungent odor of breath and gastric contents
  • Prolonged coma (up to 2 wk)
  • Acute respiratory distress syndrome (ARDS) predominates in IV use
• Chloral hydrate
• • Synergistic with alcohol (knockout drops, Mickey Finn)
  • Cerebellar incoordination
  • Severe gastritis and GI bleed
  • Multiple dermatologic effects, including purpura, bullae, urticaria, and erythema multiforme (EM)
  • CNS depression with cardiopulmonary collapse
  • Associated with hepatitis, gastritis, proteinuria, and dysrhythmias
  • Odor of pears
  • Radiopaque
• Imidazopyridine
• • Sleepwalking or other complex bizarre behaviors
  • Chromaturia (blue-green urine discoloration) has been reported with zaleplon (Sonata) overdose.
  • Prolonged coma and respiratory failure

• Meprobamate

• • CNS and respiratory depression
  • Hypotension (common)
• GHB and GBL
• • Mild intoxication
  • • Slurred speech
    • Disinhibition
    • Euphoria
    • Mild lethargy
    • Moderate intoxication
    • CNS and mild respiratory depression
    • Agitation when stimulated
    • Myoclonus
  • Severe intoxication
  • • Unresponsive coma
    • Miosis
    • Bradycardia
    • Mild hypotension
    • Seizures
    • Respiratory depression and apnea
  • After ingestion, the onset of effects occurs within 15 minutes and peaks in 1.5-2 hours. Elimination of GHB is rapid (elimination half-life 1-2 h). The duration of clinical effects is 2-8 hours.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Obtain a complete blood count (CBC), arterial blood gas (ABG), glucose, chemistry, and toxicology screen. Screen for alcohol, salicylate, and acetaminophen with all intentional exposures.
• Quantitative serum drug concentrations are recommended for patients with serious toxicity
• • Barbiturates: For short-acting drugs, the lethal dose is 3 g or a serum concentration higher than 3.5 mg/dL. For long-acting drugs, the lethal dose is 5-10 g or a concentration higher than 8 mg/dL.
  • Methaqualone: A serum concentration higher than 8 mg/L is life threatening.
  • Glutethimide: Consider hemodialysis if the serum concentration is higher than 3 mg/dL.
  • Methyprylon: A serum concentration higher than 3 mg/dL is associated with severe toxicity and concentration higher than 6 mg/dL is typically fatal.
  • Ethchlorvynol: Perform charcoal hemoperfusion for an ingestion more than 100 mg/kg or a serum concentration higher than 10 mg/dL.
  • Chloral hydrate: The lethal dose is 10 g and a concentration higher than 100 mcg/mL is toxic.
  • Meprobamate: Coma occurs at 6-20 mg/dL. The drug is fatal at serum concentrations higher than 20 mg/dL.

Imaging Studies

• Obtain an abdominal radiograph. Chloral hydrate is radiopaque.

Other Tests

• Obtain an electrocardiogram (ECG); co-ingested drugs may have direct cardiac effects (eg, tricyclic antidepressants).
• On urinalysis, blue-green urine has been reported with zaleplon (Sonata) overdose.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Prehospital Care

• Establish ABCs, obtain IV access, provide oxygen, and perform aggressive supportive care with airway protection as necessary.
• Ipecac syrup is not recommended for home use because of the fear of emesis after onset of respiratory depression.
• Ensure adequate airway and ventilation. Consider and reassess the need for endotracheal intubation.

Emergency Department Care

• General
• • Given that the major issues in an overdose are aspiration, respiratory depression or failure, hypoxia, hypotension, and cardiac arrhythmias, the most important aspects in managing an overdose situation are, as usual, the ABCs—airway, breathing, and circulation.
• Prevention of absorption
• • Gastric lavage may be performed if the patient presents obtunded within 1 hour of ingestion or rapidly deteriorates while in the emergency department. The airway should be secured in such instances prior to gastric intubation and lavage.
  • The use of activated charcoal has become debated, and its liberal use is discouraged. In general, measures to prevent absorption (eg, emesis, gastric lavage) or increase excretion (eg, diuresis, catharsis) of the drug have not been shown consistently to reduce mortality associated with drug toxicity. Considerable morbidity is associated with charcoal aspiration. Its use should be limited to substances that would be well absorbed and have a high likelihood of toxic dose ingestion. 
  • It is not recommended in instances in which GHB or GBL are known to be the only intoxicants.
  • Multi-dose activated charcoal (20-50 g q4h) is recommended for overdoses with barbiturates, glutethimide, and meprobamate.
• Elimination enhancement
• • Alkaline diuresis enhances elimination of phenobarbital and other long-acting barbiturates. It is recommended for all symptomatic patients with long-acting barbiturate toxicity.
  • Consider hemodialysis or hemoperfusion in glutethimide, methyprylon, phenobarbital, meprobamate, and chloral hydrate poisoning.
• Flumazenil
• • Flumazenil competitively and reversibly binds benzodiazepine receptors (ie, GABA).
  • The use of flumazenil for suspected benzodiazepine overdoses is controversial. Some sources would go so far as to suggest that flumazenil has no role in the routine treatment of a coma unless the patient is known not to be benzodiazepine dependent and the overdose is known to result only from benzodiazepines. If used, flumazenil should be administered slowly (0.2 mg/min up to 3-5 mg) because large doses cause agitation and withdrawal. Serious risk of inducing seizures exists, particularly in patients with co-ingestions or long-term use of benzodiazepines.
  • This drug is contraindicated in patients with increased intracranial pressure (ICP) or closed head injury (CHI), those with a history of epilepsy, or those known to have ingested a tricyclic antidepressant (TCA) agent.
• Meprobamate
• • Forced diuresis
  • Hemodialysis in severe intoxication
  • Whole bowel irrigation (recommended for serious meprobamate poisoning because of the high predilection for bezoar formation)
• Methaqualone (Quaalude)
• • No diuresis
  • Diazepam for severe tonicity or seizures (strongly consider phenytoin as an anticonvulsant because barbiturates potentiate this drug)
• Chloral hydrate
• • Lidocaine may be used for ventricular dysrhythmias.
  • Beta-blockers (eg, propranolol) and overdrive pacing have also been reported to be effective. Intravenous propranolol is, perhaps, the drug of choice for chloral hydrate-associated ventricular dysrhythmias. Chloral hydrate sensitizes the myocardium to catecholamines, and propranolol blocks this effect.
  • Strongly avoid beta-adrenergic agonists (eg, dopamine) because they increase risk of fatal dysrhythmias.
  • Consider hemodialysis.

Consultations

Consider a consultation with a toxicologist and psychiatrist.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The only available antidotelike drug is flumazenil for benzodiazepine intoxication. Use of flumazenil in intentional drug overdose of unknown etiology is not cost effective or particularly prudent and is not encouraged. All other therapy is supportive or designed to limit absorption or enhance elimination.

Drug Category: GI decontaminant

Empirically used to minimize systemic absorption of the toxin. May only be of benefit if administered within 1-2 h of ingestion.

Drug Category: Antagonist

Reverses benzodiazepine sedation and respiratory depression.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Assess for suicide risk.
• With barbiturate toxicity, patients may be discharged after 6 hours of observation, provided that they are asymptomatic or minimally symptomatic.
• Observe patients with benzodiazepine toxicity for at least 2 hours after recovery from flumazenil for late respiratory depression or resedation.
• Patients with glutethimide (Doriden) toxicity require 24 hours of observation in the hospital.

Complications

• Some sedative-hypnotics may have teratogenic or mutagenic effects.

Patient Education

• For excellent patient education resources, visit eMedicine's Substance Abuse Center, Poisoning - First Aid and Emergency Center, and Mental Health and Behavior Center. Also, see eMedicine's patient education articles Barbiturate Abuse, Drug Overdose, Substance Abuse, Activated Charcoal, and Poison Proofing Your Home.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• The use of flumazenil can be dangerous because of the potential to elicit withdrawal agitation or seizure. Its role in acute overdose is marginal because benzodiazepine overdose resulting in airway compromise can be adequately treated in an emergency setting without the dangers of flumazenil use. Recall that flumazenil's effect is likely to be shorter than that of many of the benzodiazepines.
• Identification of the sedative or sedatives involved is important because some drug-specific treatments are available. Do not assume that addressing the ABCs is sufficient in a sedative overdose.
• However, managing the ABCs is paramount. In particular, the airway should be protected if giving activated charcoal to a patient with declining mental status or obtundation. 
• Be sure to consider co-ingestions. Sedatives are often abused in order to offset the effects of other drugs of abuse.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Barnett R, Grace M, Boothe P, et al. Flumazenil in drug overdose: randomized, placebo-controlled study to assess cost effectiveness. Crit Care Med. Jan 1999;27(1):78-81. [Medline].
• Bledsoe BE. No more coma cocktails. Using science to dispel myths & improve patient care. JEMS. Nov 2002;27(11):54-60. [Medline].
• Clark RF, Sage TA, Tunget C, Manoguerra AS. Delayed onset lorazepam poisoning successfully reversed by flumazenil in a child. Case report and review of the literature. Pediatr Emerg Care. Feb 1995;11(1):32-4. [Medline].
• Giri AK, Banerjee S. Genetic toxicology of four commonly used benzodiazepines: a review. Mutat Res. Jun 1996;340(2-3):93-108. [Medline].
• Greenberg DA, Simon RP. Flexor and extensor postures in sedative drug-induced coma. Neurology. Apr 1982;32(4):448-51. [Medline].
• Hamad A, Sharma N. Acute zolpidem overdose leading to coma and respiratory failure. Intensive Care Med. Jul 2001;27(7):1239. [Medline].
• Höjer J, Salmonson H, Sundin P. Zaleplon-induced coma and bluish-green urine: possible antidotal effect by flumazenil. J Toxicol Clin Toxicol. 2002;40(5):571-2. [Medline].
• Isbister GK, O'Regan L, Sibbritt D, Whyte IM. Alprazolam is relatively more toxic than other benzodiazepines in overdose. Br J Clin Pharmacol. Jul 2004;58(1):88-95. [Medline].
• Liskow B, Pikalov A. Zaleplon overdose associated with sleepwalking and complex behavior. J Am Acad Child Adolesc Psychiatry. Aug 2004;43(8):927-8. [Medline].
• Lovett B, Watts D, Grossman M. Prolonged coma after eszopiclone overdose. Am J Emerg Med. Jul 2007;25(6):735.e5-6. [Medline].
• Meyer S, Kleinschmidt S, Gottschling S, Gortner L, Strittmatter M. [Gamma-hydroxy butyric acid: neurotransmitter, sedative and party drug]. Wien Med Wochenschr. Jul 2005;155(13-14):315-22. [Medline].
• Riegel W. Use of continuous renal replacement therapy for detoxification?. Int J Artif Organs. Feb 1996;19(2):111-2. [Medline].
• Rosen P, Barkin R, et al, eds. Emergency Medicine: Concepts and Clinical Practice. 3^rd ed. St Louis: Mosby-Year Book; 1996.
• Rossman PG, Knesper DJ. The early phase of hospital treatment for disruptive adolescents! The integration of behavioral and dynamic techniques. J Am Acad Child Psychiatry. 1976;15(4):693-708. [Medline].
• Tintinalli JE, et al, eds. Emergency Medicine: A Comprehensive Study Guide. 4^th ed. New York: McGraw-Hill; 1995.
• Worthley LI. Clinical toxicology: part I. Diagnosis and management of common drug overdosage. Crit Care Resusc. Sep 2002;4(3):192-215. [Medline].

Article Last Updated: Dec 10, 2007