Benzodiazepines and barbiturates are sedatives that are used therapeutically as hypnotics, anxiolytics, and anesthetics. When used as drugs of abuse, they are usually ingested or injected. Diagnosis is by history and physical examination, excluding other drugs (eg, alcohol, opioids), and sometimes urine testing. Mild toxicity is managed with observation. Severe toxicity may require mechanical ventilation or hemodialysis. Withdrawal manifests as drug craving, insomnia, agitation, and seizures. In general, dependence is managed by slow tapering.
The short-term therapeutic benefits of sedatives in treating anxiety, panic, and sleep disorders are well-established. However, use for longer than 1 to 2 weeks can be habit-forming, leading to behavioral and physical dependence.
Street names for benzodiazepines include Benzos or Downers. Street names for barbiturates include Barbs, Goof Balls, and Yellow Jackets.
Pathophysiology of Benzodiazepine and Barbiturate Use
Benzodiazepines and barbiturates bind to gamma-aminobutyric acid (GABA)-A receptors, increase the affinity of the receptor for GABA, and promote inhibitory neurotransmitter effects. The effect on a single neuron is to increase the rate of action potentials by increasing the chloride current. The effect on groups of neurons with multiple layers of inhibition is not well understood.
Routes of use include ingestion or injection.
Symptoms and Signs of Benzodiazepine and Barbiturate Toxicity
Benzodiazepines and barbiturates have similar effects. Distinctions are that benzodiazepines have a shorter duration of toxicity and cause less respiratory depression.
Intoxication with benzodiazepines and barbiturates causes somnolence, slowed reactions, depression of deep tendon reflexes, postural unsteadiness, and ataxia.
Signs of toxicity are characteristic of the sedative-hypnotic toxidrome, and include severe somnolence, nystagmus on forward gaze, miosis, marked ataxia with falling, confusion, stupor, respiratory depression, and, ultimately, death.
Overdose of a benzodiazepine rarely causes hypotension, and these drugs do not cause arrhythmias. Overdoses of barbiturates can cause hypotension.
Diagnosis of Benzodiazepine and Barbiturate Toxicity
History and physical examination
Urine drug testing
Serum phenobarbital level
For suspected benzodiazepine toxicity, sometimes flumazenil administration (do not give to patients who use antiepileptic medications)
A presumptive diagnosis can be made in a patient with a history of ingestion of sedatives, a physical examination consistent with the sedative-hypnotic toxidrome, an undetectable alcohol level, and either a normal respiratory rate or hypoventilation with no response to naloxone (single intravenous dose, 40 microgram). In the acute setting, treatment may precede based on a presumptive diagnosis.
The clinician should proceed with the usual evaluation of a sedative-hypnotic toxidrome. For patients with hypoventilation, a single dose of naloxone is administered to exclude opioid toxicity. A blood gas should be obtained and other blood tests include: serum glucose (use a rapid point-of-care test, if available); complete metabolic profile; concentrations of salicylate, acetaminophen, and ethanol; and concentrations of any current medications prescribed to the patient. A urinalysis and a urine toxicological screen should be performed. A head CT should be ordered if there is any concern for head injury or spontaneous intracranial hemorrhage.
The definitive diagnosis of benzodiazepine or barbiturate toxicity requires a blood test to demonstrate a toxic level of benzodiazepine or barbiturate, with concordant symptoms. Many hospital laboratories have the capacity to test phenobarbital levels, but testing for other benzodiazepines or barbiturates typically requires sending the sample to an outside laboratory.
A positive urine screening test for benzodiazepines is suggestive of use within the last week if there is a history of ingestion. A negative screening test does not exclude recent use. Most urine benzodiazepine screening tests detect only benzodiazepines with an oxazepam nucleus; commonly used medications with this structure are temazepam, oxazepam, chlordiazepoxide, and diazepam. High-dose oral ingestions or parenteral administration of lorazepam, which is also a 3-hydroxy substituted benzodiazepine, may cross-react with these agents and yield a positive urine test. However, a positive test based on this cross-reaction is not sensitive or specific. The cross-reactivity of the urine assay for triazolo compounds like alprazolam is also not reliable enough for clinical use.
Some hospitals have urine tests for barbiturates. The most frequently used assay looks for a concentration of 200 ng/ml of secobarbital, not the more commonly used phenobarbital ("peanut butter balls"). Similar to the urine screening tests for benzodiazepines, the cross-reactivity of the barbiturate assay for barbiturates other than secobarbital is not reliable enough for clinical use.
Flumazenil administration may be diagnostic and transiently therapeutic. The benzodiazepine receptor antagonist flumazenil can reverse sedation and respiratory depression secondary to benzodiazepine overdose. The dose is 0.2 mg IV given over 30 seconds; 0.3 mg may be given after 30 seconds; followed by 0.5 mg every 1 minute to a total of 3 mg. Similar to how a response to naloxone establishes the diagnosis of acute opioid toxicity, a response to flumazenil establishes the diagnosis of acute benzodiazepine toxicity.
In patients who are dependent on benzodiazepines and have a seizure disorder, there is about a 1 in 5 chance that administration of flumazenil will precipitate a seizure. Giving flumazenil in polysubstance ingestions that include antiepileptic medication or tricyclic antidepressants is not recommended. Nevertheless, in a previously healthy patient who presents with the sedative-hypnotic toxidrome after overdose by oral ingestion, a response to flumazenil suggests that patient's sedation is unlikely to deepen to the point of requiring intubation.
The clinician may encounter requests for testing of a victim of a drug-facilitated sexual assault. Such cases should involve a medical toxicologist and a trained clinical sexual assault response team. The most well known agent used for drug-facilitated sexual assault is flunitrazepam, but all benzodiazepines can have the effects of sedation, hypotonia, and anterograde amnesia. Flunitrazepam is not detected reliably on the routine urine immunoassay. Like clonazepam, it is a 7-nitro substituted benzodiazepine. For most illicit substances, a qualitative test may suffice because the concentration of the illicit substance should be zero. Unless performed immediately after the event, quantitative testing is usually informative only in cases in which the patient regularly uses substances and there is a question of which substance gave rise to the clinical effects. The quantitative testing may identify the suspected substance if it is present in sufficient amounts to result in the stated clinical effects. The longer the interval between the event and sample acquisition, the more difficult it is to extrapolate to the concentration of the substance during the event.
Treatment of Benzodiazepine and Barbiturate Toxicity
For oral ingestion with 2 hours, oral activated charcoal
For phenobarbital toxicity, sodium bicarbonate and possibly hemodialysis
For respiratory depression, sometimes intubation and mechanical ventilation
Acute mild intoxication generally requires only monitoring the respiratory and cardiovascular status until mental status returns to baseline.
Preventing absorption
If ingestion was within the prior 2 hours and the patient is alert enough to swallow oral substances safely,activated charcoal may be given to attempt to reduce absorption. However, if the patient is too somnolent to participate in an interview, the risk of aspiration pneumonitis from activated charcoal likely outweighs any benefit. Single dose activated charcoal has not been shown to reduce morbidity or mortality of benzodiazepine or barbiturate toxicity, despite its sound theoretical basis. Most involved healthy volunteers who ingested subtoxic doses. One large randomized study showed no effect, but that study involved pesticides and oleander, not prescription medications (1). No study has shown that it increases the absorption of a xenobiotic.
Multidose activated charcoal, which is repeated administration of activated charcoal, enhances elimination of phenobarbital. The rationale for this is because of enterohepatic circulation of phenobarbital, although studies supporting positive clinical outcomes are lacking.
Enhancing excretion
If phenobarbital overdose is diagnosed, urine alkalinization with sodium bicarbonate may enhance excretion. Urinary pH should be maintained as close to 8 as possible for effective alkalinization.
Hemodialysis has been used successfully in some studies for treatment of high-dose phenobarbital overdose (2). Many oral barbiturates, for example primidone, have volumes of distribution close to 1 L/kg. The volume of distribution of phenobarbital is 0.5 L/kg. It is 50% protein bound at therapeutic concentrations. At toxic concentrations, protein-binding sites will saturate, leading to an increasingly large unbound fraction that is dialyzable.
Mitigating toxicity
Flumazenil administration is more useful as a diagnostic method than a therapeutic one for benzodiazepine toxicity. The effects of flumazenil last about 1 hour. In a large ingestion, this is not enough time to metabolize a clinically significant amount of the benzodiazepine. The effects will wear off and the toxic effects will recrudesce. Repeated administrations of flumazenil will rapidly reach the maximum dose of 3 mg, beyond which the risk of seizures increases dramatically.
For patients with respiratory depression, intubation and mechanical ventilation may be required.
Treatment references
1. Eddleston M, Juszczak E, Buckley NA, et al. Multiple-dose activated charcoal in acute self-poisoning: a randomised controlled trial. Lancet. 2008;371(9612):579-587. doi:10.1016/S0140-6736(08)60270-6
2. Hoyland K, Hoy M, Austin R, et al: Successful use of haemodialysis to treat phenobarbital overdose. BMJ Case Rep 2013: bcr2013010011, 2013. doi: 10.1136/bcr-2013-010011
Chronic Use of Benzodiazepines or Barbiturates
Complications
Patients who habitually take high doses of sedatives develop difficulty thinking, slow speech (with some dysarthria), decreased comprehension, poor memory, impaired judgment, narrowed attention span, and emotional lability.
Use in pregnancy
Use of benzodiazepines during pregnancy may cause neonatal withdrawal syndrome or other toxicities, like apnea, hypothermia, or hypotonia. Meprobamate, a nonbenzodiazepine anxiolytic, can also cause neonatal withdrawal.
Phenobarbital use in pregnancy increases the risk of congenital malformations in the fetus (1). Prolonged use of barbiturates during pregnancy can cause barbiturate withdrawal in the neonate.
Tolerance and dependence
In susceptible patients, psychological dependence on benzodiazepines or barbiturates may develop within 1 to 2 weeks.
Physiologic dependence develops over weeks to months in chronic users. The extent of physical dependence is related to dose and duration of use. For example, pentobarbital 200 mg/day taken for many months may not induce significant tolerance, but 300 mg/day for > 3 months or 500 to 600 mg/day for 1 month may induce a withdrawal syndrome when the drug is stopped.
Tolerance and tachyphylaxis to benzodiazepines and barbiturates develop irregularly and incompletely.
Some cross-tolerance exists between alcohol and sedatives, especially drugs that act on GABA-A receptors. Barbiturates and alcohol are similar in the dependence, withdrawal symptoms, and chronic intoxication they cause.
Withdrawal
Stopping or markedly reducing therapeutic doses of sedatives leads to a mild, self-limited withdrawal syndrome, even after only a few weeks of use. Attempts to discontinue the drug can exacerbate insomnia and result in restlessness, disturbing dreams, frequent awakening, and feelings of tension in the early morning.
Benzodiazepine withdrawal after discontinuing higher doses results in tachypnea, tachycardia, tremulousness, hyperreflexia, and confusion. Seizures of status epilepticus may occur. The symptoms of benzodiazepine withdrawal may fluctuate, and the intensity of the symptoms may not decrease steadily.
Patients taking short-acting benzodiazepines develop withdrawal within 1 to 2 days from the last dose. The onset of withdrawal from long-acting benzodiazepines is several days to a week after the cessation. Withdrawal may be most severe in patients who used drugs with rapid absorption and a quick decline in serum levels (eg, alprazolam, lorazepam, triazolam). Withdrawal from alprazolam but not other benzodiazepines has been associated with hallucinations, usually visual.
Many people who misuse benzodiazepines are current or past heavy users of alcohol, and a delayed benzodiazepine withdrawal syndrome may complicate alcohol withdrawal.
Managing benzodiazepine withdrawal is best done by increasing the dose of the benzodiazepine the patient has become dependent on until symptoms abate and then decreasing the dose gradually. If the patient has lost access to an illicit supply, the patient can be given a longer-acting benzodiazepine such as chlordiazepoxide or diazepam. Confirmatory urine testing is performed to identify the benzodiazepine the patient was actually using, which may be the easiest to taper the patient with, and to identify contaminants like fentanyl that would require additional treatment (eg, naltrexone or buprenorphine). There is no established optimum taper schedule.
Patient who develop seizures or hepatic or renal insufficiency should be admitted to the hospital for medication titration under monitored circumstances.
Barbiturate withdrawal is similar to alcohol withdrawal. A potentially life-threatening withdrawal syndrome similar to delirium tremens may occur when the drug is discontinued in people who chronically take large doses or in those who abruptly discontinue the drug or decrease the dosage.
Occasionally, seizures may occur even after properly managed withdrawal over 1 to 2 weeks.
Without treatment, withdrawal of a short-acting barbiturate causes increasingly severe effects. Onset of symptoms is typically 8 to 12 hours after the last dose of the drug, and include anxiety, insomnia, dizziness, weakness, nausea, and vomiting. Symptoms progressively worsen, and muscle twitching, hand tremor, distortion in visual perception, and orthostatic hypotension may develop. Major withdrawal symptoms, eg, seizures and delirium, may occur within 16 hours and can last up to 5 days after abrupt cessation of barbiturates.
Management of barbiturate withdrawal is best done by increasing the dose of the barbiturate the patient has become dependent on until symptoms lessen and then slowly decreasing the dose.
In contrast to benzodiazepines, essentially any patient going through withdrawal from barbiturates after abrupt cessation should be hospitalized because of the risk of seizures and cardiac dysrhythmias.
Chronic use reference
1. Veroniki AA, Cogo E, Rios P, et al: Comparative safety of anti-epileptic drugs during pregnancy: A systematic review and network meta-analysis of congenital malformations and prenatal outcomes. BMC Med 15 (1):95, 2017. doi: 10.1186/s12916-017-0845-1
Key Points
Benzodiazepines and barbiturates are sedatives that are used therapeutically as hypnotics, anxiolytics, and anesthetics and can also be drugs of abuse.
High doses decrease the level of consciousness and may lead to respiratory depression and coma, requiring intubation and mechanical ventilation.
Diagnose with history and physical examination, excluding other drugs (eg, alcohol, opioids), and sometimes urine testing.
Treatment of mild toxicity with observation. Severe toxicity may require mechanical ventilation or hemodialysis.
Withdrawal manifests as drug craving, insomnia, agitation, and seizures. In general, dependence is managed by slow tapering.
Drug Information for the Topic
