Chapter 103. Sedatives and Hypnotics

Sedative and hypnotic medications are commonly used pharmaceuticals. The three classes include barbiturates, benzodiazepines, and nonbenzodiazepines (buspirone, carisoprodol, meprobamate, chloral hydrate, γ-hydroxybutyrate, melatonin, ramelteon, zaleplon, zolpidem, and zopiclone).

Clinical Features

Among the sedative-hypnotic class of medications, barbiturates are associated with the greatest morbidity and mortality. Owing to safer alternatives for seizure management, the clinical use of barbiturates has declined.

Barbiturates cause a dose-dependent spectrum of neuronal depression. With mild to moderate ingestions, toxicity resembles that of ethanol or other sedative-hypnotic medications: confusion, ataxia, slurred speech, drowsiness, and disinhibition. Gastrointestinal motility may be slowed. Severe intoxication follows a 10-fold overdose and loss of deep tendon and corneal reflexes may occur. Hypothermia, hypotension, and respiratory depression are common. Complicating features of the toxicity include hypoglycemia, aspiration pneumonia, pulmonary edema, and acute lung injury.

Barbiturate withdrawal syndrome may occur in the habituated patient who suddenly stops taking their medication. The syndrome occurs within 24 hours of cessation and begins with mild symptoms, which may become severe over the next 2 to 8 days. Short-acting barbiturates generally cause a more robust withdrawal syndrome than the long-acting products. Minor symptoms include anxiety, restlessness, depression, insomnia, anorexia, nausea, and vomiting. Major symptoms include psychosis, hallucinations, delirium, generalized seizures, hyperthermia, and cardiovascular collapse. Barbiturate withdrawal has a high mortality and gradual inpatient withdrawal of the addicting agent is recommended.

Diagnosis and Differential

Serum barbiturate levels may help establish an etiology for altered mental status in a comatose patient; however, decisions regarding management are based primarily on clinical grounds. Mixed sedative-hypnotic ingestions may be inappropriately ascribed to the barbiturate alone. Due to variability among patients with barbiturate overdoses, heart rate, pupil size and reactivity, and nystagmus are not clinically distinguishing signs. Skin bullae are rarely evident and are not specific to barbiturates. Myocardial depression is more common with barbiturates than benzodiazepines.

Bedside glucose measurement is imperative in the patient with altered mental status and may help narrow the differential diagnosis. Other useful diagnostic testing include arterial blood gas analysis, liver function tests, urine toxicology screen, salicylate and acetaminophen concentrations, blood urea nitrogen and creatinine levels, complete blood count, and creatinine phosphate kinase.

Emergency Department Care and Disposition

Treatment begins with airway management and supportive care. Once pulmonary and cardiovascular function have been adequately assessed and stabilized, enhancing elimination can be considered.

1. Stabilize the airway. Endotracheal intubation in the severely poisoned patients is commonly required and should be initiated early in the ED course. Due to the potential for myocardial depression, place 2 large-bore IVs and initiate fluid resuscitation with isotonic saline for hypotension.

2. Consider empiric treatment with naloxone and thiamine early in the management.

3. Dopamine or norepinephrine may be needed if fluid boluses fail to reverse hypotension. Hypothermia between 30°C (86°F) and 36°C (96.8°F) requires standard rewarming techniques.

4. Activated charcoal helps reduce absorption. In the awake, cooperative patient, 50 to 100 grams orally (1 gram/kilogram in children) should be administered. For sedated or unconscious patients, airway protection should precede the administration of activated charcoal. Multidose charcoal will reduce serum levels, but has not been shown to change clinical outcome.

5. Forced diuresis is not indicated due to risks of sodium and fluid overload and a lack of proven efficacy.

6. Urinary alkalinization is not considered first-line therapy. While it may enhance the clearance of phenobarbital and primidone, it is less effective than multidose charcoal alone, and has no role in the management of short-acting barbiturates.

7. Hemodialysis, hemoperfusion, and hemodiafiltration are reserved for patients who deteriorate despite aggressive medical support, but are only effective with phenobarbital toxicity.

8. Disposition depends on the degree of intoxication: evidence of toxicity greater than 6 hours from time of arrival requires hospital admission. Obtain psychiatric consult for intentional overdose. Toxicology or poison center consultation is recommended to assist with management.

Clinical Features

Benzodiazepine overdoses are common but carry a low mortality rate in isolation. There is, however, variation in the clinical outcome among agents due to differences in potency. Parenteral administration in the ED may produce significant complications. Benzodiazepines, when mixed with other sedative-hypnotics, may produce profound toxicity including respiratory depression, hypotension, and death.

The primary effect of benzodiazepines is neurologic and is characterized by somnolence, dizziness, slurred speech, confusion, ataxia, incoordination, and general impairment in intellectual function. Neurologic effects in the elderly, very young, or malnourished may be prolonged or enhanced. Disinhibition, extrapyramidal reactions, and paradoxical excitation are uncommon but reported. Short-term, anterograde amnesia is a common, sometimes desirable, effect with the administration of certain benzodiazepines.

Chronic use of benzodiazepines is associated with physiologic addiction. Withdrawal from benzodiazepines may occur following abrupt cessation. Symptoms are more intense following withdrawal from short acting agents. Clinical findings may mimic alcohol withdrawal and include anxiety, irritability, insomnia, nausea, vomiting, tremor, and sweating. Serious manifestations include hallucinations, psychosis, disorientation, and seizures. Treatment begins with reintroduction of a benzodiazepine with subsequent, gradual tapering.

Diagnosis and Differential

There is limited value in toxicological testing as serum levels do not correlate well with clinical findings. Qualitative urine screening is unreliable and a positive test does not prove causation of clinical signs as clinical features are nonspecific and may be seen with overdose of any sedative-hypnotic.

Emergency Department Care and Disposition

1. Priorities include assessment and stabilization of the airway, breathing, and circulation (see the preceding section on barbiturates for guidance regarding initial management, resuscitation and laboratory monitoring).

2. Do not induce emesis. Activated charcoal (1 gram/kilogram in children or 25 to 50 grams in adults) will bind benzodiazepines. Exercise caution in the sedated patient, and secure the airway before administration. Multidose charcoal is not indicated. Gastric lavage, forced dieresis, enhanced elimination, hemodialysis and hemoperfusion are ineffective and unnecessary.

3. Flumazenil is a unique, selective antagonist of the central effects of benzodiazepines. Unlike naloxone, flumazenil should not be used empirically for the undifferentiated sedative-hypnotic toxidrome as it may precipitate seizures (Table 103-1). The ED applications of flumazenil are limited to the setting of respiratory depression following procedural sedation with benzodiazepines. The dose is 0.2 milligram IV and titrated every min to a maximum total dose of 3 (0.01-0.02 milligram/kilogram in children). The half-life of flumazenil is approximately 1 hour and rebound sedation can occur in the setting of overdose with long-acting benzodiazepines.

4. In general, care is supportive. Admit patients with significant alterations of mental status, respiratory depression, or hypotension. Consultation with mental health specialists may be appropriate.

Clinical Features

The hallmark of all sedative-hypnotic medications, regardless of subclass, is sedation. Exposure to nonbenzodiazepine agents is common and coingestion with other sedatives may be synergistic and produce profound sedation. Three agents, ethclorvynol, glutethimide, and methaqualone, have recently been removed from the markets in the United States and Canada.

Buspirone

Buspirone has a complex mechanism of action and rapid absorption. Side effects include sedation, GI distress, vomiting, and dizziness. The symptoms with overdose are exaggerations of the side effects noted with therapeutic dosing. The drug is generally well tolerated in overdose, and treatment is primarily supportive. Due to effects on the serotoninergic system, serotonin syndrome has been reported. Seizures, hypotension, priapism, and dystonia are rare complications.

Carisoprodol and Meprobamate

Carisoprodol and its active metabolite, meprobamate, are used as central-acting muscle relaxants and anxiolytics, respectively. In overdoses, both may cause sedation, coma, and cardiopulmonary depression. Carisoprodol, but not meprobamate, can cause myoclonus, which may be a clue in an unknown overdose. Meprobamate has been associated with pharmacobezoars, and may be a cause of prolonged toxicity.

Chloral Hydrate

Chloral hydrate is the oldest sedative-hypnotic available today. At therapeutic doses, chloral hydrate produces mental status depression without loss of airway and respiratory reflexes. Vomiting and paradoxical excitation can occur in a small percentage of children. In overdose, coma and respiratory depression can occur. Chloral hydrate is a myocardial sensitizer and cardiac arrhythmias, decreased cardiac contractility, and asystole have been reported. When combined with alcohol, a potent, “knock-down” cocktail known as a “Mickey Finn” is created. A withdrawal syndrome similar to ethanol has been described.

Chloral hydrate may produce a characteristic pear-like odor. Abdominal radiographs may aid in the diagnosis of pharmacobezoars, as chloral hydrate is radiopaque. Respiratory depression and coma are treated supportively. Treat ventricular arrhythmias with IV β-blockers.

γ-Hydroxybutyrate

γ-Hydroxybutyrate (GHB) has been marketed as a muscle builder, fat burner, antidepressant, anxiolytic, hypnotic, and cholesterol-lowering medication. The only approved use in the United States is for the treatment of narcolepsy. GHB has a narrow therapeutic window and may produce a range of toxicity from mild sedation to coma. Seizures, bradycardia, hypothermia, and cardiac depression may occur. Rapid sedation with abrupt recovery 6 to 12 hours later is a common feature with GHB. Due to its amnestic effects and rapid sedation, GHB has been illicitly used for drug-facilitated sexual assault. Two compounds, 1,4 butanediol and γ-butyrolactone are GHB precursors and have been abused to produce similar effects. Treatment is primarily supportive with focus on airway management. Rapid awaking and self-extubation may be a clue to GHB intoxication. Toxicologic detection of GHB is difficulty owing to its very short half-life and rapid elimination. Withdrawal from GHB mimics alcohol withdrawal and may be severe, lasting from 3 days to 2 weeks.

Melatonin

The endogenous hormone melatonin is secreted by the pineal gland and is believed to help regulate the sleep-wake cycle. Melatonin can be purchased without prescription. Side effects following therapeutic dosing include headache, dizziness, fatigue, and irritability. Overdose data are limited, and signs and symptoms exaggerate the side effects from therapeutic doses.

Ramelteon

Ramelteon is a relatively new medication use to treat insomnia. It binds to melatonin receptors in the brain. Absorption following oral dosing is rapid. In overdose, sedation is common and treatment is supportive. Abuse and withdrawal have not been reported.

Zolpidem, Zaleplon, and Zopiclone

Zolpidem, zaleplon, and zopiclone have gained increased popularity for the treatment of insomnia. Though initially thought to produce little or no psychomotor impairment, addiction or withdrawal, experience has proved otherwise. Side effects in therapeutic doses include nausea and somnolence. Vivid dreams, sleep-walking, and driving have been reported with zolpidem. Fatalities following zolpidem overdoses have been reported, but are usually associated with mixed ingestions. There are limited data to guide management in overdoses of zaleplon and zopiclone.

Emergency Department Care and Disposition

1. In general, management for the nonbenzodiazepines is supportive (see the preceding section on benzodiazepines for treatment priorities). Flumazenil is ineffective for these medications.

2. For ventricular arrhythmias in the setting of chloral hydrate intoxication, IV β-blockers (e.g. propranolol, 1 milligram IV or 0.01 to 0.1 milligram/kilogram IV in children) are first-line agents.

3. Disposition is largely guided by the degree of symptoms. Have a low threshold for admission of any patient with altered mental status, abnormal vital signs, or arrhythmias. Consult psychiatric services when appropriate.