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Sedatives and hypnotics are very commonly abused agents and include; benzodiazepines, barbiturates, and nonbenzodiazepines (zolpidem, zopicline, buspirone, GHB gamma-hydroxybutyric acid). Their use is frequently combined with alcohol and other drugs such as opiates. Typically patients have depressed neurological signs and can develop cardiac, respiratory, renal and gastrointestinal dysfunction. Withdrawal from sedative-hypnotics is often associated with seizures, which can be fatal.

Benzodiazepines

Benzodiazepines (alprazolam, diazepam, lorazepam) are sedative-hypnotic agents used to treat anxiety, seizures, withdrawal states, insomnia and drug associated agitation. Benzodiazepines enhance the inhibitory effect of the neurotransmitter gamma-aminobutyric acid (GABA), which manifests in central nervous system depression.

Clinical Features

Benzodiazepine overdose produces a specific sedative-hypnotic toxidrome. Mild to moderate overdose resembles that of ethanol. The majority of symptoms and signs are neurological and include somnolence, emotional lability, confusion, incoordination, impaired cognition, ataxia, and slurred speech, and may induce horizontal and vertical nystagmus, midriasis and hyporeflexia. Cardiovascular signs include hypotension and bradycardia. Short-term amnesia is a common and often desirable effect especially when used for procedural sedation or general anesthesia. Ingested alone these agents rarely cause significant toxicity, however coma and respiratory and cardiac arrest can be seen in the setting of co-ingestion with other depressants. Rarely patients can exhibit paradoxical excitement, agitation and disinhibition. Predisposition appears to be for younger and older age groups, as well as underlying psychiatric disorders though the mechanism remains unknown.

Differential Diagnosis

Barbiturates, nonbenzodiazepine sedatives (zolpidem, gamma hydroxybutyrate, etc), alcohol and opiates can all cause similar features. Serum and urine toxicological testing is of limited value, as levels do not correlate with clinical findings.

Treatment

Supportive care is the mainstay of treatment including stabilization of the airway, breathing and circulation followed by routine lab tests, control of agitation and seizures and management of any subsequent complications (see general principles of overdose and poisoning). Decontamination with activated charcoal should be considered if ingestion is within 1 hour of presentation. Due to the sedating effects of benzodiazepines and risk of aspiration, the airway should be secured prior to administration. Gastric lavage, forced diuresis and enhanced elimination techniques are not effective.

Specific Therapy—Administration of flumazenil, a competitive antagonist of the benzodiazepine receptor, remains controversial due to the low morbidity and mortality associated with overdose, and the potential for inducing withdrawal seizures in patients who chronically take or abuse benzodiazepines, or in cases of pro-convulsant co-ingestion. Therefore flumazenil should not be used empirically for the sedative-hypnotic toxidrome. Its use is reserved for iatrogenic respiratory depression, in a benzodiazepine naïve patient, undergoing procedural sedation with benzodiazepines. The dose is 0.2mg IV over 30 seconds. Onset of action may take 6 to 10 minutes, with repeat dosing sometimes necessary. A maximum of 3 mg should not be exceeded in a one hour period.

Withdrawal

Withdrawal from benzodiazepines may be fatal. Abrupt abstinence is marked by tremor, anxiety, perceptual disturbances, dysphoria, insomnia, sweating, psychosis, and seizures. Onset is usually within 8 to 48 hours dependent on the half-life of the benzodiazepine and the chronicity of use.

Treatment usually involves reintroduction of a benzodiazepine. Tapering of a long-acting benzodiazepine, such as diazepam, over a few months may circumvent withdrawal, and should initially be started at a dose that abates symptoms.

Barbiturates

Barbiturate use is much less common than benzodiazepine use however is associated with greater mortality and morbidity. Barbiturates cause a dose dependent neuronal depression with symptoms and signs similar to benzodiazepines. Blood levels of barbiturates are useful and may help guide therapy. Treatment is supportive. Myocardial depression is more common with barbiturates over other sedatives and may require vasopressor therapy to maintain blood pressure. Decontamination with activated charcoal within 1 hour of ingestion helps reduce absorption. The AACT/EAPCCT recommends multiple-dose activated charcoal should be considered for cases of phenobarbital toxicity. Alkalization of the urine with sodium bicarbonate may enhance renal elimination. Hemodialysis can be used in severe cases of phenobarbital toxicity.

Nonbenzodiazepine Sedative-Hypnotics

This includes medications such as buspirone, carisoprodol, chloral hydrate, melatonin, and zolpidem. In general treatment is supportive. Activated charcoal is recommended within 1 hour of ingestion. Of note flumazenil is ineffective. Gamma hydroxybutyrate (GHB) is a nonbenzodiazepine sedative that is potentially fatal and becoming more popular in Europe and the United States and is discussed in detail below.

Gamma Hydroxybutyrate (GHB)

Gamma hydroxybutyrate or gamma hydroxybutyric acid (GHB) is a naturally occurring 4-carbon central nervous system (CNS) depressant with a structure similar to gamma aminobutyric acid (GABA) capable of crossing the blood brain barrier. GHB is lipid-soluble with no significant protein binding and exerts its effects via a novel GHB receptor as well as GABA B receptors.

Initially it was synthesized in Europe and used as a general anesthetic however, its use was discontinued due to numerous adverse effects. GHB has also been used legitimately as treatment for insomnia, narcolepsy, depression and to help wean people from alcohol. It is currently FDA approved in the USA for treatment of narcolepsy and cataplexy as sodium oxybate. GHB causes numerous different clinical effects and was marketed in the 1980s as a bodybuilding and weight loss supplement due to its effects on increasing growth hormone levels. The drug more recently has become abused in nightclubs for its euphoric, relaxation and sexual stimulation effects. GHB is currently illegal in most countries and is produced illicitly and is easily available on the internet or can be produced at home. The drug is also available as GBL (gamma butyrolactone) and BD (1,4 butanediol) both precursor drugs that are not as tightly controlled, however are rapidly metabolized to GHB in the bloodstream. GBL and BD are found in many industrial organic solvents such as acetone-free nail polish removers, paint strippers, cleaning products, and glue debonders and are often marketed as such to avoid detection. The prevalence of GHB use is not known, partly because the drug is not included in drug surveys or on hospital drug screens. Assays are available but are not easily accessible. However due to the low cost, ease of availability and questionable legal status its use is becoming more popular. Users develop dependence and experience significant withdrawal on discontinuation.

GHB is sold as a sodium salt, in a powder or granular form and dissolves in water to form a clear, colorless, odorless liquid. GBL is sold directly as a colorless, odorless liquid. GHB has a salty taste and is frequently added to various drinks to mask the flavor. GHB is rapidly absorbed and eliminated with a half-life of approximately 30 minutes. It exhibits zero order kinetics at low doses and has a very narrow therapeutic index. Users find it difficult to titrate doses and only need to consume slightly more than their usual dose to develop significant toxicity. GHB manifests a steep dose-effect curve with rapid onset of effect followed by abrupt clearing. Typically the effects last up to 2 hours however, dependent users may dose the drug every 30 minutes to 1 hour.

Clinical Features

Illicit users of GHB and GBL generally fall into two groups. The first group uses the drugs for possible therapeutic health benefits, such as bodybuilders and people attempting self-treatment of insomnia, depression and anxiety. GHB has been shown to increase growth hormone levels and lean body mass. A second group is recreational users, who take the drug at clubs, and bars. At low therapeutic doses GHB has stimulant properties with users experiencing euphoria, disinhibition and enhanced sensuality and empathic states. This can lead to unsafe sexual practices and increased rates of sexually transmitted diseases. Also the drug is often abused concurrently with other illicit drugs such as MDMA, methamphetamine, cocaine, and alcohol.

Due to the narrow therapeutic index acute toxicity is common and users may accidently overdose. Toxicity manifests as a dose dependent CNS depressant. Hypotension, bradycardia, hypothermia, and respiratory depression are common. At lower doses patients can be agitated and show self-destructive behavior. At higher doses rapid sedation and coma is common and patients can be completely unresponsive to painful stimuli. However due to the steep dose-effect curve, abrupt recovery is common, and users can awake suddenly 1-2 hours after intoxication. Miosis may be evident as well as nystagmus. Respiratory arrest is the most common cause of death. Amnesia after use is common and this combined with its sedating effects makes GHB a choice for drug-facilitated sexual assault.

Differential Diagnosis

GHB toxicity is a clinical diagnosis and assays are not easily available. Agitation followed by obtundation, bradycardia, and hypothermia followed by abrupt recovery points towards GHB. Barbiturates, benzodiazepines, alcohol and opiates can all cause similar features. Urine toxicology screen may not necessarily reflect current intoxication, and may serve as a distracter rather than a diagnostic aid.

Treatment/Work Up

Supportive care is the mainstay of treatment including stabilization of the airway, breathing and circulation followed by routine lab tests, control of agitation and seizures and management of any subsequent complications (see general principles of overdose and poisoning). Decontamination with activated charcoal should be considered if ingestion is within 1 hour of presentation as long as the airway is stable. Other elimination techniques are ineffective.

Specific Therapy—In general the treatment is supportive with no effective antidote. Vasopressors may be required for low blood pressure. Bradycardia should be treated with atropine or temporary pacing if severe. Typically once patients wake up they should be observed for several hours however, patients rarely comply and often leave against medical advice.

Withdrawal and Dependence

Due to the short half-life and dependent nature of the drug users may have to dose every 1 to 6 hours. As a result withdrawal symptoms can develop as early as 1 hour after the last dose and usually last between 4 and 14 days. Patients who use the drug for bodybuilding or to relieve insomnia or other medical conditions are more likely to develop dependence and withdrawal when compared to recreational users that use the drug only when socializing. Users admitted to the ICU for acute intoxication, or other unrelated conditions, may develop withdrawal while an inpatient. Neuropsychiatric symptoms are the most common symptoms experienced during withdrawal. Initially users may have some autonomic symptoms including tachycardia, hypertension, and diaphoresis however vitals signs can remain normal, unlike in alcohol withdrawal. After 24 hours patients develop extreme agitation, combativeness and anxiety and often will need to be physically restrained. Psychiatric symptoms can develop including paranoia, hallucinations and delirium. On physical exam patients often have a tremor, increased muscle tone, myoclonic jerks and nystagmus. Unlike with alcohol and benzodiazepines seizures are less common. Hyperthermia and rhabdomyolysis can develop from the extreme agitation leading to electrolyte abnormalities and renal failure. Death can occur due to cardiac arrest from electrolyte abnormalities. Supportive care is the mainstay of treatment. Long acting benzodiazepines such as diazepam are titrated to control agitation and anxiety. Extremely large doses may be required which may cause significant respiratory depression and require endotracheal intubation and mechanical ventilation. Baclofen (GABA agonist) can be given in combination with benzodiazepines. Patients resistant to benzodiazepines may require barbiturates or propofol and a secure airway. Creatine kinase (CK) levels should be followed due to the risk of rhabdomyolysis, which should be treated with fluids. The role of urine alkalization with bicarbonate to treat rhabdomylosis in poisoned patients is unclear.

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