INTRODUCTION — Benzodiazepines (BZDs) are sedative-hypnotic agents that have been in clinical use since the 1960s. The first benzodiazepine, chlordiazepoxide, was discovered serendipitously in 1954 by the Austrian scientist Leo Sternbach. Three years later, it was marketed as a therapeutic medication under the brand name Librium. Diazepam was released in 1963; multiple other compounds followed over subsequent years.

BZDs have replaced older sedative-hypnotic agents, which were less safe. They are used for sedation and to treat anxiety, seizures, withdrawal states, insomnia, and agitation. They are frequently combined with other medications for procedural sedation. Due to their many uses, BZDs are widely prescribed and nearly 50 different agents are available worldwide. The high incidence of BZD overdose mirrors their widespread use and availability [1-4].

The diagnosis and management of acute benzodiazepine poisoning will be reviewed here. A general approach to the poisoned patient and the management of poisonings involving other agents with sedative properties are discussed elsewhere. (See "General approach to drug poisoning in adults" and "Ethanol intoxication in adults" and "Acute opioid intoxication in adults" and "Gamma hydroxybutyrate (GHB) intoxication".)

PHARMACOLOGY AND CELLULAR TOXICITY — Benzodiazepines (BZD) are organic bases with a benzene ring and a seven member diazepine moiety; various side chains determine the potency, duration of action, metabolite activity, and rate of elimination for specific agents [5]. BZDs exert their effect via modulation of the gamma-aminobutyric acid A (GABA-A) receptor. Gamma-aminobutyric acid (GABA) is the chief inhibitory neurotransmitter of the central nervous system.

The GABA-A receptor is a ligand-gated ion channel composed of five subunits arranged in various combinations of alpha, beta, and gamma [6-11]. The composition of subunits determines the affinity of the various xenobiotics that bind to the receptor. Benzodiazepines bind at the interface of the alpha and gamma subunits and, once bound, lock the GABA-A receptor into a conformation that increases its affinity for GABA (which binds between alpha and beta subunits). BZDs do not alter the synthesis, release, or metabolism of GABA but rather potentiate its inhibitory actions by augmenting receptor binding. This binding increases the frequency of the flow of chloride ions through the GABA ion channel, causing postsynaptic hyperpolarization and a decreased ability to initiate an action potential. The low incidence of respiratory depression with orally ingested BZDs appears to be related to the low density of binding sites in the brainstem respiratory center [10]

KINETICS — Benzodiazepines are commonly divided into three groups based upon half-life duration: short-acting (half-life of less than 12 hours), intermediate-acting (half-life between 12 and 24 hours), and long-acting (half-life greater than 24 hours). A table describing the kinetics of common BZDs is provided (table 1).

Short-acting benzodiazepines generally have few active metabolites, do not accumulate with repeated doses, and demonstrate clearance that is largely unaffected by age and liver disease. Examples include triazolam and oxazepam. Although midazolam possesses a short half-life, it has active metabolites that can accumulate with repeated dosing.

Intermediate-acting benzodiazepines include lorazepam and temazepam. Long-acting benzodiazepines generally have pharmacologically active metabolites, accumulate in tissues after multiple doses, and demonstrate impaired clearance in older patients and those with liver disease. Examples include diazepam and chlordiazepoxide [12-14].

BZDs are rapidly absorbed in the GI tract and most are highly lipophilic and highly protein bound. The metabolism of BZDs is primarily hepatic. Within the liver, most BZDs are metabolized to a significant extent by the CYP2C19 and CYP3A4 enzymes. Alprazolam and midazolam are metabolized by CYP3A4. Diazepam is metabolized by both CYP3A4 and CYP2C19.

Interactions with other drugs that are metabolized by CYP enzymes may prolong the half-lives of certain BZDs, leading to prolonged clinical effects and therapeutic misadventures [12-14]. Examples of drugs that inhibit the CYP3A4 enzyme and reduce the metabolism of BZDs, thereby prolonging their effects, include macrolide antibiotics, diltiazem, HIV protease inhibitors, and grapefruit juice (table 2). Inducers of CYP3A4, which may enhance metabolism of BZDs, include phenobarbital, phenytoin, carbamazepine, rifampin, and St. John's wort (table 2).

Oxazepam, temazepam, and lorazepam are directly conjugated to an inactive, water-soluble glucuronide metabolite that is excreted by the kidney [5,15]. Therefore, these agents are not susceptible to CYP interactions and are less likely to accumulate in patients with CYP inhibition. Chlordiazepoxide, diazepam, and flurazepam are metabolized to active metabolites, which then are conjugated and excreted [5].

The main active metabolite of diazepam is desmethyldiazepam. Diazepam's other active metabolites include temazepam and oxazepam. Active metabolites of chlordiazepoxide include desmethylchlordiazepoxide, demoxepam, desmethyldiazepam, and oxazepam. Triazolam, alprazolam, and midazolam are converted to hydroxylated intermediates that are rapidly conjugated and do not contribute to the drug's overall effect.

Midazolam has a very rapid onset of clinical effect and a shorter duration of action than other benzodiazepines, which explains its preferential use in procedural sedation [16]. However, successive doses of midazolam lead to bioaccumulation of its hydroxy-metabolites and may prolong the drug's sedative effects [17]. (See "Procedural sedation in adults outside the operating room".)

CLINICAL FEATURES OF OVERDOSE

Benzodiazepine poisoning — Oral benzodiazepines (BZDs), taken in overdose without a coingestant, rarely cause significant toxicity [18]. The classic presentation of a patient with an isolated BZD overdose consists of CNS depression with unremarkable vital signs ("coma with normal vitals"). Many patients are arousable and able to provide an adequate history. Of note, most intentional ingestions of BZDs do involve a coingestant, the most common being ethanol.

Patients with a clinically apparent ingestion manifest slurred speech, ataxia, and altered (most commonly depressed) mental status. Respiratory compromise is uncommon with isolated oral ingestions, but may be seen when patients ingest additional sedative hypnotic agents (such as ethanol) or opioids, or when clinicians administer BZDs as one of several agents for procedural sedation. The latter scenario more often leads to respiratory depression due to the intravenous (IV) administration of BZDs and the consequent rapid rise in central nervous system concentrations.

The doses required to produce respiratory compromise are difficult to quantify and depend upon many factors, including tolerance, weight, age, coingestants, and genetics.

Patients with severe toxicity can present stuporous or comatose. One observational study found oxazepam to be the least and temazepam the most sedating BZD in intentional overdose [19]. The authors speculate that this is because temazepam is more rapidly absorbed and oxazepam more slowly absorbed than other BZDs. Another observational study found that alprazolam overdose resulted in significantly longer hospital stays, higher ICU admission rates, and a greater need for mechanical ventilation and the use of reversal agents (ie, flumazenil) [20]. These studies, while providing some information, are limited by their observational nature.

Propylene glycol poisoning — Propylene glycol (1,2 propanediol) is the diluent used in parenteral formulations of diazepam and lorazepam and the cause of a unique complication related to the prolonged parenteral administration of these BZDs. The potential effects of PG toxicity include skin and soft tissue necrosis (from extravasation), hemolysis, cardiac dysrhythmias, hypotension, lactic acidosis, seizure, coma, and multisystem organ failure.

PG toxicity is rare but may be considered when patients receiving large or continuous infusions of parenteral BZDs (eg, mechanical ventilation, severe sedative hypnotic or ethanol withdrawal syndromes, undifferentiated agitated delirium, management of chloroquine or hydroxychloroquine overdose) develop an anion gap metabolic acidosis. The osmolal gap correlates with PG concentrations and can be used as a surrogate marker of PG toxicity [21]. PG poisoning from IV BZD infusions is discussed in greater detail separately. (See "Sedative-analgesic medications in critically ill adults: Properties, dosage regimens, and adverse effects", section on 'Propylene glycol toxicity'.)

Of note, PG is also used in food, cosmetics, and oral medicines, and rare cases of poisoning from intentional ingestion have been reported.

DIFFERENTIAL DIAGNOSIS — Altered mental status, a common finding in BZD overdose, is found in a wide range of medical and toxicologic conditions (table 3 and table 4). (See "Diagnosis of delirium and confusional states" and "Evaluation of abnormal behavior in the emergency department".)

BZD overdose is usually suspected on the basis of history and the clinical scenario. Any number of sedative-hypnotic medications share clinical features with BZDs in overdose, including ethanol, barbiturates, gamma hydroxybutyrate (GHB), phenibut, and chloral hydrate. (See "Gamma hydroxybutyrate (GHB) intoxication".)

The sedative hypnotic toxidrome is characterized by a depressed mental status, an unremarkable physical examination, and normal vital signs, hence the common description "coma with normal vitals." Ethanol and phenobarbital intoxication can be assessed by obtaining serum concentrations. Patients with GHB intoxication often manifest abrupt alterations in mental status without intervention and severe respiratory depression can occur. (See "Ethanol intoxication in adults" and "Gamma hydroxybutyrate (GHB) intoxication".)

Other life-threatening causes of depressed mental status must be considered in the differential diagnosis, including hypoglycemia and carbon monoxide exposure. Stroke, meningitis and encephalitis, and head trauma can present with altered mental status and should be investigated as clinically indicated. An isolated overdose with oral BZDs rarely causes profound respiratory depression requiring invasive airway management or cardiopulmonary instability. In such cases, the presence of coingestants should be investigated. (See "Carbon monoxide poisoning" and "Overview of the evaluation of stroke" and "Clinical features and diagnosis of acute bacterial meningitis in adults" and "Viral encephalitis in adults" and "Initial management of trauma in adults".)

LABORATORY EVALUATION

Testing for benzodiazepine toxicity — Benzodiazepines (BZDs) are themselves not detected in standard urine screening tests for drugs of abuse. However, the most common BZD urine test identifies metabolites of 1,4-benzodiazepines, such as oxazepam. This test may not detect clonazepam, lorazepam, midazolam, or alprazolam. Importantly, a positive urine drug screen only indicates recent exposure; it does not confirm causality for acute symptoms, toxicity, or overdose. More specific screening tests that can detect agents not traditionally measured by standard tests may be available at some laboratories.

A number of factors, such as the amount of drug ingested, the presence of coingestants, and patient age and weight, can alter pharmacokinetics and affect urine drug tests. In general, BZD metabolites can be detected as early as three hours after ingestion and may remain detectable for up to two weeks [22]. Of note, efavirenz, a non-nucleoside reverse transcriptase inhibitor used to manage HIV infection, is well known to cause a false positive result for benzodiazepine [23].

Serum BZD concentrations are not routinely available in the emergency setting, correlate poorly with clinical findings, and do not aid management.

General diagnostic testing — Routine laboratory evaluation of the poisoned patient should include the following:

●Fingerstick glucose, to rule out hypoglycemia as the cause of any alteration in mental status

●Acetaminophen and salicylate levels, to rule out these common coingestions

●Electrocardiogram (ECG), to screen for conduction system poisoning by drugs that affect the QRS or QTc intervals

●Pregnancy test in women of childbearing age

It is reasonable to obtain a serum ethanol concentration in patients with suspected BZD overdose, given the difficulty of distinguishing between the clinical effects of BZDs and ethanol.

Clinicians should obtain additional tests based upon clinical findings. As examples, altered mental status in association with fever raises concern for meningitis or other infections and warrants a thorough evaluation, including assessment of the cerebral spinal fluid. A head computed tomography scan should be obtained if there is evidence or concern for intracranial pathology or trauma.

MANAGEMENT

Initial treatment — As with any poisoning, the management of benzodiazepine (BZD) overdose begins with a rapid assessment of the patient's airway, breathing, and circulation. Endotracheal intubation should not be delayed if warranted. Oxygen should be administered as needed, intravenous (IV) access established, and continuous cardiac monitoring employed. A fingerstick serum glucose is immediately obtained. End tidal CO₂ (ie, capnography) can be useful for monitoring patients at risk for hypoventilation, as can occur with severe benzodiazepine overdose. General discussions of the basic facets of the management of poisonings are found elsewhere. (See "General approach to drug poisoning in adults".)

In cases of isolated BZD overdose, a history, physical examination (with particular attention paid to signs of respiratory dysfunction, trauma, and poisoning from coingestants), and regular monitoring are likely to be all that is necessary. The period of observation and disposition depend upon the clinical scenario. (See 'Disposition' below.)

BZD overdose involving a coingestant, such as an opioid or ethanol, increases the risk for dangerous complications [24-26]. In patients with BZD overdose complicated by respiratory depression or failure, a concomitant opioid overdose may be present, and it is reasonable to administer appropriate doses of parenteral naloxone. Naloxone is much safer than flumazenil, which can cause seizures by precipitating acute benzodiazepine withdrawal. (See "Acute opioid intoxication in adults", section on 'Basic measures and antidotal therapy' and 'Antidote (flumazenil)' below.)

Decontamination — Gastrointestinal decontamination with activated charcoal (AC) is usually of NO benefit in cases of isolated BZD ingestion and increases the risk of aspiration. We suggest that patients with BZD overdose NOT be treated with AC, unless a life-threatening coingestant amenable to treatment with charcoal is suspected and the patient's airway is protected (naturally or with a cuffed endotracheal tube).

Whole bowel irrigation is generally unnecessary because of the rarity of sustained release preparations and the difficulty of initiating treatment in the obtunded patient. Neither multidose activated charcoal nor hemodialysis is effective as an enhanced elimination technique.

Antidote (flumazenil) — Flumazenil is a nonspecific competitive antagonist of the BZD receptor. It can be used to reverse BZD-induced sedation following general anesthesia, procedural sedation, or overdose [27,28]. However, the use of flumazenil in the setting of overdose remains highly controversial. Administration of flumazenil can precipitate withdrawal seizures in patients who have developed a tolerance to BZDs through chronic use or abuse. Such risks may be further increased if the patient has taken coingestants with proconvulsant properties [27-29].

Young children are more susceptible to respiratory depression from BZDs and less likely to be tolerant of these medications. Thus, the contraindications for flumazenil reversal are of less concern in the pediatric population, and flumazenil may be used if deemed necessary. However, it is uncommon for an isolated ingestion to lead to a need for reversal. The need for flumazenil is more common following iatrogenic complications, such as oversedation during a procedure. Of note, flumazenil does not consistently reverse respiratory depression caused by BZD overdose [30].

Because oral BZD overdose has a low rate of morbidity and mortality is rare, the risks of flumazenil treatment often outweigh its benefits. The purported benefit of flumazenil is to avoid the need for procedures, such as endotracheal intubation, CT imaging, and lumbar puncture, should the patient's mental status return to normal when the BZD's sedative effects are reversed. We suggest consultation with a medical toxicologist or poison control center whenever the use of flumazenil is contemplated. (See 'Additional resources' below.)

Flumazenil appears to be safe and effective when used to reverse the sedating effects of a BZD given for procedural sedation in patients who do not use BZDs chronically. In adults, the recommended initial dose is 0.2 mg IV given by slow push over one to two minutes. Repeated doses of 0.2 mg, to a maximum dose of 1 mg, can be given until the desired effect is achieved [31]. In the event of resedation, the dosing regimen described here can be repeated, but no more than 3 mg of flumazenil should be given within any one hour.

In children, the initial dose is 0.01 mg/kg given by slow IV push over one to two minutes (maximum dose 0.2 mg). The initial dose may be followed at one-minute (or longer) intervals with up to four repeat doses of 0.005 to 0.01 mg/kg (maximum 0.2 mg) per dose. The maximum dose should NOT exceed 1 mg total or 0.05 mg/kg; the lower dose is preferable.

The peak effect of a single flumazenil dose occurs approximately 6 to 10 minutes after IV administration. For patients at greater risk of seizure or agitation with BZD reversal, a longer wait of several minutes between subsequent doses may be warranted.

The duration of flumazenil is short (0.7 to 1.3 hours) and the duration of effect of a long-acting BZD or a large BZD dose can exceed that of flumazenil. Resedation may be treated in adults by using 0.2 mg doses (maximum total dose 1 mg) until the desired effect is achieved. For patients with exposures to BZDs with prolonged durations of action or those with hepatic insufficiency with prolonged exposure to BZDs, a continuous flumazenil infusion (0.25 to 1 mg per hour) may be needed [32,33]. Again, we suggest consultation with a medical toxicologist or poison control center whenever a flumazenil infusion is thought to be necessary.

Disposition — Patients who require mechanical ventilation or have been exposed to a dangerous coingestant are admitted to a critical care setting.

Most patients with an isolated BZD ingestion can be safely discharged or cleared for psychiatric evaluation following an observation period of four to six hours, provided that any concerning symptoms, such as CNS depression, have resolved. The patient should be able to ambulate safely by the end of this period. Patients with persistent signs of intoxication beyond six hours should be admitted to a monitored setting until symptoms resolve.

WITHDRAWAL

Mechanism, signs, and prevention — Any abrupt or overly rapid reduction in benzodiazepine (BZD) dose among chronic users can produce withdrawal. Rapid recognition and treatment of BZD withdrawal is crucial because the syndrome can be life-threatening. The symptoms and signs of BZD withdrawal can include any of the following [34]:

●Tremors

●Anxiety

●Perceptual disturbances

●Dysphoria

●Psychosis

●Seizures

●Autonomic instability

The occurrence and time of BZD withdrawal symptoms are related in part to the pharmacologic properties of the drug, dose, duration of use, and abruptness of discontinuation [35]. In general, heavier use of BZD over a longer period increases the risk for withdrawal. However, there is no known set dose or duration of use that increases the risk of withdrawal in tolerant patients.

The onset of withdrawal can vary according to the half-life of the BZD involved. Symptoms may be delayed up to three weeks in BZDs with long half-lives, but may appear as early as 24 to 48 hours after cessation of BZDs with short half-lives. The severity and duration of withdrawal is determined by many factors, including the period of BZD use, how rapidly use was tapered (if at all), the pharmacokinetics of the particular drug, as well as possible genetic factors [36,37]. Although the onset and duration of withdrawal symptoms can vary widely based on these variables, most patients experience symptoms that last from one to two weeks, although there is a small subset that can experience prolonged symptoms [38,39].

Chronic ingestion of BZDs leads to conformational changes in the GABA receptor, which ultimately reduce the receptor's affinity for the agent and result in decreased GABA activity [34]. This decreased activity manifests as tolerance to the agent. When BZDs are no longer present or present at lower concentrations, this decreased GABA receptor activity has less inhibition of excitatory neurotransmitters, and thus, there is a pro-excitatory state.

Withdrawal can usually be avoided or minimized through the use of BZDs with a long half-life, such as diazepam or chlordiazepoxide, and a gradual tapering of the patient's BZD dose over several months, depending upon the dosage and degree of dependency.

Treatment — BZD withdrawal is treated with a BZD that has a prolonged clinical effect, such as diazepam, given intravenously (IV) and titrated to effect. The goal is to eliminate withdrawal symptoms without causing excessive sedation or respiratory depression. Once symptoms are controlled, the BZD dose should then be tapered gradually over a period of months [40-43]. BZD therapy should be used cautiously in patients with obstructive sleep apnea, although in cases of withdrawal, benefit may outweigh risk. (See "Management of obstructive sleep apnea in adults", section on 'Concomitant medications'.)

For patients in mild BZD withdrawal, a long-acting oral BZD may be given; it is also reasonable to give such a patient the BZD that they had been using chronically.

Numerous studies have investigated a range of medications to treat BZD withdrawal, but none has been found to be as effective as BZDs themselves [43-45]. Beta receptor antagonists, antipsychotics, gabapentin and other gabapentinoids, selective serotonin reuptake inhibitors, and antihistamines have all been shown to be inferior to standard treatment [40,43]. Although no controlled trials have assessed valproic acid in the treatment of BZD withdrawal, a systematic review of valproic acid for the management of alcohol withdrawal found no benefit [46]. Another systematic review identified one trial in which carbamazepine showed a trend toward benefit in BZD withdrawal, but this was in patients already receiving BZD therapy [47,48]. A 2018 systematic review of 38 trials noted a high risk of bias in all but one study and concluded that it is not possible to draw firm conclusions regarding pharmacologic interventions to facilitate BZD discontinuation in chronic BZD users [45]. Pending further study, treatments other than BZDs cannot be recommended for the management of BZD withdrawal.

ADDITIONAL RESOURCES — Regional poison control centers in the United States are available at all times for consultation on patients who are critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have clinical and/or medical toxicologists available for bedside consultation and/or inpatient care. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is available at the website in the following reference [49].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: General measures for acute poisoning treatment" and "Society guideline links: Benzodiazepine use disorder and withdrawal" and "Society guideline links: Treatment of acute poisoning caused by recreational drug or alcohol use".)

SUMMARY AND RECOMMENDATIONS

●Benzodiazepines (BZD) are widely prescribed and commonly involved in cases of drug overdose and substance abuse. They are commonly categorized by half-life duration (table 1). (See 'Pharmacology and cellular toxicity' above and 'Kinetics' above.)

●Oral BZDs taken in overdose without a coingestant rarely cause significant toxicity. The classic presentation of a patient with an isolated BZD overdose consists of CNS depression with normal vital signs. Severe overdose can cause respiratory depression and stupor or coma. Coingestants are common in cases of overdose. (See 'Clinical features of overdose' above.)

●Propylene glycol (1,2 propanediol), the diluent used in parenteral formulations of diazepam and lorazepam, is the cause of a unique and rare complication related to prolonged parenteral administration of BZDs. Potential adverse effects include hemolysis, cardiac dysrhythmias, hypotension, anion gap metabolic acidosis with hyperlactatemia, seizure, coma, and multisystem organ failure.

●Altered mental status, a common finding in BZD overdose, is found in a wide range of medical and toxicologic conditions (table 3 and table 4). Life-threatening causes of depressed mental status include hypoglycemia, carbon monoxide poisoning, stroke, meningitis and encephalitis, and head trauma. (See 'Differential diagnosis' above.)

●Many BZDs are not detected in standard urine screening tests for drugs of abuse. However, the most common BZD urine test identifies metabolites of 1,4-benzodiazepines, such as oxazepam. This test may not detect clonazepam, lorazepam, midazolam, or alprazolam. The need for further testing is discussed in the text. (See 'Laboratory evaluation' above and "Testing for drugs of abuse (DOAs)".)

●Most cases of isolated BZD ingestion are managed successfully with supportive care alone. Gastrointestinal decontamination with activated charcoal (AC) is usually of NO benefit and increases the risk of aspiration. (See 'Management' above.)

●Flumazenil is a nonspecific competitive antagonist of the BZD receptor. It can be used to reverse BZD-induced sedation following general anesthesia, procedural sedation, or overdose. Administration of flumazenil can precipitate withdrawal seizures in patients who have developed a tolerance to BZDs. Therefore, the use of flumazenil in the setting of overdose remains highly controversial. We suggest consultation with a medical toxicologist or poison control center whenever the use of flumazenil is contemplated. (See 'Antidote (flumazenil)' above.)

●Any abrupt or overly rapid reduction in BZD dose among chronic users can produce withdrawal. Rapid recognition and treatment of BZD withdrawal is crucial because the syndrome can be life-threatening. Symptoms and signs can include tremors, anxiety, perceptual disturbances, dysphoria, psychosis, and seizures. BZD withdrawal is treated with a BZD that has a prolonged clinical effect (eg, diazepam) given intravenously (IV) and titrated to effect. (See 'Withdrawal' above.)