INTRODUCTION — Benzodiazepines (BZDs) are sedative-hypnotic agents that have been in clinical use since the 1960s. BZDs are safer than older sedative-hypnotic agents, such as barbiturates, and thus are commonly used for sedation and to treat anxiety, seizures, withdrawal states, insomnia, and agitation. They are also frequently combined with other medications for procedural sedation. Due to their many uses and wide therapeutic index, 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]. BZDs are also commonly misused and diverted. The pediatric rate of misuse, severity of outcomes, and presence of co-ingestants have steadily increased since 2000, especially in adolescents [5]. Alprazolam, clonazepam, and lorazepam are the most commonly misused BZDs by both adolescents and adults.
The diagnosis and management of acute BZD poisoning and withdrawal 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".)
●(See "Initial management of the critically ill adult with an unknown overdose".)
●(See "Ethanol intoxication in adults".)
●(See "Acute opioid intoxication in adults".)
●(See "Gamma hydroxybutyrate (GHB) intoxication".)
●(See "Stupor and coma in adults".)
PHARMACOLOGY — 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. BZDs 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].
PHARMACOKINETICS
●Absorption/distribution - BZDs are rapidly absorbed in the gastrointestinal tract, and most are highly lipophilic and highly protein bound.
●Metabolism/elimination - BZDs are primarily hepatically metabolized, most by the CYP2C19 and CYP3A4 enzymes. Alprazolam and midazolam are metabolized by CYP3A4. Diazepam is metabolized by both CYP3A4 and CYP2C19. Oxazepam, temazepam, and lorazepam are directly conjugated to an inactive, water-soluble glucuronide metabolite that is excreted by the kidney [12,13]. Chlordiazepoxide, diazepam, and flurazepam are metabolized to active metabolites, which are then conjugated and excreted [12].
BZDs are commonly divided into three groups based upon elimination 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) BZDs (table 1).
Short-acting BZDs, such as triazolam, alprazolam, and midazolam, generally have few active metabolites, do not accumulate with repeated doses, and demonstrate clearance that is largely unaffected by age and liver disease. Midazolam has a short half-life, very rapid onset of clinical effect, and a shorter duration of action than other BZDs, which explains its preferential use in procedural sedation [14]. However, successive doses of midazolam lead to bioaccumulation of its hydroxy-metabolites and may prolong the drug's sedative effects [15]. (See "Procedural sedation in adults outside of the operating room: General considerations, preparation, monitoring, and mitigating complications".)
Long-acting BZDs, such as diazepam and chlordiazepoxide, generally have pharmacologically active metabolites, accumulate in tissues after multiple doses, and demonstrate impaired clearance in older patients and those with liver disease. [16-18]. 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.
●Drug interactions – Drugs that are metabolized by CYP450 enzymes can interact with BZDs, potentially prolonging or decreasing their clinical effects [16-18]. Examples of common drugs that inhibit the CYP3A4 enzyme and reduce the metabolism of BZDs, thereby prolonging their effects, are shown in the table (table 2). Since oxazepam, temazepam, and lorazepam do not undergo hepatic metabolism, they are less likely to be affected by CYP450 interactions [14,15].
CLINICAL FEATURES OF OVERDOSE
Sedation — The classic presentation of a patient with an isolated BZD overdose consists of central nervous system depression with unremarkable vital signs ("coma with normal vitals"). Many patients are arousable and able to provide an adequate history. Other signs include slurred speech, nystagmus, and ataxia.
Respiratory compromise is uncommon with isolated oral ingestions; however, many intentional BZD ingestions involve a co-ingestant, commonly ethanol [19]. BZD overdose involving a co-ingestant, such as an opioid or ethanol, increases the risk for dangerous complications such as synergistic respiratory depression [20-22].
Ataxia — In young children (five years old and younger), ataxia has been described as the most common sign of BZD toxicity, even more prevalent than central nervous system depression. Children can also present with isolated ataxia without somnolence [23].
Respiratory depression — Respiratory compromise may develop when an additional sedative hypnotic agent (such as ethanol) or opioid is a co-ingestant, or when clinicians administer intravenous (IV) BZDs as one of several agents for procedural sedation. Patients typically are comatose and are unable to protect their airway. Respiratory depression clearly occurs after IV administration due to a rapid rise in central nervous system concentrations leading to greater clinical effects [24].
The doses required to produce respiratory compromise are difficult to predict and depend upon many factors, including tolerance, weight, age, co-ingestants, and genetics. (See "Procedural sedation in adults outside of the operating room: General considerations, preparation, monitoring, and mitigating complications".)
Parenteral diluent toxicity — Propylene glycol toxicity can occur in patients receiving prolonged parenteral administration of diazepam or lorazepam, which contain propylene glycol (1,2 propanediol) as a diluent. The classic toxicity is an elevated anion gap metabolic acidosis with elevated lactate; other potential effects are skin and soft tissue necrosis (from extravasation), hemolysis, cardiac dysrhythmias, hypotension, seizure, coma, and multisystem organ failure.
An elevated osmolal gap correlates with elevated propylene glycol concentrations and can be used as a surrogate marker of toxicity [25]. Propylene glycol poisoning from IV BZD infusions is discussed in greater detail separately. (See "Sedative-analgesic medications in critically ill adults: Properties, dose regimens, and adverse effects", section on 'Propylene glycol toxicity'.)
DIAGNOSIS
Confirmed by history — BZD poisoning is a clinical diagnosis and usually suspected on the basis of clear corroborating history in a sedated patient. The diagnosis can be made in the following circumstances that support the history, although this is not an exhaustive list:
●Patient admits to a BZD ingestion
●The BZD ingestion was witnessed
●A recently filled empty bottle of BZD pills is found near the patient
●The patient left a suicide note
●Parents noticed pill fragments in a young child's mouth
Suspected but not confirmed — In the absence of clear corroborating history, BZD poisoning should be considered a diagnosis of exclusion. Non-toxicologic and other toxicologic etiologies must be ruled out, especially conditions in which diagnostic delay will hold up critical interventions and definitive care. (See 'Differential diagnosis' below.)
A positive urine BZD test result is not diagnostic because it only confirms BZD use at some point in the recent past and not poisoning or etiology of the altered mental status. A negative urine BZD result does not exclude the diagnosis as these tests are not sensitive for all BZDs.
We do not routinely administer the antidote flumazenil to establish the diagnosis when BZD poisoning is strongly considered to be the etiology of the patient's mental status and instead prefer to rule out other etiologies and observe the patient for clinical improvement. However, in young children (ie, five years old and younger) with altered mental status suspected from a BZD ingestion, we would administer flumazenil to aid in confirming the diagnosis. (See 'Commonly accepted indications' below.) If the child's mental status or neurologic impairment, such as ataxia, resolves after flumazenil administration, this confirms the diagnosis and avoids an extensive and potentially invasive evaluation.
Other experts have broader indications in adults for use of flumazenil to aid in confirming BZD ingestion as the etiology of a patient's altered mental status (see 'Controversial indications' below). If the patient's lethargy improves after flumazenil administration, this confirms that a BZD contributed to the altered mental status but does not necessarily exclude co-ingestions, other neurologic issues, or comorbid conditions. It may provide an opportunity to obtain further history from the patient and confirm if a BZD ingestion contributed to the altered mental status.
GENERAL DIAGNOSTIC TESTING
Overview — Routine laboratory and diagnostic testing of the patient with sedation, including when a BZD ingestion is suspected, is aimed at excluding other diagnoses and includes:
●Fingerstick blood glucose to rule out hypoglycemia as the cause of altered mental status
●Serum acetaminophen, salicylate, and ethanol concentrations to rule out these common co-ingestions
●Electrocardiogram (ECG) to screen for poisoning by drugs that affect the QRS or QTc intervals
●Pregnancy test in females of childbearing age
Urine and serum BZD testing have limited utility due to test characteristics. (See 'Role of laboratory benzodiazepine testing' below.)
Additional tests are obtained based upon historical and clinical findings. (See 'Differential diagnosis' below.)
Role of laboratory benzodiazepine testing — Despite widespread use of urine drug screens that include BZDs, laboratory testing has limited value and rarely changes management, similar to testing for other drug use. (See "Testing for drugs of abuse (DOAs)", section on 'Indications: When is a DOA screen useful (or not)?'.)
Urine testing — Most hospital clinical laboratories only have access to qualitative urine BZD screens, which are immunoassays that have poor sensitivity and specificity for identification of a BZD. A positive urine BZD drug screen only indicates recent exposure; it does not confirm causality for acute symptoms, toxicity, or overdose. The most common BZD urine test identifies metabolites of 1,4-BZDs such as oxazepam. This test may not detect commonly encountered BZDs such as clonazepam, lorazepam, midazolam, or alprazolam. More specific screening tests that can detect agents not traditionally measured by common immunoassays may be available at some laboratories.
A number of factors, such as the amount of drug ingested, the presence of co-ingestants, 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 [26]. Of note, efavirenz (a non-nucleoside reverse transcriptase inhibitor used to manage human immunodeficiency virus [HIV] infection) as well as sertraline may cause a false-positive result for BZDs on many urine immunoassays [27].
Serum testing — Serum BZD concentrations are not routinely available in the emergency setting, correlate poorly with clinical findings, do not aid in the acute management, and have long turn-around times. Serum concentrations may be helpful confirmatory forensic tests (eg, a patient who denies ingestion after sedation has improved and BZD poisoning is strongly suspected).
DIFFERENTIAL DIAGNOSIS — The sedative-hypnotic toxidrome is characterized by a physical examination only remarkable for a depressed mental status and unremarkable vital signs (hence the common description "coma with normal vitals"). In any suspected ingestion when the patient cannot provide a history, an exploration of alternative sources of information is warranted, including but not exclusive to emergency medical services, family members, pill bottles if available, medical records, and pharmacy information. Other common ingestions that present similar to BZD poisoning include:
●Ethanol and phenobarbital intoxication, which can be assessed by obtaining serum concentrations. (See "Ethanol intoxication in adults".)
●Gamma hydroxybutyrate (GHB) intoxication, which often manifests severe central nervous system depression followed by abrupt awakening. GHB intoxication is difficult to distinguish from other causes of obtundation without a clear history. (See "Gamma hydroxybutyrate (GHB) intoxication".)
●Atypical antipsychotic agents (eg, quetiapine), which are commonly misused and intentionally ingested, can cause sedation as well as tachycardia and anticholinergic delirium. (See "Second-generation (atypical) antipsychotic medication poisoning" and "Anticholinergic poisoning".)
●Gabapentin, zolpidem, zopiclone, and trazodone are examples of commonly misused sedatives that can only be excluded by history.
●Etizolam (also called "tizzies" or "street vallies"), a commonly misused BZD-like sedative that binds to the BZD receptor, is available by prescription in Japan and India and has been implicated in causing fatal respiratory depression when combined with opioids [28,29]. Etizolam intoxication is difficult to distinguish from other causes of obtundation without a clear history and is not detected on routine urine BZD screens.
●Novel commonly misused BZDs include clonazolam, bromazolam, flubromazolam, bromazepam, flubromazepam, and flualprazolam [30-32]. Identification of these agents requires sophisticated analytical testing that is not available in most hospital laboratories.
Sedation (table 3) and delirium (table 4 and table 5), common findings in BZD overdose, are found in a wide range of medical and toxicologic conditions. The approach to patients with these symptoms is reviewed in detail separately (see "Diagnosis of delirium and confusional states" and "Evaluation of abnormal behavior in the emergency department"). As a synopsis, unless the diagnosis of BZD toxicity is obvious, other life-threatening non-toxicologic causes must be considered in the differential diagnosis:
●Hypoglycemia must be excluded in every patient with altered mental status, even if BZD poisoning is suspected.
●In patients with profound respiratory depression or cardiopulmonary instability, which is rare with isolated BZD overdoses, the presence of co-ingestants or non-toxicologic etiologies should be investigated.
●Altered mental status in association with fever or leukocytosis raises concern for meningitis or other infections and warrants a thorough evaluation, often including assessment of the cerebral spinal fluid. (See "Clinical features and diagnosis of acute bacterial meningitis in adults" and "Viral encephalitis in adults".)
●Any focal neurologic findings or seizures raise concern for a central nervous system process such as stroke, intracranial hemorrhage, or encephalitis. (See "Overview of the evaluation of stroke".)
●A history of trauma or clinical findings of injuries should prompt obtaining a head computed tomography (CT) scan. (See "Initial management of trauma in adults".)
MANAGEMENT
Address airway, breathing, and circulation — As with any poisoning or potentially critically ill patient, the initial treatment begins with rapidly assessing and addressing the patient's airway, breathing, and circulation. Administer naloxone to a patient with altered mental status and concern for signs or symptoms of an opioid exposure (eg, respiratory depression). (See "General approach to drug poisoning in adults" and "Acute opioid intoxication in adults", section on 'Basic measures and antidotal therapy'.)
In patients who present with anything more than trivial sedation, we suggest establishing intravenous (IV) access and continuous cardiac monitoring. End tidal carbon dioxide (EtCO2; ie, capnography) is useful for monitoring patients at risk for hypoventilation. Oxygen should be administered as needed. Placing a nasopharyngeal airway (ie, nasal trumpet) may be sufficient to overcome upper airway obstruction from central nervous system depression and preclude the need for endotracheal intubation. (See "Basic airway management in adults", section on 'Nasopharyngeal airway'.)
●Respiratory depression – We suggest a trial of parenteral or intranasal naloxone in patients with confirmed or suspected BZD overdose complicated by respiratory depression or failure. Naloxone is used to treat an alternative etiology of respiratory depression that may be quickly and safely reversed (eg, opioid co-ingestion).
If there is no clinical improvement after naloxone, we do not routinely use flumazenil and prefer to proceed with definitive airway management. However, some experts will administer flumazenil in patients deemed to be at low risk for precipitating BZD withdrawal or seizures in an attempt to prevent endotracheal intubation. (See "Acute opioid intoxication in adults", section on 'Basic measures and antidotal therapy' and 'Controversial indications' below.)
The decision to perform endotracheal intubation for airway protection and respiratory support is similar to any other critically ill patients after naloxone and/or flumazenil has been either tried or excluded.
Role of decontamination — We suggest not performing routine gastrointestinal decontamination with activated charcoal (AC) in patients with isolated BZD ingestion since intoxication will often improve with supportive care and metabolism of the BZD. Administering AC provides no additional benefits but can increase the risk of aspiration and complicate airway management if the patient becomes more sedated. (See "Gastrointestinal decontamination of the poisoned patient", section on 'Activated charcoal'.)
However, AC may be beneficial in selected patients, such as those with a history or suspicion of a life-threatening co-ingestion that AC will adsorb to (eg, colchicine, aspirin, etc) and a protected airway (naturally or with a cuffed endotracheal tube). AC is administered orally or via gastric tube at a dose of 1 g/kg.
Whole-bowel irrigation is generally unnecessary because of the rarity of sustained-release preparations and, if administered, should also be in a patient with a protected airway to prevent aspiration.
Role of antidote (flumazenil)
Clinical scenarios
Commonly accepted indications — We use flumazenil, a nonspecific competitive antagonist of the BZD receptor, to reverse BZD sedation in the following clinical scenarios:
●Reverse procedural sedation in patients who do not use BZDs chronically (see "Procedural sedation in adults outside of the operating room: General considerations, preparation, monitoring, and mitigating complications", section on 'Anticipating and mitigating Complications')
●Young children with an isolated BZD ingestion with severe central nervous system depression or isolated ataxia, except those who take BZDs for a seizure disorder or with iatrogenic BZD toxicity from treatment of status epilepticus (see 'Use in young children' below)
Controversial indications — Some experts use flumazenil in the following select scenarios, although we would not administer flumazenil given the controversy around precipitating BZD withdrawal and seizures (see 'Precipitated BZD withdrawal or seizures' below):
●A patient with suspected but unconfirmed BZD ingestion, no concern for proconvulsant co-ingestion (eg, tricyclic antidepressant [TCA], bupropion), and not having a witnessed or suspected seizure. Since the patient typically is unable to provide a history, the clinician should exclude availability of proconvulsant medication from other sources such as asking family members, consulting electronic medical records, or contacting the patient's pharmacy. In this setting, flumazenil administration may avoid extensive and invasive testing.
●A patient with confirmed BZD ingestion, no proconvulsant co-ingestion (eg, TCA, bupropion), and no witnessed or suspected seizure who has respiratory depression or is not protecting their airway. Flumazenil in this setting can improve respiratory drive and airway tone and avoid endotracheal intubation.
Contraindications — All experts agree that flumazenil should not be administered in the following clinical scenarios:
●As part of "coma cocktail" routinely in all patients with undifferentiated obtundation [33]
●Altered mental status with a witnessed or suspected seizure
●Any suspicion for proconvulsant co-ingestion (eg, TCA, bupropion)
●Patient taking a BZD for a seizure disorder
●Iatrogenic BZD overdose caused by treatment of status epilepticus
Adult dosing
●Patients without BZD tolerance and no history of seizure disorder – In adults, the initial flumazenil dose is 0.2 mg IV given by slow push over one to two minutes. A response is expected in two to five minutes with peak effect at approximately 6 to 10 minutes after dosing.
Subsequent doses are 0.3 mg and 0.5 mg IV every one to two minutes to an initial cumulative maximum dose of 1 mg or until the desired effect is achieved [34].
●BZD-tolerant patient or history of seizure disorder – We do not administer flumazenil to patients who take BZDs chronically or have a history of a seizure disorder. However, experts who use flumazenil in these patients will lower the starting dose to 0.1 mg IV to decrease the chance of precipitating BZD withdrawal.
Subsequent doses are 0.2 mg, 0.3 mg, and 0.5 mg IV at intervals of 10 to 15 minutes, titrated to desired effect. The time interval is increased because these patients are at greater risk of precipitated seizure or agitation with BZD reversal.
●Resedation after flumazenil – Flumazenil's plasma elimination half-life is short (0.7 to 1.3 hours); thus, the duration of effect of a long-acting BZD or a large BZD overdose can exceed that of flumazenil. In the event of resedation, repeat the dosing regimen described above until the desired effect is achieved, but no more than 3 mg of flumazenil should be given within any one hour.
A continuous flumazenil infusion (0.25 to 1 mg per hour) is an option for patients with exposures to BZDs with prolonged durations of action or those with hepatic insufficiency with prolonged exposure to BZDs [35,36]. However, we suggest using either intermittent dosing or consulting a medical toxicologist or poison control center whenever a flumazenil infusion is thought to be needed given increased risk of adverse effects from a continuous infusion.
Use in young children — Flumazenil is less likely to cause complications in young children (ie, five years old and younger) as compared with adults because children do not commonly take BZDs chronically. The concern for precipitated seizures is based on adult data; limited evidence suggests that previously healthy children may be less likely to have a seizure after flumazenil administration [37]. Regardless, flumazenil should not be given to a child who takes BZDs for a seizure disorder or with iatrogenic BZD overdose caused by treatment of status epilepticus. Young children (two years old and younger) are also more susceptible to respiratory depression from BZDs [23]. Flumazenil, given as a diagnostic challenge, has been reported to reverse isolated ataxia when the history of BZD ingestion in a child was uncertain [38]. This may prevent an extensive neurologic workup. Flumazenil should be administered in cases where oversedation occurs during procedural sedation using IV BZD. Of note, flumazenil does not consistently reverse respiratory depression caused by BZD overdose [39].
●Dosing – 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). Repeat the initial dose 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 or until the desired effect is achieved. The maximum dose should not exceed 1 mg total or 0.05 mg/kg; the lower dose is preferable.
Precipitated BZD withdrawal or seizures — The use of flumazenil in a patient with undifferentiated altered mental status remains controversial among experts. Administration of flumazenil can precipitate withdrawal symptoms or seizures in patients who have developed a tolerance to BZDs, have a seizure disorder, have a proconvulsive co-ingestant (eg, TCA), or are receiving BZDs for control of increased intracranial pressure or status epilepticus [40-42]. Given the controversies, we suggest consultation with a medical toxicologist or poison control center if contemplating but uncomfortable using flumazenil. (See 'Additional resources' below.)
A meta-analysis of 13 trials of flumazenil for adult patients with impaired consciousness due to a suspected or known BZD ingestion (either as a single drug or as part of a multi-drug intoxication) included 994 patients (498 received flumazenil); adverse events were more frequent with flumazenil (25 versus 9 percent), as were serious adverse events (2.4 versus 0.4 percent). Most of the adverse events were transient and mild, including agitation, anxiety, and gastrointestinal symptoms. Out of the 12 serious events in the flumazenil group, seven were narrow complex tachycardia, one was multiple ventricular beats, and one was a fall in blood pressure, none of which were life threatening. There were three seizures, but these were related to proconvulsant co-ingestions [43].
●Argument against flumazenil use – Oral BZD overdose has a low rate of morbidity and mortality, so the risks of flumazenil treatment are felt to outweigh the benefits of earlier arousal. Furthermore, resedation is likely. The patient with a confirmed isolated oral BZD ingestion is not expected to need airway management and will improve with general supportive care and metabolism of the inciting agent. Additionally, in a sedated patient, the clinician can never be completely certain that the patient did not have a proconvulsant co-ingestion, a seizure, an underlying seizure disorder, or a tolerance to BZDs. In trials, the rate of adverse events from flumazenil is relatively high, and the trials did not follow subjects for sufficient duration to evaluate clinical outcomes such as hospital length of stay, time on ventilator, or aspiration pneumonia.
The routine use of flumazenil as part of the "coma cocktail" (ie, medications routinely given to unresponsive patients) has been discouraged due to risks of precipitating seizures or BZD withdrawal in the BZD-tolerant patient or patient with a seizure disorder [33]. Instead, aggressive airway control and respiratory support is preferred.
●Argument supporting flumazenil use – If the etiology of sedation (or ataxia in a child) is not clearly from a BZD ingestion, the clinician must exclude non-toxicologic etiologies that may need specific treatment. In this case, the purported benefit of flumazenil is to avoid the need for procedures, such as endotracheal intubation, neurologic imaging, and lumbar puncture, if a history can be obtained should the patient's mental status or neurologic impairment return to baseline with reversal of the BZD's sedative effects. In one trial, there was a 27 percent decreased need for intubation with flumazenil compared with placebo [44].
Some experts believe the perceived risk of precipitated BZD withdrawal from flumazenil is overstated and that it is safe to use flumazenil in an obtunded patient with a suspected overdose that does not involve a proconvulsant ingestion, even if the patient is known to have a seizure disorder or use a BZD chronically (although these groups have an increased risk of precipitated BZD withdrawal). Seizure activity was not demonstrated in multiple trials when flumazenil was administered for BZD overdose or for coma from suspected poisoning [36,44-47]. In other studies, the vast majority of patients who had a seizure after flumazenil also had a proconvulsant co-ingestion (specifically TCA) [48-50]. In these trials, even though the rate of adverse events related to precipitated BZD withdrawal from flumazenil was relatively high, these events were mostly agitation, anxiety, and gastrointestinal distress; they were not clinically significant nor difficult to manage.
Managing adverse effects — In the unlikely scenario of a flumazenil-precipitated sustained seizure, we suggest administering a BZD dose in the upper normal range, phenobarbital, or propofol. Despite concerns that flumazenil precipitated seizure, agitation or withdrawal will be difficult to treat due to gamma-aminobutyric acid A (GABA-A) antagonism, flumazenil is a competitive antagonist at the GABA-A receptor, and only 50 percent of the BZD binding sites are occupied by flumazenil after a 1 mg cumulative dose. Therefore, any adverse effects from flumazenil can be overcome by either routine or slightly increased BZD dosing.
Additionally, flumazenil only binds the BZD site on the GABA-A receptor, which possesses distinct barbiturate and propofol binding sites that also potentiate gamma-aminobutyric acid (GABA) activity. Therefore, any difficult-to-treat seizures can be controlled with phenobarbital or propofol administration [39,51].
Supportive care — In cases of isolated BZD overdose, routine supportive care and monitoring is typically all that is necessary. The period of observation and disposition depend upon the clinical scenario. Supportive care is described in more detail separately. (See "General approach to drug poisoning in adults", section on 'Supportive care'.)
No role for enhanced elimination — There are no effective techniques to enhance BZD elimination. Forced IV diuresis, multidose AC, and hemodialysis are ineffective at increasing BZD elimination.
Disposition — Patients who require mechanical ventilation or have been exposed to a dangerous co-ingestant 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 central nervous system 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.
BENZODIAZEPINE WITHDRAWAL — Chronic use of BZDs results in development of tolerance. Any abrupt or overly rapid reduction in BZD dose can produce withdrawal, a potentially life-threatening pro-excitatory state if not recognized and treated.
Mechanism — Chronic use of BZDs leads to conformational changes in the gamma-aminobutyric acid (GABA) receptor, which ultimately reduces the receptor's affinity for the agent, resulting in decreased GABA activity and physiologic tolerance to the agent [52]. When BZDs are no longer present or present at lower concentrations, this decreased GABA receptor activity has less inhibition of excitatory neurotransmitters, resulting in a pro-excitatory state.
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 [53]. In general, larger 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.
Clinical features — The symptoms and signs of BZD withdrawal are typical of a pro-excitatory sedative-hypnotic withdrawal syndrome and can include any of the following [52]:
●Tremors
●Anxiety
●Perceptual disturbances
●Dysphoria
●Psychosis
●Seizures
●Autonomic instability
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, and possible genetic factors [54,55]. 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, and there is a small subset that can experience prolonged symptoms [56,57].
Prevention — 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 tolerance.
Treatment
●Mild withdrawal – In patients with mild BZD withdrawal who can tolerate oral agents, 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 at their previous dose.
●Moderate/severe withdrawal – In patients with more significant withdrawal symptoms, administer 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 [58-61]. 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 'Alcohol avoidance'.)
●Alternative medications – Numerous studies have investigated a range of medications to treat BZD withdrawal, but none has been found to be as effective as BZDs themselves [61-63]. Beta receptor antagonists, antipsychotics, gabapentin and other gabapentinoids, selective serotonin reuptake inhibitors, and antihistamines have all been shown to be inferior to standard treatment [58,61]. A 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 [64]. Another systematic review of 38 trials noted a high risk of bias in all but one trial and concluded that it is not possible to draw firm conclusions regarding pharmacologic interventions to facilitate BZD discontinuation in chronic BZD users [63]. Pending further study, treatments other than BZDs cannot be recommended for the management of BZD withdrawal.
ADDITIONAL RESOURCES
Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. 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 provided separately. (See "Society guideline links: Regional poison control centers".)
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
●Pharmacology – Benzodiazepines (BZD) (table 1) exert their effect via potentiation of the inhibitory activity of the gamma-aminobutyric acid A (GABA-A) receptor. Gamma-aminobutyric acid (GABA) is the chief inhibitory neurotransmitter of the central nervous system. (See 'Pharmacology' above.)
●Clinical features of overdose – Oral BZDs taken in overdose without a co-ingestant rarely cause significant toxicity. The classic presentation of a patient with an isolated BZD overdose consists of central nervous system depression with normal vital signs. Massive overdose, sedative co-ingestant (eg. opioids, ethanol), or intravenous (IV) administration can cause respiratory depression and stupor or coma. (See 'Clinical features of overdose' above.)
●Diagnosis – The definitive diagnosis of BZD poisoning is made on the basis of history and corroborating data in a sedated patient. In the absence of clear corroborating history, BZD poisoning should be considered a diagnosis of exclusion. (See 'Diagnosis' above.)
●Laboratory BZD testing – BZD urine screens have poor sensitivity and specificity for BZD toxicity. A positive urine BZD drug screen only indicates recent exposure and does not confirm causality for acute symptoms, toxicity, or overdose. A negative urine screen does not rule out BZD toxicity since common urine tests identify metabolites of 1,4-BZDs, such as oxazepam, and may not detect clonazepam, lorazepam, midazolam, or alprazolam. (See 'Role of laboratory benzodiazepine testing' above and "Testing for drugs of abuse (DOAs)".)
●Differential diagnosis – Sedation (table 3) and delirium (table 4 and table 5), common findings in BZD overdose, are found in a wide range of medical and toxicologic conditions. Unless the diagnosis of BZD toxicity is obvious, other life-threatening non-toxicologic causes must be excluded, especially conditions in which diagnostic delay will hold up critical interventions and definitive care. A bedside fingerstick glucose must be checked in any patient with altered mental status. (See 'Differential diagnosis' above.)
●Management
•Treatment is aimed at addressing airway, breathing, and circulation and providing supportive care. In patients with respiratory depression, we suggest a trial of parenteral or intranasal naloxone since a concomitant opioid overdose may be present. (See 'Address airway, breathing, and circulation' above.)
•Routine gastrointestinal decontamination with activated charcoal (AC) has no benefit in oral BZD overdose. AC may be beneficial in selected patients, such as those with a history or suspicion of a life-threatening co-ingestion that AC will absorb (eg, colchicine, aspirin) and a protected airway (naturally or with a cuffed endotracheal tube). (See 'Role of decontamination' above.)
•Most cases of isolated BZD ingestion are managed successfully with supportive care alone. (See 'Supportive care' above.)
•Flumazenil is a nonspecific competitive antagonist of the BZD receptor that can be used to reverse BZD-induced sedation but can also precipitate BZD withdrawal symptoms and seizures. The use of flumazenil in the setting of overdose remains controversial. In the following patients, we suggest giving flumazenil to avoid more invasive airway procedures (Grade 2C) (see 'Role of antidote (flumazenil)' above):
-Reverse procedural over-sedation in patients who do not use BZDs chronically
-Children five years old and younger with an isolated BZD ingestion with severe central nervous system depression or isolated ataxia, except those who take BZDs for a seizure disorder or are receiving iatrogenic BZDs for treatment of status epilepticus
Generally accepted absolute contraindications to flumazenil are a proconvulsant co-ingestion, sustaining a seizure during course of altered mental status, or receiving BZDs for a seizure disorder, control of increased intracranial pressure, or status epilepticus. (See 'Contraindications' above.)
●BZD withdrawal – 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, the choice and route depending on the severity of the clinical presentation, and titrated to effect. (See 'Benzodiazepine Withdrawal' above.)
