Benzodiazepine withdrawal

INTRODUCTION — Chronic use of a benzodiazepine can cause physiologic dependence and the potential for a withdrawal syndrome upon rapid discontinuation. Benzodiazepine dependance can develop from use of prescribed, illicit (ie, non-prescribed use of compounds used medically), and designer (ie, compounds not used medically) agents.

The diagnosis and management of benzodiazepine withdrawal will be reviewed here. Other related topics are discussed separately:

●The general evaluation of delirium and confusional states and abnormal behavior in the emergency department (see "Diagnosis of delirium and confusional states" and "Evaluation of abnormal behavior in the emergency department")

●The evaluation and management of benzodiazepine and other substance use disorders (see "Benzodiazepine use disorder" and "Substance use disorders: Clinical assessment" and "Substance use disorder in adolescents: Treatment overview")

●Withdrawal syndromes from other agents with sedative properties (see "Management of moderate and severe alcohol withdrawal syndromes" and "Opioid withdrawal: Clinical features, assessment, and diagnosis" and "Opioid withdrawal in adolescents" and "Cannabis withdrawal: Epidemiology, clinical features, diagnosis, and treatment" and "Gamma hydroxybutyrate (GHB) withdrawal and dependence" and "Gabapentinoid poisoning and withdrawal" and "GABA-B agonist (baclofen, phenibut) poisoning and withdrawal")

●Withdrawal from sedative or analgesic started for treatment during a critical illness (see "Sedative-analgesia in ventilated adults: Management strategies, agent selection, monitoring, and withdrawal", section on 'Discontinuation')

EPIDEMIOLOGY — Precise data on the incidence of benzodiazepine withdrawal are not available but likely reflect benzodiazepine dependence and benzodiazepine use disorder. Benzodiazepine prescriptions have been increasing in the United States over the past two decades, to an estimated 62.6 million ambulatory visits in 2015 [1]. The 2020 National Survey on Drug Use and Health in the United States indicated 4.8 million benzodiazepine misusers (in the previous year) among individuals 12 years and older [2]. The epidemiology of benzodiazepine use disorder is discussed in detail separately. (See "Benzodiazepine use disorder", section on 'Epidemiology'.)

PATHOPHYSIOLOGY AND RISK FACTORS — Chronic benzodiazepine use downregulates signaling through gamma aminobutyric acid (GABA) A receptors [3]. GABA is the primary inhibitory neurotransmitter in the central nervous system. As long as the benzodiazepine is present, the GABA-A receptors can provide inhibitory signaling. Upon benzodiazepine discontinuation, inhibitory signaling decreases, causing excitatory clinical manifestations. The underlying molecular processes of GABA-A receptor regulation have not been completely elucidated. The pharmacology of benzodiazepines is discussed separately. (See "Benzodiazepine poisoning", section on 'Pharmacology'.)

The time to onset, severity, and duration of withdrawal are affected by pharmacokinetic parameters of the benzodiazepine that had been used. Risk factors for severe withdrawal include the following:

●Use of an agent with short half-life or thiazole moiety – Manifestations of withdrawal from agents with shorter half-lives (eg, alprazolam) begin earlier and are more severe compared with benzodiazepines with active metabolites and/or longer half-lives (eg, chlordiazepoxide, diazepam) (table 1) [4,5]. Withdrawal from alprazolam, in particular, can be difficult to treat, and manifestations do not improve following administration of other benzodiazepines in some cases [6]. Additionally, alprazolam and triazolam are triazolobenzodiazepines with a triazole moiety not found in other benzodiazepines, which may confer a binding affinity to a unique subset of benzodiazepine receptors and thus limit cross-reactivity [7].

●Higher dose, potency, and duration or use – Chronic use of a high-potency benzodiazepine (eg, alprazolam, clonazepam, etizolam, lorazepam, or triazolam) can lead to withdrawal manifestations that are difficult to treat with low-potency benzodiazepines (eg, diazepam or chlordiazepoxide) at standard doses. Even though little controlled data exist on in vivo potency of designer benzodiazepines (eg, clonazolam, flubromazolam, flunitrazolam), these agents are dosed in micrograms when used recreationally and thus may need larger doses of whichever alternative benzodiazepine is used for treatment of withdrawal manifestations [8].

Nonprescription sources of benzodiazepines can include substances either sold as a benzodiazepine or as unexpected additions to other street drugs. In these nonprescription sources, exposures may be to agents not available for human use in the country where the drug is found, such as etizolam, or to designer benzodiazepines such as clonazelam or flubromazolam [8-10]. For example, an illicit "Xanax bar" was found to contain flualprazolam instead of alprazolam [11].

●Concurrent use or cessation of other substances or medications – This can modify the course of clinical manifestations of withdrawal and impact both diagnosis and treatment. For example, coincident withdrawal from another substance (eg, opioids) can increase the severity of manifestations and complicate the diagnosis since multiple withdrawal syndromes may contribute to the manifestations. Concurrent use of various medications or substances may delay or mask withdrawal manifestation; for example, a patient taking an alpha-2 adrenergic agonist (eg, clonidine) may have blunted tachycardic or hypertensive responses after cessation of benzodiazepine use.

●Abrupt discontinuation after regular use

CLINICAL MANIFESTATIONS

Time course and natural history — Withdrawal manifestations typically begin within two to three days and last 10 to 14 days or longer following cessation of benzodiazepine use [12-14]. However, these timeframes can vary depending on the specific agent. For example, withdrawal from agents with short half-lives typically begins earlier and has been reported to start as quickly as within six hours of the last dose [4,15]. Abrupt cessation of benzodiazepines after therapeutic use of as little as two weeks has been reported to cause withdrawal seizures [16].

In a patient with mild withdrawal, manifestations will typically resolve without intervention. However, in a patient with severe withdrawal (eg, delirium, seizures), life-threatening manifestations and complications can develop unless promptly treated. Seizures can start as early as 24 hours or up to one week or longer after cessation [13,16]. (See 'Life-threatening manifestations and complications' below.)

Common manifestations — Manifestations of benzodiazepine withdrawal are similar to other sedative withdrawal syndromes but can vary based on factors such as pharmacokinetic properties of the agent. Common manifestations (ie, typically occurring in at least one-third to one-half of cases) include the following [5,17-19]:

●Anxiety

●Diaphoresis

●Hallucinations (with preserved sensorium)

●Headaches

●Insomnia

●Irritability

●Myalgias

●Nausea and vomiting

●Tremor

●Hypertension

●Hyperthermia

●Tachycardia

Signs and symptoms of the underlying disease process (eg, anxiety) may reappear and can overlap with the manifestations of the withdrawal syndrome.

Life-threatening manifestations and complications — Manifestations and complications of life-threatening benzodiazepine withdrawal include the following [19]:

●Agitation (53 to 100 percent)

●Psychosis (2 to 7 percent) – Can include hallucinations but also manifests delusions or bizarre behavior [20,21]

●Seizures (4 percent)

Seizures are typically generalized, tonic-clonic, isolated, and self-limited. Nonconvulsive status epilepticus can occasionally develop, most commonly reported in older adults [22-24]. (See "Convulsive status epilepticus in adults: Classification, clinical features, and diagnosis", section on 'Etiology'.)

General complications of the hyperadrenergic state or seizures (if prolonged or multiple) can also develop if not promptly controlled. These can include volume depletion, respiratory dysfunction, hypoglycemia, rhabdomyolysis, acute kidney injury, cardiac dysfunction, cerebral edema, hepatic injury, and disseminated intravascular coagulation. (See "Refractory status epilepticus in adults", section on 'Outcomes' and "Severe nonexertional hyperthermia (classic heat stroke) in adults", section on 'Complications and sequelae'.)

EVALUATION

History and examination — The following are important elements of a clinical history in a patient with suspected benzodiazepine withdrawal:

●Symptoms consistent with benzodiazepine withdrawal

●Duration, agent, dose, and frequency of benzodiazepine use

●Designer benzodiazepine (eg, clonazelam, flubromazolam) use obtained illicitly

●Last benzodiazepine dose

●Other medications and any recent changes

●Reason for benzodiazepine cessation or decrease in use

●Similar signs or symptoms with prior episodes of benzodiazepine cessation or dose decrease

●Indication for taking a benzodiazepine

●History of substance or alcohol use disorder

●History of seizure disorder

In a patient who is unable to provide a reliable history, previous medical records and/or state pharmacy prescription databases can be valuable sources of information. The patient may not disclose misuse of nonprescribed benzodiazepines, and these would not appear in a state pharmacy database.

A targeted physical examination should be performed to assess vital sign abnormalities, diaphoresis, mental status, airway protection, focal neurologic deficit, tremulousness, and signs of a recent seizure (eg, lateral tongue abrasions, urinary incontinence).

History and physical examination should also assess for other potential etiologies. (See 'Differential diagnosis' below.)

Ancillary studies — Ancillary studies are targeted towards excluding alternative etiologies since no particular study provides a definitive diagnosis of benzodiazepine withdrawal (eg, computed tomography [CT] scan of the head, thyroid function tests, lumbar puncture). Every patient with altered mental status requires a fingerstick blood glucose.

In a patient with manifestations of severe withdrawal, testing should focus on evaluating for complications (eg, creatine kinase, complete blood count, serum chemistries, blood urea nitrogen, creatinine, coagulation studies, liver enzymes, urinalysis).

Urine and serum benzodiazepine testing are generally not helpful since urine immunoassays are neither sensitive nor specific and serum testing typically has long turnaround times and does not correlate with clinical manifestations. (See "Benzodiazepine poisoning", section on 'Role of laboratory benzodiazepine testing'.)

DIAGNOSIS — Benzodiazepine withdrawal is a clinical diagnosis in a patient with compatible signs and symptoms (eg, tachycardia, diaphoresis, anxiety, irritability, tremors, nausea, vomiting, seizure), a history of prolonged benzodiazepine use, and a history of recent cessation or dose reduction. Similar signs or symptoms with prior episodes of benzodiazepine cessation or dose decrease suggest physiologic dependence and support the diagnosis.

In a patient with an unclear history, benzodiazepine withdrawal 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 (eg, meningitis). However, presumed benzodiazepine withdrawal should still be treated during the ongoing evaluation for other causes.  

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of benzodiazepine withdrawal is similar to other hyperadrenergic states and includes other withdrawal syndromes, intoxication, drug-induced movement disorders, metabolic abnormalities, infections, and other processes. A table summarizing causes of hyperadrenergic states including unique features and diagnostic tools is provided (table 2). The mnemonic FIND ME (functional [ie, psychiatric], infectious, neurologic, drugs, metabolic, endocrine) may be helpful to organize a diagnostic search for the etiology of delirium or confusion (table 3), if present. (See "Diagnosis of delirium and confusional states" and "Evaluation of abnormal behavior in the emergency department".)

INITIAL MANAGEMENT — The treatment goals are to replace the pharmacologic activity of the original benzodiazepine while managing any complications, such as agitation, seizures, rhabdomyolysis, volume depletion, or acute kidney injury.  

All patients: Supportive care — Standard supportive care of a patient with benzodiazepine withdrawal includes the following:

●Rapidly assess and address the patient's airway, breathing, and circulation ("ABCs"). Provide supplemental oxygen as needed. Establish intravenous (IV) access in a patient with significant vital sign abnormalities, vomiting, signs of severe withdrawal, or other situations when the need for IV fluid or medications is anticipated.

●A postictal patient may require airway suctioning, recumbent positioning, and/or airway opening maneuvers (eg, jaw-thrust, nasal trumpet). Seizure precautions (eg, pads on the bedside rails, keeping bed at lowest position) should be instituted if the patient had a seizure.

●Vital signs and neurological status should be checked frequently (eg, every one to two hours) and after each intervention or change in patient's status. We place a patient with severe withdrawal on a continuous cardiac and pulse oximetry monitor. A patient with sedation (possibly iatrogenic from therapy) should be placed on an end-tidal carbon dioxide (EtCO₂; ie, capnography) monitor to assess for hypoventilation.

●Volume depletion (such as from vomiting, diaphoresis, or inadequate fluid intake) or rhabdomyolysis is treated with IV crystalloid administration. (See "Prevention and treatment of heme pigment-induced acute kidney injury (including rhabdomyolysis)".)

●Nausea and vomiting can be treated with an antiemetic (eg, ondansetron).  

●An established scoring system should be used to quantify the severity and response to interventions. We prefer the revised Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) scale (table 4) (calculator 1) given its familiarity for most clinicians. Other reasonable options include the Clinical Institute Withdrawal Assessment for Benzodiazepines (CIWA-B) and the Benzodiazepine Withdrawal Symptom Questionnaire [18,25], although we do not routinely use these.

●Hyperthermia, if present, should improve with treatment of psychomotor agitation. Severe hyperthermia (generally >40.5°C [105°F]) should be treated with rapid cooling (eg, immersion in ice or ice water, evaporative spray with water). (See "Severe nonexertional hyperthermia (classic heat stroke) in adults", section on 'Management'.)

Severe withdrawal — We define a patient with severe withdrawal as having altered mental status (including psychosis), persistently abnormal vital signs (eg, heart rate >140 beats per minute), status epilepticus, or manifestations that are refractory to treatment with a benzodiazepine. However, an established definition for severe withdrawal does not exist.

There is also no accepted benzodiazepine dose threshold for when to consider the withdrawal as refractory to benzodiazepines. This dose threshold should account for potential differences in potency between the agent being used to treat the withdrawal and the agent to which the patient originally developed tolerance. Occasionally, some patients do not improve when treated with a benzodiazepine that is different from their original agent [26]. Withdrawal manifestations from benzodiazepines with a triazole moiety (eg, alprazolam) may initially appear refractory since other benzodiazepines are often less effective but improve quickly upon switching treatment to the original agent. (See 'Pathophysiology and risk factors' above.)

Severe withdrawal is commonly encountered in patients who are referred to a higher level of care after initial management attempts started in an alternate setting (eg, outpatient, substance use facility, non-critical care inpatient ward) are found to be ineffective.

Initial pharmacologic management — In an adult with severe withdrawal, we start with an IV benzodiazepine. We prefer diazepam 20 mg IV, but lorazepam 2 to 4 mg IV and midazolam 2 to 5 mg IV are reasonable options. In a patient without IV access, midazolam 2 to 5 mg can be given intramuscularly (IM) until IV access is established.

Diazepam IV and midazolam IV/IM can be re-dosed every 5 to 10 minutes, and lorazepam IV every 20 minutes. However, if signs and symptoms are not improving after multiple doses (instead of temporarily or partially improving as would be expected if treated with an agent with a short duration of effect or low potency), we consider the withdrawal to be refractory to benzodiazepines.

Patient with benzodiazepine-refractory manifestations — If withdrawal manifestations are being treated with a benzodiazepine that is different from the agent to which the patient originally developed tolerance, we prefer switching to the original benzodiazepine if the situation allows, particularly in the case of alprazolam. This would not be feasible if the original agent was a designer illicit benzodiazepine or a benzodiazepine only available in another country.

If it is not possible to switch to the original agent or manifestations are not improving with the original agent, we suggest administering a gamma aminobutyric acid (GABA)-A receptor agonist from a separate pharmacologic class (eg, barbiturate) instead of continuing with a benzodiazepine. We prefer phenobarbital 130 to 260 mg IV initially followed by repeat doses every 15 to 20 minutes as necessary until symptom control is achieved. Concurrent benzodiazepine administration is unnecessary since the synergistic effects with phenobarbital increase the risk of respiratory depression. Phenobarbital also increases the risk of medication interactions since it induces the cytochrome P450 enzyme system (CYP2B6, CYP3A4) and uridine diphosphate-glucuronosyltransferase (UGT)-glucuronidation, which is of particular concern in patients with opioid use disorder (ie, taking methadone or buprenorphine) or in patients taking most forms of hormonal contraception (table 5) [27-29].

In a patient who is tracheally intubated and mechanically ventilated, we often start with phenobarbital 10 mg/kg IV. A reasonable alternative is propofol (although withdrawal symptoms may recrudesce with cessation of infusion), which is discussed separately. (See "Sedative-analgesia in ventilated adults: Medication properties, dose regimens, and adverse effects", section on 'Propofol'.)

A retrospective study found phenobarbital was effective for the management of benzodiazepine withdrawal, but a fixed-dose regimen caused sedation in one-fourth of patients [30]. There is extensive experience with phenobarbital for treating alcohol withdrawal, which is discussed separately. (See "Management of moderate and severe alcohol withdrawal syndromes", section on 'Refractory delirium tremens, including use of phenobarbital'.)

Patient with status epilepticus — We initially treat with lorazepam 0.1 mg/kg IV (4 mg fixed dose, repeated if still seizing) or midazolam 10 mg IM if IV access is not available. Case reports describe benzodiazepines effectively treating status epilepticus caused by benzodiazepine withdrawal [22-24]. The benefit of lorazepam over diazepam and evidence of benzodiazepine efficacy for generalized convulsive status epilepticus is discussed separately. (See "Convulsive status epilepticus in adults: Management", section on 'Benzodiazepine efficacy'.)

Initial treatment with phenobarbital 20 mg/kg IV would be a reasonable option. We would also administer phenobarbital if status epilepticus does not resolve after the initial benzodiazepine dose, although we would most likely perform rapid sequence intubation given the risk of respiratory depression in the setting of escalating GABA receptor agonist therapy. (See "Convulsive status epilepticus in adults: Management", section on 'Second- or third-line medications' and "Rapid sequence intubation in adults for emergency medicine and critical care".)

Patient with psychosis — In a patient with psychosis from benzodiazepine withdrawal, we initially treat with a benzodiazepine as described above. (See 'Initial pharmacologic management' above.)  

In addition to a benzodiazepine, we also administer an antipsychotic agent such as haloperidol 5 mg IM/IV (table 6) (with dose reduced by one-half in older adults). However, antipsychotic agents should not be routinely used in the treatment of benzodiazepine withdrawal and should not be administered without a benzodiazepine since they do not exhibit cross-tolerance with benzodiazepines and may also interfere with heat dissipation. (See "First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects", section on 'Administration'.)

In the experience of some of our contributors, patients with psychosis from benzodiazepine withdrawal will often need phenobarbital if they are requiring an antipsychotic agent and an IV benzodiazepine.

Mild to moderate withdrawal — A patient with normal mental status can typically be managed with an oral benzodiazepine even if they had an isolated seizure. We prefer to start with diazepam 10 to 20 mg orally in the following scenarios:

●Patient was taking an agent with a short half-life

●Desire to consolidate multiple agents to a single agent

●Patient was misusing the original agent

●The original agent was nonprescription or designer

Diazepam can also be given IV, but this formulation is occasionally unavailable due to drug shortages. As long as signs and symptoms are improving, we re-dose the diazepam orally every one to two hours until all signs and symptoms of withdrawal have resolved. Diazepam has active metabolites (which provide a self-taper) but should be avoided in patients with severe hepatic impairment.

Lorazepam (1 to 4 mg orally/IV) is a reasonable alternative and preferable in a patient with severe hepatic impairment. It can be re-dosed every 20 minutes IV and every hour orally until signs have resolved.

Chlordiazepoxide (25 to 50 mg orally) is another reasonable option since it has a long duration of action but should not be used in a patient with severe hepatic impairment. It can be re-dosed every hour until signs have resolved.

The original agent can also be administered to control withdrawal manifestations, which may be preferable if the patient ran out of their prescription benzodiazepine and was not misusing it.

CONTINUING MANAGEMENT AND DISPOSITION

Indications for admission — Indications for hospital admission include the following:

●Failing an outpatient taper or treatment at an inpatient substance use program

●Severe withdrawal (altered mental status, psychosis, status epilepticus)

●Complications of withdrawal (acute kidney or liver injury, rhabdomyolysis, respiratory or cardiac dysfunction, cerebral edema, disseminated intravascular coagulation)

●Persistent uncontrolled signs and symptoms (including vital sign abnormalities and vomiting)

●Complicated medical or psychiatric comorbidities

Tapering — After the patient is initially stabilized, we implement a controlled process of dose reduction (ie, taper) to reduce the risk of uncontrolled withdrawal. The initial goal is to address severe withdrawal effects, if present, as described above. (See 'Severe withdrawal' above.)

Symptom-triggered versus scheduled — For a patient being admitted, we continue the symptom-triggered treatment that was started in the initial stages of therapy. We administer a gamma aminobutyric acid (GABA)-A receptor agonist (eg, benzodiazepine, phenobarbital) when a patient meets the predefined threshold on an established scoring system such as the revised Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) scale (table 4) (calculator 1). Evaluation intervals as frequent as every 10 to 15 minutes are appropriate for patients with more severe symptoms, followed by hourly reassessment when severe symptoms are controlled. An interval of four to six hours is reasonable for stable patients with mild symptoms receiving oral pharmacologic treatment.

If the patient's signs and symptoms are readily controlled in the emergency department, or if admitted, once signs and symptoms are controlled and pharmacologic treatment doses are decreasing, a scheduled dose reduction taper should be started, especially if the patient is being discharged. The taper can be started prior to discharge from the emergency department or hospital. A reasonable alternative in a hospitalized patient is short-term detoxification using continued symptom-triggered treatment.

Taper doses and rate

●Benzodiazepine taper – We administer an initial total daily taper dose that is the same or less than the total daily dose most recently received during the stabilization phase. We typically choose the same agent that was used to control the acute withdrawal manifestations. Taper reductions range from 10 to 50 percent every one to two weeks [31]. If a more rapid taper is chosen, we decrease the original dose by 25 to 50 percent every two to three days, with the greater reductions earlier in the course. The outpatient taper rate and monitoring are discussed separately. (See "Benzodiazepine use disorder", section on 'Medically supervised taper'.)

●Phenobarbital taper – In a patient who received phenobarbital during the stabilization phase, we administer a phenobarbital taper. The maintenance doses are typically less than the dose required for initial stabilization. In an adult, we typically administer 130 to 260 mg intravenously (IV) or orally divided across two to three doses per day. In a usual taper, we then decrease the total daily dose by 10 to 20 percent every one to two days. For a more rapid taper, we decrease the total daily dose 30 to 60 mg every one to two days depending on symptoms, with a goal of finishing the taper in three to five days. We do not concurrently administer benzodiazepines given the increased risk of respiratory depression.

The taper rate depends on the patient’s capacity to tolerate withdrawal symptoms, adverse effects from the tapering agent, and the dose and duration of benzodiazepine use. The dose reductions should be adjusted based on recrudescence of intolerable withdrawal symptoms or adverse effects (eg, sedation, weakness). A taper dose should not be administered if the patient is exhibiting excess sedation or signs of intoxication (eg, slurred speech, ataxia, nystagmus).

Tapering schedules vary widely and depend on the clinical setting [32]. Longer tapers are associated with decreased withdrawal effects, increased rates of discontinuation, and lower rates of relapse even though shorter tapers may be medically safe [32-34].

Outpatient taper and follow-up care — For a patient being discharged (either from the emergency department or hospital), our decision to prescribe an outpatient taper depends on the patient's motivation to follow the taper, psychosocial factors that would preclude safe outpatient treatment, and the availability of outpatient follow-up (ideally within one week). It is important to promote outpatient follow-up (either with a substance use disorder treatment program or primary care clinician) to facilitate adjustments in the taper to individualize care. We prescribe enough medication to continue the taper through the appointment to minimize potential overuse. (See "Benzodiazepine use disorder", section on 'Monitoring and symptom management'.)

Compared with abrupt cessation, dose tapering is more effective for achieving initial cessation and maintaining sustained abstinence [31,33,35]. Especially in patients using nonprescribed benzodiazepines, completing the taper reduces the risk of relapse. Individualized dosing plans may be helpful for long-term success.

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: Benzodiazepine use disorder and withdrawal".)

SUMMARY AND RECOMMENDATIONS

●Risk factors for severe withdrawal – These include withdrawal from agents with shorter half-lives (especially alprazolam) (table 1) or higher-potency agents (especially some designer benzodiazepines), abrupt discontinuation after regular use, or concurrent use or cessation of other substances. (See 'Pathophysiology and risk factors' above.)

●Clinical manifestations – Abrupt cessation of benzodiazepines after as little as two weeks of use has been reported to cause withdrawal symptoms beginning within two to three days and lasting 10 to 14 days or longer. Common manifestations include tachycardia, hypertension, diaphoresis, anxiety, irritability, insomnia, headaches, myalgias, tremor, nausea, and vomiting. (See 'Clinical manifestations' above.)

Life-threatening manifestations can include agitation, psychosis, delirium, seizures, and hyperthermia with resultant complications (eg, acute kidney injury, cardiac dysfunction, cerebral edema, hepatic injury, disseminated intravascular coagulation). Seizures are typically generalized, tonic-clonic, isolated, and self-limited, but status epilepticus can also occur. (See 'Life-threatening manifestations and complications' above.)

●Evaluation – Ancillary studies are targeted towards excluding alternative etiologies. Every patient with altered mental status requires a fingerstick blood glucose. In a patient with manifestations of severe withdrawal, testing should focus on evaluating for complications (eg, creatine kinase, complete blood count, serum chemistries, blood urea nitrogen, creatinine, coagulation studies, liver enzymes, urinalysis). (See 'Evaluation' above.)

●Diagnosis – Benzodiazepine withdrawal is a clinical diagnosis in a patient with compatible signs and symptoms and a history of prolonged benzodiazepine use with recent cessation or dose reduction. In a patient with an unclear history, benzodiazepine withdrawal should be considered a diagnosis of exclusion. (See 'Diagnosis' above.)

●Management – The goal is to replace the pharmacologic activity of the original benzodiazepine while providing supportive care and managing any complications. A patient with severe withdrawal (ie, psychosis, altered mental status, refractory to benzodiazepines, status epilepticus, persistently abnormal vital signs) may require treatment in an intensive care unit or treatment with an alternate gamma aminobutyric acid (GABA) receptor agonist (eg, phenobarbital). (See 'Initial Management' above.)

•Mild to moderate withdrawal – A patient with normal mental status can typically be managed with an oral benzodiazepine even if they had an isolated seizure. We suggest diazepam, rather than other benzodiazepines (Grade 2C), owing to its active metabolites providing a self-taper. The dose is 10 to 20 mg orally but should be avoided in a patient with severe hepatic impairment. Lorazepam (1 to 4 mg orally/intravenously [IV]) is a reasonable alternative. (See 'Mild to moderate withdrawal' above.)

•Severe withdrawal – We start with an IV benzodiazepine. We suggest diazepam rather than other agents (Grade 2C). The dose is 20 mg IV; lorazepam 2 to 4 mg IV and midazolam 2 to 5 mg IV/intramuscularly (IM) are reasonable options. (See 'Initial pharmacologic management' above.)

In a patient with withdrawal manifestations that are not improving after multiple benzodiazepine doses and the benzodiazepine is different from the agent to which the patient originally developed tolerance, we prefer switching to the original benzodiazepine (if possible), particularly in the case of alprazolam.

In a patient with withdrawal manifestations that are not improving after multiple benzodiazepine doses (including the originally prescribed benzodiazepine), we suggest administering phenobarbital instead of another agent or continuing with a benzodiazepine (Grade 2C). We administer phenobarbital 130 to 260 mg IV followed by repeat doses every 15 to 20 minutes, if necessary, until symptom control is achieved. In a patient who is tracheally intubated and mechanically ventilated, we often start with phenobarbital 10 mg/kg IV. (See 'Patient with benzodiazepine-refractory manifestations' above.)

•Status epilepticus – We initially treat with lorazepam 0.1 mg/kg IV (4 mg fixed dose, repeated if still seizing) or midazolam 10 mg IM if IV access is not available. Initial treatment with phenobarbital 20 mg/kg IV or if status epilepticus does not resolve after the initial benzodiazepine dose are reasonable options. (See 'Patient with status epilepticus' above.)

•Psychosis – In addition to a benzodiazepine, we also administer an antipsychotic agent (eg, haloperidol 5 mg IM/IV). In our experience, patients with psychosis from benzodiazepine withdrawal will often need phenobarbital. (See 'Patient with psychosis' above.)

●Disposition and tapering – Indications for admission include failing an outpatient taper, severe withdrawal, complications of withdrawal, persistent vomiting, uncontrolled withdrawal signs and symptoms, and comorbidities. After the patient is stabilized, a controlled process of dose reduction (ie, taper) should be implemented, thus reducing the risk of withdrawal recrudescence and relapse. (See 'Continuing management and disposition' above.)