Physical examination

• Common findings ^r4r6
  • Autonomic hyperactivity with sympathomimetic signs
    • Tachycardia ^c38
    • Hypertension ^c39
    • Diaphoresis ^c40
    • Fever ^c41
    • Mydriasis ^c42
    • Tachypnea ^c43
  • Central nervous system hyperstimulation
    • Coarse tremor ^c44
      • Often most easily found in the hands or tongue
    • Hyperreflexia ^c45
    • Hallucinations ^c46
    • Seizures ^c47
    • Delirium ^c48
• Findings concerning for concurrent Wernicke encephalopathy
  • Nystagmus or oculomotor abnormalities ^c49c50
  • Ataxia or gait disturbance ^c51c52

Causes

• Underlying cause of alcohol withdrawal syndrome is multifactorial; undetermined genetic factors likely play a role
  • Long-term alcohol use causes a depressant effect on the central nervous system, leading to adaptive changes in neurotransmitter and receptor physiology ^r4
    • Central nervous system depression occurs with long-term alcohol use
      • Enhanced inhibitory tone occurs through GABA receptor modulation (affecting several proteins involved in γ-aminobutyric acid pathways) ^r2
      • Inhibited excitatory tone occurs through NMDA receptor modulation (affecting several proteins involved in N-methyl-D-aspartate pathways) ^r2
    • Alcohol administration increases catecholamine levels affecting central α- and β-adrenergic receptors ^r1r4
    • Alterations of balance in other neurochemical systems (eg, serotonin, endogenous opioid, nicotinic cholinergic, dopamine), electrolytes (eg, hypomagnesemia), and vitamin deficiencies (eg, thiamine) occur with long-term alcohol intake
  • Functional adaptations result in development of tolerance phenomenon in patients with alcohol use disorder
  • Kindling phenomenon ^c53
    • Refers to development of neuronal networks that may result in worsening episodes of withdrawal on subsequent episodes
• Discontinuation or dramatic reduction in alcohol consumption ^c54
  • Central nervous system hyperstimulation results from loss of GABA receptor inhibition and potentiation of NMDA receptor excitation ^r2
  • Dopaminergic dysregulation may also play a role in agitation, hallucinations, and delirium ^r7
  • Gradual increase in adrenergic activity results from an excess glutamate activity on excitatory NMDA receptors and excess catecholamine effects on central α- and β-adrenergic receptors ^r1r4
  • Abnormalities in the balance of other neurochemical systems, electrolytes, and vitamins may also contribute to development of withdrawal

Risk factors and/or associations

Primary diagnostic tools

• Withdrawal is a clinical diagnosis and a diagnosis of exclusion ^r2
  • DSM-5 diagnostic criteria define the diagnosis
  • Exclude alternate diagnoses that mimic withdrawal
  • Consider presence of concomitant condition (eg, comorbidities, complications of alcohol use disorder) that may have contributed to the withdrawal state by forcing abstinence
  • Consider risk of progression to severe withdrawal ^r15
• Measure severity of withdrawal with applicable severity assessment tool
  • Several scales are available; most commonly used include:
    • Short Alcohol Withdrawal Scale ^r10
      • 10-item scale requiring patient participation; most common tool used for outpatients
    • Clinical Institute Withdrawal Assessment for Alcohol (Revised) scale ^r4r20
      • 10-item scale requiring patient cooperation; most common tool used for inpatients
    • Richmond Agitation-Sedation Scale ^r4r21
      • Reliable scale for patients requiring ICU care
  • Scales are not diagnostic tools; rather, scales objectively measure degree of withdrawal in a patient with clinical diagnosis of withdrawal ^r2r15
• Evaluate for other disease that may have contributed to precipitation of withdrawal ^r2
  • Consider presence of concomitant condition or complication of long-term alcohol use, especially in the presence of severe withdrawal (eg, delirium) ^r3
    • Withdrawal is often precipitated in patients with comorbid medical or surgical conditions during periods of abstinence when illness or surgery prevents alcohol intake ^r4
    • Investigations may be necessary to exclude conditions such as pneumonia, sepsis, meningitis or encephalitis, pancreatitis, liver failure, gastrointestinal bleeding, head trauma, intracerebral hemorrhage, acute coronary syndrome, drug overdose, hypoglycemia, and electrolyte abnormalities
    • Guide additional diagnostic testing and work-up based on individual clinical presentation
  • Wernicke encephalopathy may present in association with withdrawal and triad of altered mental status, ophthalmoplegia, and ataxia
    • Full triad is present in only about one-third of patients and diagnosis is missed in up to 80% of cases ^r2
• Obtain baseline admission studies for patients with moderate to severe alcohol withdrawal syndrome based on individual presentation (routine laboratory testing is not necessary for most patients with mild withdrawal) ^r4r10
  • Obtain finger stick glucose measurement for all patients with altered mental status or seizures ^r17
  • Most experts order the following:
    • Metabolic panel with serum electrolyte, magnesium, phosphate, and glucose levels, plus renal function testing ^r17
    • CBC ^r17
    • Liver function tests, including INR and serum AST, ALT, bilirubin, and ammonia ^r17
  • Consider the following:
    • Head CT or other brain imaging for patients with seizures ^r15
    • Blood alcohol concentration and urine drug screen
    • Serum calcium, phosphate, lipase, and creatinine kinase levels
    • Chest radiograph
    • ECG, cardiac biomarkers, and echocardiogram
    • Urinalysis
    • Arterial blood gas analysis
    • Blood, urine, and sputum cultures
    • Lumbar puncture with studies to assess for central nervous system infection in patients presenting with fever and mental status changes
    • Pregnancy test for premenopausal women
• Refer to regionally specified protocols to guide evaluation strategy ^r22

Laboratory ^{c93c94c95c96c97c98c99c100c101c102c103c104}

• Serum blood alcohol concentration ^c105
  • Serum blood alcohol concentration may assist in determining likelihood of withdrawal
    • High likelihood of withdrawal exists after prolonged heavy alcohol consumption when early manifestations (eg, autonomic hyperactivity) appear in the context of a moderately high but falling alcohol level ^r3
    • Anticipate worsening of withdrawal manifestations as ethanol concentration falls in patients presenting with alcohol withdrawal and an elevated ethanol concentration ^r2
• Metabolic panel with serum electrolyte (including magnesium) and glucose levels ^{r23c106c107c108c109}
  • Abnormal findings are common in long-term alcohol use and may include: ^r24
    • Hypoglycemia
    • Hypokalemia
    • Hypomagnesemia
    • Hypophosphatemia
• Renal function tests (BUN, creatinine) ^c110c111
  • Renal insufficiency can guide choice of doses in treatment ^r25
• Liver function testing ^c112
  • Evaluation of hepatic transaminases and synthetic liver function (eg, prothrombin time, INR) may help guide medication choice and assess for alcohol-related hepatic injury ^r25

Imaging

• Head CT ^c113
  • May be indicated to exclude alternate causes of manifestations or with concern for trauma
• Chest radiograph ^c114c115
  • May be indicated to assess for acute pneumonia or other concurrent pulmonary disease

Other diagnostic tools

• DSM-5 clinical diagnostic criteria
  • Alcohol withdrawal syndrome ^r3c116
    • A: cessation of (or reduction in) alcohol use that has been heavy and prolonged
    • B: 2 (or more) of the following, developing within several hours to a few days after the cessation of (or reduction in) alcohol use described in criterion A:
      • Autonomic hyperactivity (eg, sweating, pulse greater than 100 beats per minute)
      • Increased hand tremor
      • Insomnia
      • Transient visual, tactile, or auditory hallucinations or illusions
      • Psychomotor agitation
      • Anxiety
      • Generalized tonic-clonic seizures
    • C: the signs and symptoms in criterion B cause clinically significant distress or impairment in social, occupational, or other important areas of functioning
    • D: the signs or symptoms are not attributable to another medical condition and are not better explained by another mental disorder, including intoxication or withdrawal from another substance
  • Substance withdrawal delirium ^r26
    • Substance withdrawal delirium diagnosis should be made instead of substance withdrawal when symptoms in criteria A and C predominate in the clinical picture and when they are sufficiently severe to warrant clinical attention
    • Delirium criteria
      • A: disturbance in attention (ie, reduced ability to direct, focus, sustain, and shift attention) and awareness (reduced orientation to the environment)
      • B: disturbance develops over a short period (usually hours to a few days), represents a change from baseline attention and awareness, and tends to fluctuate in severity during course of day
      • C: additional disturbance in cognition (eg, memory deficit, disorientation, language, visuospatial ability, or perception)
      • D: the disturbance in A and C are not better explained by another preexisting, established, or evolving neurocognitive disorder and do not occur in the context of reduced level of arousal (eg, coma)
      • E: there is evidence from the history, physical examination, or laboratory findings that the disturbance is a direct physiological consequence of another medical condition, substance intoxication or withdrawal (ie, due to drug use disorder or medication), or exposure to a toxin, or is due to multiple causes
• Short Alcohol Withdrawal Scale ^c117
  • Validated for use in outpatient setting ^r10
    • Symptoms that are scored include anxiety, confusion, restlessness, feeling miserable, memory issues, tremors (shakes), nausea, heart pounding, sleep disturbance, and sweating in the past 24 hours
    • Score is based on presence and severity of each symptom
      • None: 0 points
      • Mild: 1 point
      • Moderate: 2 points
      • Severe: 3 points
    • Mild withdrawal: score less than 12 points
    • Moderate to severe: score of 12 points or higher
• Clinical Institute Withdrawal Assessment for Alcohol (Revised) ^r20c118
  • Objectively measures severity of withdrawal and determines likelihood of progressing alcohol withdrawal syndrome; clinical uses may include: ^r4
    • Determination of need for medically supervised withdrawal management
      • An initial score of greater than 10 is correlated with risk of developing severe withdrawal; requires further evaluation and development of admission goals of therapy ^r4
    • Monitor course of withdrawal and guide symptom-triggered treatment when alcohol use history is known
      • Patients with score less than 10 do not usually need additional medication ^r10
      • Patients requiring treatment with scores of 15 or less likely respond to moderate benzodiazepine doses ^r11
      • Patients with scores higher than 15 require close monitoring and aggressive treatment to avoid seizures and alcohol withdrawal delirium ^r11
  • Score is based on symptoms including nausea/vomiting, tremors, paroxysmal sweating, anxiety, agitation, tactile disturbances, auditory disturbances, visual disturbances, headache/head fullness, and orientation/clouding of sensorium ^r2
  • Scores are altered by pain, other medical and surgical issues, and administration of sedation agents ^r4
  • Scoring-based severity is variably reported and not rigorously standardized; refer to regional protocol to guide symptom-triggered treatment based on specific score
    • One source suggests the following: ^r10
      • Absent or very mild withdrawal: score of 8 or lower
      • Mild withdrawal: score of 9 to 14
      • Moderate withdrawal: score of 15 to 20
      • Severe withdrawal: score of 21 to 67
    • Other sources suggest the following levels of severity based on score
      • Absent, minimal, or mild: 9 or less,^r27less than 8,^r110 to 8^r15
      • Moderate: 10 to 18,^r278 to 15,^r119 to 15^r15
      • Severe: 19 or higher,^r27higher than 15,^r1116 or higher^r15
• Richmond Agitation-Sedation Scale ^{r4r21c119c120c121}
  • Use to assess effectiveness of sedation in patients who lack the ability to cooperate (eg, heavily sedated, intubated, combative)
  • Score is based on overall patient responsiveness and general level of sedation
    • +4: patient is combative; immediate danger to staff
    • +3: patient is very agitated; aggressive toward staff, removes catheters/tubes
    • +2: patient is agitated; patient-ventilator dyssynchrony, persistent nonpurposeful movement
    • +1: patient is restless; movements are not aggressive or vigorous, anxious or apprehensive mood
    • 0: patient is calm and alert
    • −1: patient is drowsy; awakening to voice, with eye contact, for periods of 10 seconds or more
    • −2: patient is lightly sedated; awakens to voice, with eye contact, for brief periods (less than 10 seconds)
    • −3: patient is moderately sedated; movement in response to voice, without eye contact
    • −4: patient is deeply sedated; movement in response to physical stimulation, but does not respond to voice
    • −5: patient is unarousable; does not respond to physical stimulation or voice
  • Goal is score of 0 to −2 (patient is in a calm, arousable state) ^r2

Most common

• Sedative-hypnotic medication withdrawal ^r28r29c122
  • Withdrawal from chronically used sedative-hypnotic medications, including benzodiazepines, barbiturates, baclofen, or γ-hydroxybutyrate (GHB) ^r30r31
  • May present with symptoms similar to those of alcohol withdrawal syndrome such as anxiety, restlessness, tremor, tachycardia, delirium, hallucinations, and seizures
  • Sedative-hypnotic medication withdrawal and alcohol withdrawal are virtually indistinguishable from a clinical standpoint
  • History of long-term alcohol use may point toward a diagnosis of alcohol withdrawal or mixed withdrawal syndrome
  • Laboratory testing for potential drug use and blood alcohol concentration may help narrow specific cause of manifestations; review of state prescription drug database may reveal fulfillment of benzodiazepine prescriptions
• Stimulant intoxication ^r32c123d1
  • Intoxication with substances such as cocaine, methamphetamine, amphetamine, and synthetic cathinones (eg, bath salts) can present similarly to alcohol withdrawal with agitation, tremor, sympathomimetic hyperactivity, and occasionally hallucinations and/or seizures
  • Clinical differentiation may be difficult; however, patients with stimulant intoxication characteristically exhibit stereotyped behaviors such as picking at objects (real or imagined) on the skin or bed sheets and paranoid behavior
  • Mydriasis is more consistently present and pronounced in patients with stimulant intoxication than with alcohol withdrawal
  • Laboratory testing for potential drug use and blood alcohol concentration may help narrow specific cause of manifestations; caveat: most synthetic cathinones are not detectable on standard drug testing
• Schizophrenia ^r33c124d2
  • Chronic psychiatric disorder characterized by faulty perceptions and withdrawal from reality that may present similarly to alcohol withdrawal with delusions and hallucinations
  • Onset of schizophrenia is typically in adolescence or young adulthood and may be more gradual than onset of alcohol withdrawal syndrome
    • While substance use is common among schizophrenic patients, a history of long-term alcohol use would be present in patients with alcohol withdrawal syndrome
  • Delusions, movement disorders, and paranoia are common in patients with schizophrenia
  • Signs such as tremors and tachycardia may not be present in schizophrenia; sustained sympathomimetic findings should not be present in patients with schizophrenia
  • Schizophrenia is a clinical diagnosis based on DSM-5 criteria ^r34
• Encephalitis ^r35c125d3
  • Rapid onset of inflammation of the brain usually caused by an infectious or autoimmune process
  • Presents similarly with hallucinations, delirium, tremors, and/or seizures
  • Signs of inflammation (eg, fever) are common
  • While historical features can usually be used to differentiate between encephalitis and alcohol withdrawal, objective testing may be necessary
  • MRI of the brain, lumbar puncture with cerebrospinal fluid analysis, and/or continuous EEG monitoring can aid in diagnosis
• Hepatic encephalopathy ^r4c126d4
  • Encephalopathy associated with chronic liver dysfunction characterized by delirium and asterixis
  • May present similarly with seizures and altered sensorium
  • Other stigmata of chronic liver disease (eg, jaundice, scleral icterus, coagulopathy, caput medusa) may be present
  • In contrast to alcohol withdrawal syndrome, hepatic encephalopathy is typically associated with central nervous system depression and asterixis, as opposed to coarse tremor and central nervous system excitation
  • Elevated serum ammonia level can assist in differentiating from alcohol withdrawal syndrome
• Thyrotoxicosis ^r36c127d5
  • Caused by exposure to excess circulating thyroid hormones
  • Similar manifestations include restlessness, tremors, palpitations, tachycardia, and hypertension
  • History of long-term alcohol use and recent cessation or reduction of alcohol use can differentiate alcohol withdrawal syndrome from thyrotoxicosis
  • Physical examination findings such as thyromegaly and/or exophthalmos are sometimes seen in hyperthyroidism but will be absent in alcohol withdrawal syndrome
  • Laboratory testing can be used if history is not sufficient to differentiate cause of patient's presentation
    • Low or nondetectable TSH level and elevated thyroid hormone levels will be present in thyrotoxicosis
• Epilepsy ^r37c128d6
  • Often idiopathic or related to a previous medical cause, an underlying chronic seizure disorder may be mistaken for alcohol withdrawal syndrome
  • If seizures are generalized and tonic-clonic, they will appear similar to alcohol withdrawal seizures
  • History of recurrent seizures or long-term anticonvulsant use is more commonly associated with epilepsy
    • Status epilepticus may occur as part of alcohol withdrawal syndrome but is relatively uncommon
  • Thorough medication and alcohol use histories can differentiate these diagnoses
  • Diagnosis is clinical and usually based on occurrence of at least 2 unprovoked seizures occurring more than 24 hours apart; central nervous system imaging and EEG may aid in diagnosis
• Cranial trauma ^r38r39c129
  • Patients with cranial trauma may have confusion, altered mental status, and seizures; physical signs of trauma to the head and neck may be present
  • Patients with alcohol use disorder are at increased risk of trauma
  • Cranial trauma presentation usually does not include other signs seen in alcohol withdrawal syndrome (such as tremors)
  • History of long-term alcohol use, as opposed to acute alcohol intoxication, can help differentiate between these entities
  • If significant cranial trauma is suspected, obtain CT scan of brain (without contrast material) to evaluate for fractures or intracranial hemorrhage
• ICU delirium ^r40c130
  • Delirium is a generic syndrome with many causes; delirium seen in the ICU setting is associated with critical illness and often respiratory failure
  • Both ICU delirium and delirium tremens present with alterations in sensorium and can occur after admission to ICU setting
  • ICU delirium will typically occur in older adults with critical illness and is associated with more adverse prognosis
  • While delirium tremens presents with a hyperactive delirium, ICU delirium will typically be of a mixed or hypoactive subtype ^r4
  • Diagnosis of delirium is clinical and based on DSM-5 diagnostic criteria ^r41

Admission criteria

Admission criteria to medical unit or inpatient medically supervised detoxification center ^r4

• Patients with more than mild alcohol withdrawal plus all of the following:
  • No underlying medical or surgical condition requiring ICU-level care ^r2
  • Normalization or near-normalization of vital signs within emergency department ^r2
  • Clear sensorium ^r2
  • Responsive to 10 to 20 mg diazepam and tolerating 2 to 4 hours between benzodiazepine doses ^r2
• Clinical Institute Withdrawal Assessment for Alcohol (Revised) score higher than 15 ^r42
• Clinical Institute Withdrawal Assessment for Alcohol (Revised) score 8 to 15 and a history of delirium tremens or alcohol withdrawal seizures ^r42
• Patients at high risk for progression to worsening stage of withdrawal (ie, mild withdrawal despite a detectable ethanol concentration, concomitant use of benzodiazepines, history of severe withdrawal^r17)
• Patients with concomitant major electrolyte disorder, decompensated medical illness,^r42 psychiatric illness, or pregnancy ^r17
• Presence of medical or psychiatric condition or suicidal ideation requiring inpatient admission ^r2

Recommendations for specialist referral

• Treatment of severe withdrawal or patients at high risk for severe withdrawal (eg, comorbidity, concurrent acute illness) should be managed by a clinician well trained in management of alcohol withdrawal syndrome (eg, addiction medicine specialist) ^r7r11
• Consult a medical toxicologist or addiction medicine specialist for patients with benzodiazepine-resistant withdrawal and severe withdrawal for further diagnostic and treatment recommendations

Drug therapy

• Benzodiazepines ^r6
  • Diazepam ^c131
    • Rapid onset of action allows for ease of titration with less risk of dose stacking than with lorazepam ^r2
    • Active metabolites result in a longer duration of action compared with lorazepam ^r2
    • Readminister drug in an escalating dose fashion every 5 to 10 minutes until sedation goals and normalized vital signs are achieved ^r2
      • Common escalating dosing pattern for diazepam: ^r2
        • Initial dose is 10 mg, then observe for 5 to 10 minutes for clinical effects
        • When required, administer second dose of 20 mg then observe for 5 to 10 minutes for effects
        • When required, administer third dose of 40 mg then observe for 5 to 10 minutes for effects
        • Extremely high doses may be required for management of manifestations
          • Requirement of up to 500 mg for initial front-loading dose and cumulative dose of up to 2000 mg over 48 hours are reported ^r2
    • Can be administered intravenously, orally, or rectally
      • Diazepam Solution for injection; Adults: 10 mg IV initially, followed by 5 to 10 mg IV every 3 to 4 hours PRN. Doses of 5 to 10 mg IV may be given every hour if required. Hold if sedated.
    • Example of outpatient oral diazepam dosing regimens ^r10
      • Fixed-schedule
        • Diazepam Oral tablet; Adults: Day 1: 10 mg PO every 6 hours; Day 2: 10 mg PO every 8 hours; Day 3: 10 mg PO every 12 hours; Day 4 and 5: 10 mg PO at bedtime.
      • Symptom-triggered schedule
        • Diazepam Oral tablet; Adults: Day 1:10 mg PO every 4 hours PRN; Day 2 and 3: 10 mg PO every 6 hours PRN; day 4 and 5: 10 mg PO every 12 hours PRN.
  • Lorazepam ^c132
    • Slower time to peak effect than diazepam; therefore, dose stacking may occur if re-dosed before peak effect
    • Lack of active metabolites results in shorter half-life compared with diazepam ^r2
    • Less liver metabolism than other benzodiazepine options; may be preferred in patients with liver failure
    • Readminister drug in an escalating dose fashion every 15 to 20 minutes until sedation goals and normalized vital signs are achieved ^r2
      • Common escalating dosing pattern: ^r2
        • Initial dose is 4 mg, then observe for 15 to 20 minutes for effects
        • When required, administer second dose of 8 mg then observe for 15 to 20 minutes for effects
        • When required, administer third dose of 16 mg then observe for 15 to 20 minutes for effects
        • Extremely high doses may be required for management of manifestations
    • Can be administered intravenously, intramuscularly, or orally
      • Bolus dosing
        • Lorazepam Solution for injection; Adults: Initially 1—2 mg PO/IM/IV q8h. Titrate for desired clinical response. MAX: 4 mg/dose. NOTE: Dosing is highly variable; some patients require high doses of benzodiazepines to treat acute ethanol withdrawal.
      • Continuous infusion
        • For use in patients requiring frequent treatment
        • Infusion carries risk of propylene glycol toxicity and excessive accumulation of drug (ie, dose stacking)
        • Lorazepam Solution for injection; Adults: 1 to 4 mg/hour continuous IV infusion; titrate to effect. Max: 14 mg/hour. ^r56
    • Example of outpatient oral lorazepam dosing regimens ^r10
      • Fixed-schedule
        • Lorazepam Oral tablet; Adults: Day 1 and 2: 2 mg PO every 8 hours; Day 3: 1 mg PO every 8 hours; Day 4: 1 mg PO every 12 hours; Day 5: 1 mg PO at bedtime.
      • Symptom-triggered schedule
        • Lorazepam Oral tablet; Adults: Day 1 and 2: 2 mg PO every 6 hours PRN; Day 3: 1 mg PO every 8 hours PRN; Day 4 and 5: 1 mg PO every 12 hours PRN.
  • Midazolam ^c133
    • Has the most rapid onset of action (1-2 minutes) but short duration of action
    • Can be administered intravenously, intramuscularly, or orally
      • Midazolam Hydrochloride Solution for injection; Adults: Midazolam may be considered as an alternative to commonly used benzodiazepines (e.g., lorazepam). Doses of 1 to 5 mg IV every 1 to 2 hours for mild to moderate alcohol withdrawal symptoms and 1 to 20 mg every 1 to 2 hours by continuous IV infusion for delirium tremens have been suggested from retrospective data. Case reports of larger doses exist in the literature; in 1 report delirium tremens was successfully treated with a total of 2,850 mg of midazolam administered over a 5-day period, with a rate of infusion ranging from 20 to 55 mg/hour. Until more data become available, the lowest effective dose should be used in conjunction with close monitoring for potential adverse effects on respiratory and cardiovascular function. It is advisable to periodically assess the patient for signs of fluid overload.
  • Oxazepam ^c134
    • Preferred in patients with liver dysfunction owing to lack of active metabolites
      • Oxazepam Oral capsule; Adults: 15—30 mg PO 3—4 times daily; geriatric patients may need a reduced initial dose.
  • Chlordiazepoxide ^c135
    • Longer onset and duration of action
      • Inpatient dosing
        • Chlordiazepoxide Hydrochloride Oral capsule; Adults: The suggested initial dose is 50 to 100 mg PO, may repeat q4h to q6h PRN until agitation is controlled. Then reduce to lowest maintenance dose. Max: 300 mg/day PO. Hold doses if overly sedated or lethargic.
    • Example of outpatient oral chlordiazepoxide dosing regimens ^r10
      • Fixed-schedule
        • Chlordiazepoxide Hydrochloride Oral capsule; Adults: Day 1: 25 to 50 mg PO every 6 hours; Day 2: 25 to 50 mg PO every 8 hours; Day 3: 25 to 50 mg PO every 12 hours; Day 4 and 5: 25 to 50 mg PO at bedtime.
      • Symptom-triggered schedule
        • Chlordiazepoxide Hydrochloride Oral capsule; Adults: Day 1: 25 to 50 mg PO every 4 hours PRN; Day 2 and 3: 25 to 50 mg PO every 6 hours PRN; Day 4 and 5: 25 to 50 mg PO every 12 hours PRN.

  • Benzodiazepines for alcohol withdrawal syndrome.

    From Long D et al: The emergency medicine management of severe alcohol withdrawal. Am J Emerg Med. 35(7):1005-11, 2017, Table 4.

    Drug	Time to onset	Active metabolites	Half-life in hours	Typical initial dose
    Diazepam	1 to 5 minutes intravenous	Yes	43 ± 13	10 to 20 mg intravenous or oral
    Lorazepam	5 to 20 minutes intravenous	No	14 ± 5	2 to 4 mg intravenous or oral
    Midazolam	2 to 5 minutes intravenous/intramuscular	Yes	2 ± 1	2 to 4 mg intravenous or intramuscular
    Oxazepam	2 to 3 hours oral	No	8 ± 2	15 to 30 mg oral every 8 hours
    Chlordiazepoxide	2 to 3 hours oral	Yes	10 ± 3	50 to 100 mg oral

• Barbiturates ^r47r57
  • Phenobarbital ^r58c136
    • Effective when used in combination with benzodiazepines for resistant withdrawal and delirium tremens ^r2
    • Paucity of data exists for use as monotherapy; therefore, monotherapy should only be considered in a patient whose condition is refractory to benzodiazepines ^r9
    • Patients requiring phenobarbital may require intubation and mechanical ventilation
    • Bolus dosing
      • Phenobarbital Sodium Solution for injection; Adults: 65 to 260 mg IV bolus every 15 to 30 minutes until control of symptoms is usually adequate. ^r2
    • Infusion
      • Phenobarbital Sodium Solution for injection; Adults: 10 mg/kg IV infusion over 30 minutes. ^r2
        • NOTE: Not readily titratable due to delayed peak onset of action
• Propofol ^{r59r60c137c138}
  • Reserved for severe withdrawal refractory to benzodiazepine therapy in patients requiring intubation and mechanical ventilation ^r9
  • Propofol Emulsion for injection; Adults: Dosages from 5 to 100 mcg/kg/minute (0.3 to 6 mg/kg/hour) IV have been used to reduced alcohol withdrawal symptoms. Development of hypotension may occur. Evaluate clinical effects and CNS function daily to determine minimum effective dosage. ^r61
• α₂ receptor agonists
  • May reduce autonomic signs and symptoms of alcohol withdrawal as an adjunct therapy without an increase in benzodiazepine cumulative doses ^r62r63r64
  • Clonidine ^r10c139
    • May be beneficial adjunct in mild withdrawal states to diminish symptoms in outpatient setting
    • Clonidine Hydrochloride Oral tablet; Adults: In one study, clonidine was dosed initially as 0.2 mg PO at 9PM on day 1; at 9AM, 1PM, and 6PM on day 2; at 9AM and 6PM on day 3; and a final dose at 9AM on day 4.
  • Dexmedetomidine ^r65c140
    • Clinical effects include sedation, anxiolysis, analgesia, and sympatholysis; incidence of respiratory depression is lower compared with other adjunct agents available for severe, refractory withdrawal ^r9
    • Adjunct treatment may lower benzodiazepine requirements and decrease need for mechanical ventilation in patients with severe, refractory withdrawal ^r9
    • Does not prevent or treat withdrawal seizures and may increase rate of delirium, although available data are conflicting ^r9
    • Dexmedetomidine Hydrochloride Solution for injection; Adults: Adjunctive therapy: Initiate infusion at 0.2 mcg/kg/hour IV; titrate by 0.2 mcg/kg/hour every 15 minutes to maintain desired clinical effect (Max dose: 1.4 mcg/kg/hour). ^r2
• β-blockers
  • Atenolol ^c141
    • May be a beneficial adjunct in mild withdrawal states to diminish symptoms in outpatient setting
      • Atenolol Oral tablet; Adults: 50 to 100 mg PO once daily has been studied.
        • Pulse 50 to 79 beats per minute: 50 mg typical dose ^r10
        • Pulse 80 beats per minute or higher: 100 mg typical dose ^r10
• Ketamine ^c142
  • Very limited data demonstrate safety when used as an adjunctive therapy for benzodiazepine resistant withdrawal ^r9r66
    • Ketamine Hydrochloride Solution for injection; Adults: Initially, a loading dose of 0.3 mg/kg, followed by 0.2 mg/kg/hour continuous IV infusion. ^r56r67
• Anticonvulsants
  • May be a beneficial adjunct in mild withdrawal states to diminish craving in outpatient setting ^r68
  • Carbamazepine ^c143
    • Carbamazepine Oral capsule, Extended-Release; Adults: 300 mg PO twice daily on Days 1 through 3, 300 mg PO daily on Day 4, and 100 mg PO daily on Day 5. Individualize dosage based on clinical response and tolerability. ^r69r70
  • Valproic acid ^c144
    • Valproic Acid Oral capsule; Adults: 600 mg PO twice daily for Days 1 and 2, 300 mg PO daily on Days 3 and 4. Individualize dosage based on clinical response and tolerability. ^r10r71
  • Gabapentin ^r10c145
    • Misuse has been reported and caution should be taken especially in patients with substance use disorder ^r72r73
    • Gabapentin Oral capsule; Adults: Use not FDA-approved, but has been studied. Initially, 300 mg PO at bedtime on day 1; then 300 mg PO twice daily on day 2; then 300 mg PO 3 times per day on Day 3; and then titrated upward over days 4 to 7 to reach final dosage. Doses from 600 mg/day to 1,800 mg/day PO have improved abstinence rates and relapse-related symptoms (i.e., insomnia, dysphoria, craving) in some patients.
• Thiamine (vitamin B₁) ^r15
  • Prophylactic dose ^c146
    • Vitamin B₁ (Thiamine Hydrochloride) Oral tablet; Adults: 100 mg PO once daily for 3 to 5 days. ^r42
    • Vitamin B₁ (Thiamine Hydrochloride) Solution for injection; Adults: 100 mg IV once daily for 3 to 5 days. ^r2r9
  • Treatment dose for Wernicke encephalopathy ^c147
    • Thiamine should be given before any glucose administration to avoid precipitating Wernicke encephalopathy;^r9several dosing regimens are available ^r74
    • Vitamin B₁ (Thiamine Hydrochloride) Solution for injection; Adults: 500 mg IV every 8 hours for 5 days, followed by 250 mg IV once daily for 3 to 5 days depending on response. ^r2r11r22r75
• Folate supplementation ^c148
  • Folic Acid Oral tablet; Adults: 1 mg PO once daily for 3 to 5 days. ^r2
  • Folic Acid Solution for injection; Adults: 1 mg IV once daily for 3 to 5 days. ^r2

• Doses and pharmacologic properties of common sedative hypnotics used in the treatment of alcohol withdrawal.

  *All doses on the table are for the IV form of the drug except for chlordiazepoxide because the IV form of this drug has been discontinued in the United States. †Based on longer half-life of lorazepam (and diazepam), infusion dosing generally not recommended. §Case reports of infusion rates up to 520 mg/hour. (Wolf KM et al: Prolonged delirium tremens requiring massive dosages of medication. J Am Board Fam Pract. 6(5):502-4, 1993) **Generally, not given in true infusions.

  Adapted from Stehman CR et al: A rational approach to the treatment of alcohol withdrawal in the ED. Am J Emerg Med. 31(4):734-42, 2013, Table 1.

  	Chlordiazepoxide	Diazepam	Lorazepam	Midazolam	Phenobarbital	Propofol
  Class of drug	Benzodiazepine	Benzodiazepine	Benzodiazepine	Benzodiazepine	Barbiturate	Hypnotic
  Intermittent initial dose	50 to 100 mg (oral)*	10 mg (intravenous)	2 mg (intravenous)	1 to 5 mg (intravenous)	65 mg (intravenous)	Not applicabler61
  Route of dose	Oral	Intravenous, intramuscular, oral, rectal	Intravenous, intramuscular, oral	Intravenous, intramuscular, oral	Intravenous, intramuscular, oral, rectal	Intravenous
  Infusion dosing	Not applicable	Not applicable	1 to 4 mg/hour†r56	1 to 20 mg/hour, titrate up to effect§	10 mg/kg intravenous over 30 minutes**r2	0.3 to 6 mg/kg/hour as needed for appropriate sedationr61
  Time to effect onset	2 to 3 hours	1 to 5 minutes (intravenous); 15 to 30 minutes (intramuscular); 30 to 90 minutes (oral); 10 to 45 minutes (rectal)	5 to 20 minutes	2 to 5 minutes	5 to 30 minutes (peak brain concentrations at 20 to 40 minutes)	1 to 2 minutes
  Half life	5 to 30 hours (active metabolite 30 to 200 hours)	30 to 60 hours (active metabolite 30 to 100 hours)	9 to 21 hours	2 to 6 hours	50 to 140 hours	10 minutes to 12 hours (longer if prolonged use)
  Duration of action	Long	Long	Short to medium	Short	Long	Short to medium
  Metabolism	Hepatic	Hepatic	Hepatic	Hepatic, gut	Hepatic	Hepatic
  Excretion	Renal	Renal	Renal, fecal	Renal	Renal	Renal
  Dose adjustment	Renal (creatinine clearance less than 10): 50% dose reduction; hepatic impairment: risk of accumulation	Hepatic impairment; renal impairment	Renal impairment: dose reduction	Renal failure (creatinine clearance less than 10): dose reduction	Renal failure (GFR less than 10): increase dosing interval and dose reduction; caution in hepatic impairment	None
  Notes	Extremely long-acting active metabolite, so not recommended in elderly patients	Phlebitis; erratic absorption if given intramuscularly	If more than 25 mg/hour, risk of acute tubular necrosis, lactic acidosis, and hyperosmolar state because of solvent; no active metabolite	Prolonged sedation if obese and/or low albumin; active metabolite	May cause hypotension	Risks: propofol infusion syndrome, injection site pain, hypertriglyceridemia; more hypotension than other sedative-hypnotics; may discolor urine. Caution: soy or egg allergy

Nondrug and supportive care

Electrolytes ^c149c150

• Electrolyte abnormalities are common in patients with long-term alcohol use and those with severe withdrawal; correct in standard manner when indicated ^r24
  • Hypokalemia is not uncommon; usually results from dietary deficiency
    • Potassium may require repletion depending on severity of deficiency and presence of symptoms related to deficiency ^r2
  • Hypomagnesemia and hypophosphatemia may occur; usually result from dietary deficiency
    • Routine supplementation is not recommended ^r9
    • Supplementation may be required, especially when symptomatic, given supporting laboratory evidence of severe deficiency
    • Self-correction with proper nutrition is preferred treatment for asymptomatic, mild to moderate deficiency
    • IV repletion is not routinely required ^r2

Fluids ^c151c152

• IV fluid resuscitation may be necessary in patients with severe withdrawal
• Increased fluid losses are not uncommon in patients with hyperthermia, hyperventilation, diaphoresis, and/or agitation ^r6

Nutrition ^r4

• Thiamine ^d7
  • Thiamine is a critical cofactor in carbohydrate metabolism; deficiency results in decreased glucose utilization ^r2
  • Thiamine deficiency is often present and increases risk of Wernicke encephalopathy (eg, altered mental status, ophthalmoplegia, ataxia) ^r2
  • Administer prophylactic dose for presumed thiamine deficiency to all patients presenting in withdrawal ^r2r15
  • Administer treatment dose to any patients with concerning manifestations for Wernicke encephalopathy ^r2
  • Administer thiamine before (preferred) or with glucose administration ^r9
• Folate
  • Supplementation is recommended owing to low dietary folate intake, which may lead to megaloblastic anemia in patients with long-term alcohol use disorder ^r2
  • Multivitamins containing daily recommended allowance of folic acid are often used ^r9
• Provide nutritional support to those with long-term alcohol use to prevent and/or treat ketoacidosis
  • Route of administration is individualized ^r4
    • Enteral is preferred (oral, nasogastric, or nasoduodenal) ^c153c154
    • Parenteral may be required ^c155
• Glucose ^c156
  • Some patients may require glucose supplementation for hypoglycemia because of increased metabolic requirements in the setting of diminished glycogen stores ^r6
  • Untreated hypoglycemia can lead to alcoholic ketoacidosis (hyperketonemia with anion gap metabolic acidosis without significant hyperglycemia), complicating withdrawal management
  • Avoid glucose administration alone (without thiamine administration) in patient at risk for Wernicke encephalopathy

Comorbidities

• Liver failure ^c158
  • IV lorazepam and oral oxazepam may be preferred in patients with advanced cirrhosis, hepatitis, and liver failure owing to the lower degree of hepatic metabolism compared with other benzodiazepines ^r2r6
  • Duration of any benzodiazepines may be significantly prolonged in patients with hepatic dysfunction; dose adjustment may be required ^r2
• Renal insufficiency ^c159
  • Most benzodiazepines and their metabolites are eliminated by the kidney; dose adjustment may be necessary, particularly in agents with active metabolites ^r24
• Wernicke encephalopathy ^c160
  • Administer treatment dose of thiamine for duration of 3 to 5 days to any patients with concerning manifestations for Wernicke encephalopathy ^r2r11
  • Administer thiamine before (preferred) or with glucose administration to avoid precipitating Wernicke encephalopathy in patients at risk ^r9r11

Special populations

• Pregnant women
  • There are no structured guidelines or high-level studies regarding optimal treatment of alcohol withdrawal in pregnancy ^r76
  • As maternal health is vitally important to fetal health, benzodiazepines should still be considered first line treatment
  • Manage in consultation with specialist (eg, substance misuse medicine, high-risk obstetrician)

At-risk populations

• Hospitalized and patients with active alcohol use disorder may be at increased risk ^d10

Screening tests

• Prediction of Alcohol Withdrawal Severity Scale may predict complicated withdrawal among hospitalized patients ^r8c189
  • Score of 4 or higher suggests high risk for developing moderate to severe withdrawal ^r17
    • Sensitivity is approximately 93% and specificity is approximately 99% ^r8
  • Scoring questions are as follows: ^r79
    • Have you consumed any amount of alcohol within the last 30 days? Or did the patient have a positive blood alcohol content on admission?
      • If no, then stop. Prediction of Alcohol Withdrawal Severity Scale is negative
      • If yes, then continue to score 1 point for each of the following:
        • Have you been recently intoxicated/drunk, within the last 30 days?
        • Have you ever undergone alcohol use disorder rehabilitation treatment or treatment for alcoholism?
        • Have you ever experienced any previous episodes of alcohol withdrawal, regardless of severity?
        • Have you ever experienced blackouts?
        • Have you ever experienced alcohol withdrawal seizures?
        • Have you ever experienced delirium tremens or DTs?
        • Have you combined alcohol with other "downers" like benzodiazepines or barbiturates, during the last 90 days?
        • Have you combined alcohol with any other substances of abuse, during the last 90 days?
        • Was the patient’s blood alcohol content on presentation 200 mg/dL or higher?
        • Is there evidence of increased autonomic activity (eg, heat rate above 120 beats per minute, tremor, sweating, agitation, nausea)?