Alcohol Withdrawal

Terminology

Clinical Clarification

• Alcohol withdrawal may occur after cessation or reduction of heavy and prolonged alcohol use; manifestations are characterized by autonomic hyperactivity and central nervous system excitation ^[1][2]

• Severe symptom manifestations (eg, seizures, delirium tremens) may develop in up to 5% of patients ^[4]

Classification

• Based on severity: ^[8]

  • Uncomplicated alcohol withdrawal

    • Majority of patients have uncomplicated minor withdrawal symptoms

    • Manifestations occur within the first 48 hours after last drink or decrease in consumption ^[9]

      • Manifestations develop approximately 6 hours after last drink or decrease in consumption and usually peak at approximately 24 to 36 hours; resolution occurs in 2 to 7 days if withdrawal does not progress to major alcohol withdrawal syndrome ^[10][3]

    • Characterized by mild to moderate autonomic hyperactivity (eg, tachycardia, hypertension, diaphoresis, hyperreflexia), mild tremor, anxiety, irritability, sleep disturbances (eg, insomnia, vivid dreams), gastrointestinal symptoms (eg, anorexia, nausea, vomiting), headache, and alcohol craving ^[3]

  • Complicated or severe alcohol withdrawal

    • Up to 5% of patients develop a more complicated syndrome ^[4][11]

    • Withdrawal manifestations progress and worsen, usually approximately 24 hours after onset of initial manifestations ^[3]

    • Characterized by severe autonomic hyperactivity (eg, tachycardia, hypertension, diaphoresis, hyperreflexia, fever); marked tremor; pronounced anxiety, insomnia, or irritability; anorexia; decreased seizure threshold; hallucinations; and delirium ^[3]

    • Manifestations often peak around 50 hours before gradual resolution or may continue to progress to severe (complicated) withdrawal, particularly without treatment ^[3]

    • Rigorous definition is lacking ^[5]

    • Many experts define by presence of any of the following:

      • Withdrawal seizures ^[4][5]

      • Delirium tremens

      • Clinical Institute Withdrawal Assessment for Alcohol (Revised) score higher than 20 ^[12]

      • Major alcohol withdrawal syndrome manifestations refractory to high-dose benzodiazepines ^[5]

• Based on progressive stages: ^[6]

  • Stage 1

    • Minor symptoms not usually associated with significantly abnormal vital signs ^[12]

  • Stage 2

    • Mild to moderate symptoms associated with abnormal vital signs and possibly alcoholic hallucinosis ^[12]

  • Stage 3

    • Mild to moderate symptoms associated with abnormal vital signs and development of seizures

  • Stage 4

    • Moderate to severe symptoms associated with abnormal vital signs, possibly seizures, and development of delirium ^[12]

Diagnosis

Clinical Presentation

Characteristic withdrawal syndrome develops within hours to days after cessation or reduction of heavy and prolonged alcohol use ^[2]

• Probability of developing withdrawal rises with increasing quantity and frequency of alcohol consumption ^[2]

  • Most affected patients are drinking daily for multiple days and consuming large amounts (ie, more than 8 drinks/day for multiple days) ^[2][5]

• Symptoms typically begin after sharp decline in blood alcohol concentration ^[2]

• Reduction or cessation in alcohol use may not always be intentional ^[6][13]

  • Inability to acquire or pay for alcohol

  • Gastrointestinal illness characterized by decreased oral intake

  • Hospital admission for another medical issue ^[7]

    • Up to 8% of patients admitted to hospitals with nonalcohol-related diagnoses exhibit signs of withdrawal

Earlier medical history may be significant for: ^[6]

• Alcohol use disorder

  • 50% to 80% of patients with alcohol use disorder develop some form of central nervous system stimulation and adrenergic hyperactivity with reduction or discontinuation of alcohol consumption ^[9][11]

  • Suspect alcohol dependence in female patients who: ^[12]

    • Consume more than 1 drink daily or more than 7 drinks weekly

    • Have had more than 4 drinks on a single occasion in the past year (generally within 2 hours) ^[14]

  • Suspect alcohol dependence in male patients who: ^[12]

    • Consume more than 2 drinks daily or more than 14 drinks weekly

    • Have had more than 5 drinks on a single occasion in the past year (generally within 2 hours) ^[14]

• History of prior withdrawal

  • Course of prior alcohol withdrawal episodes is the most reliable predictor of subsequent episodes ^[15]

Psychiatric history

• Alcohol may cause several psychiatric conditions such as alcohol-induced mood, anxiety, or psychotic disorder ^[6]

• Underlying psychiatric disorders (eg, antisocial personality disorder, schizophrenia, major anxiety disorders, bipolar disorder) or other drug use disorder and dependence may be present

Factors that may modify withdrawal symptoms or course

• Relief of symptoms can occur by administration of alcohol or benzodiazepines ^[2]

• Concurrent use of medication for other underlying disorders (eg, β-blockers, α₂-adrenergic agonists) may blunt typical abnormalities noted in vital signs at presentation. ^[4]

Presence of comorbidity

• Patients with underlying psychiatric disorders may use alcohol to alleviate psychiatric symptoms (eg, anxiety, depression) ^[6]

• Acute medical or surgical disorder may precipitate withdrawal ^[6]

• Poorly controlled medical comorbidity may precipitate withdrawal ^[6]

Acute withdrawal may progress in stages ranging in severity from mild to severe ^[16]

• Manifestations during stages may overlap and may not progress in a precise sequential pattern ^[6]

• Early withdrawal: symptoms of central nervous system stimulation typically occurring within 48 hours of drinking cessation ^[9]

  • Stage 1 (hangover stage)

    • Initial broad withdrawal manifestations begin 6 to 8 hours after last drink and may include: ^[4]

      • Sympathomimetic symptoms (eg, diaphoresis, palpitations)

      • Mild tremor

      • Insomnia and anxiety

      • Gastrointestinal (eg, nausea, vomiting)

      • Headache

    • If withdrawal does not progress, these manifestations may resolve within 24 to 48 hours ^[4]

  • Stage 2 (alcoholic hallucinosis stage)

    • Develops approximately 24 to 48 hours after last drink, but may be up to 8 days later ^[6]

    • Worsening sympathomimetic symptoms (eg, diaphoresis, fever), marked tremors, worsening hyperactivity, and insomnia

    • Sensorium is lucid but nightmares or illusions are not uncommon

    • Hallucinations may develop

      • Most commonly occur 12 to 24 hours after last drink ^[4]

      • Occur in 7% to 8% of untreated patients with withdrawal ^[4]

      • Can be visual, auditory, or tactile ^[4]

        • Isolated visual hallucinations are most common ^[12][17]

      • May occur in isolation without other broad withdrawal manifestations

      • Sensorium is normal (ie, delirium is absent; patient is aware that hallucinations are not real) ^[9]

  • Stage 3 (tonic-clonic seizure stage)

    • Similar to stage 2 with development of tonic-clonic seizures ^[6]

    • Withdrawal seizures (rum fits)

      • Commonly occur 12 to 48 hours after last drink ^[4]

      • May occur in up to 10% of patients ^[1]

        • Alcohol withdrawal represents 1 of the most common causes of adult-onset seizures ^[3]

      • Commonly consist of isolated, short-duration, generalized tonic-clonic seizures with short or absent postictal period ^[1]

        • May occur in clusters and may be recurrent in a minority of patients ^{[6][18][6][9]}

        • Prolonged seizures and status epilepticus are relatively uncommon ^[6]

      • Seizures impart increased risk for complications (eg, aspiration pneumonia, rhabdomyolysis) ^[6]

      • Approximately one-third of patients who develop seizures progress to delirium tremens without treatment

• Late withdrawal: symptoms typically occurring later than 48 hours after drinking cessation ^[9]

  • Stage 4 (delirium tremens stage)

    • High likelihood that a concurrent, clinically relevant medical condition exists when delirium develops ^[2]

      • May include liver failure, pneumonia, gastrointestinal bleeding, head trauma, hypoglycemia, electrolyte imbalance, and postoperative state

    • Delirium tremens

      • Consists of severe autonomic hyperactivity and ongoing agitation plus rapid-onset delirium (ie, fluctuating disturbance of attention and cognition)

        • Manifestations fluctuate in severity throughout the day and may include: ^[5]

          • Lack of attention and awareness

          • Memory loss and disorientation

          • Hallucinations

          • Agitation ^[9]

      • Usually begins 2 to 3 days after initial withdrawal symptoms appear and lasts for 1 to 8 days; may be delayed up to 12 days ^[4][6]

        • Rarely, may develop as early as 8 hours after last drink ^[4]

      • Often associated with cardiovascular, respiratory, and metabolic abnormalities ^[6]

      • Occurs in 1% to 5% of hospitalized patients with withdrawal ^[4][6]

      • Risk is significantly increased in patients with concurrent acute medical illness ^[6]

Physical examination

• Common findings ^[1][6]

  • Autonomic hyperactivity with sympathomimetic signs

    • Tachycardia

    • Hypertension

    • Diaphoresis

    • Fever

    • Mydriasis

    • Tachypnea

  • Central nervous system hyperstimulation

    • Coarse tremor

      • Often most easily found in the hands or tongue

    • Hyperreflexia

    • Hallucinations

    • Seizures

    • Delirium

• Findings concerning for concurrent Wernicke encephalopathy

  • Nystagmus or oculomotor abnormalities

  • Ataxia or gait disturbance

Causes and Risk Factors

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 ^[6]

    • 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) ^[4]

      • Inhibited excitatory tone occurs through NMDA (N-methyl-D-aspartate) receptor modulation (affecting several proteins involved in NMDA pathways) ^[4]

    • Alcohol administration increases catecholamine levels affecting central α- and β-adrenergic receptors ^[3][6]

    • 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

    • Refers to development of neuronal networks that may result in worsening episodes of withdrawal on subsequent episodes

• Discontinuation or dramatic reduction in alcohol consumption

  • Central nervous system hyperstimulation results from loss of GABA receptor inhibition and potentiation of NMDA receptor excitation ^[4]

  • Dopaminergic dysregulation may also play a role in agitation, hallucinations, and delirium ^[9]

  • Gradual increase in adrenergic activity results from excess glutamate activity on excitatory NMDA receptors and excess catecholamine effects on central α- and β-adrenergic receptors ^[3][6]

  • Abnormalities in the balance of other neurochemical systems, electrolytes, and vitamins may also contribute to development of withdrawal

Risk factors and/or associations

Age

• Risk of withdrawal increases with age ^[2]

  • Most common in middle-aged adults ^[6]

  • Relatively rare in patients aged younger than 30 years ^[2]

• Older patients are at increased risk for morbidity and mortality ^[7]

Sex

• Most patients admitted to hospitals with alcohol withdrawal syndrome are male ^[6]

Other risk factors/associations

• Risk factors for withdrawal

  • Risk increases linearly with quantity and frequency of alcohol intake ^[5]

  • Concurrent medical condition that precludes alcohol intake ^[2]

  • Family history of alcohol withdrawal ^[2]

  • Personal history of alcohol withdrawal ^[2]

  • Concurrent long-term use and then discontinuation of sedative, hypnotic, or anxiolytic drugs ^[2]

  • Tolerance phenomenon ^[9]

• Risk factors for severe withdrawal course are inconsistently reported in literature but may include:

  • Prior episode of withdrawal, especially severe withdrawal ^[18]

  • Drinking patterns that include: ^[6]

    • Greater maximum dose of daily alcohol

    • Greater number of drinking days per month

    • Need for alcoholic drink in the early morning

  • Older age, especially 60 years or older ^[2][19]

  • Acute and chronic comorbid medical problems (eg, alcoholic liver disease, cointoxications, trauma, infections, sepsis, history of structural brain lesion ) ^[20][6]

  • Nonmedical use of sedative hypnotics ^[6]

  • Detectable blood alcohol level on admission with withdrawal manifestations ^[6]

  • Severe symptoms early in withdrawal course ^[9]

  • Grade 2 severity or higher on presentation (initial Clinical Institute Withdrawal Assessment for Alcohol [Revised] score higher than 10) ^[6]

  • Abnormal liver function (serum AST activity greater than 80 units/L) ^[6]

  • Presence of significant dehydration or electrolyte abnormalities at presentation ^[16]

  • Low initial platelet count and/or serum potassium level ^[15][20]

  • Male sex ^[6]

• Risk factors for delirium tremens are inconsistently reported in literature but may include:

  • Concurrent medical illness (eg, pneumonia, active ischemia) ^[9]

  • History of delirium tremens ^[11]

  • Withdrawal seizures, specifically if left untreated or recurrent ^[9][11]

  • Clinical Institute Withdrawal Assessment for Alcohol (Revised) score of 15 or higher ^[11]

  • Sustained drinking history ^[4]

  • Systolic blood pressure greater than 150 mm Hg and/or heart rate greater than 100 beats per minute ^[11]

  • Last alcohol intake more than 2 days ago ^[4]

  • Aged older than 30 years ^[4]

  • Recent misuse of other depressants (eg, benzodiazepines) ^[11]

Diagnostic Procedures

Primary diagnostic tools

• If patients present with clinical manifestations of alcohol withdrawal, assess quantity and frequency of alcohol consumption and time last consumed ^[21]

  • Consider use of screening tool for unhealthy alcohol use

  • May gain additional information from family or friends

  • May use alcohol breath, blood, or urine test to identify recent alcohol use if patient is unable to give history

• Withdrawal is a clinical diagnosis and a diagnosis of exclusion ^[4]

  • DSM-5-TR 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 ^[16]

• Measure severity of withdrawal with applicable severity assessment tool

  • Several scales are available; most commonly used include:

    • Short Alcohol Withdrawal Scale ^[12]

      • 10-item scale requiring patient participation; most common tool used for outpatients

    • Clinical Institute Withdrawal Assessment for Alcohol (Revised) scale ^[6][22]

      • 10-item scale requiring patient cooperation; most common tool used for inpatients

    • Richmond Agitation-Sedation Scale ^[6][23]

      • 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 ^[4][16]

• Evaluate risk for severe or complicated withdrawal using risk assessment tool ^[21]

  • The following factors increase risk for complicated withdrawal or complications associated with withdrawal:

    • History of previous alcohol withdrawal delirium or seizure

    • Numerous past episodes of withdrawal

    • Comorbid conditions

    • Aged older than 65 years

    • Long duration of heavy alcohol use

    • Seizure during this presentation

    • Marked autonomic hyperactivity

    • Dependence on benzodiazepines or barbiturates

    • Moderate or worse withdrawal at presentation

  • Risk assessment tools include ASAM (American Society of Addiction Medicine) Criteria Risk Assessment Matrix, Prediction of Alcohol Withdrawal Severity Scale, and Luebeck Alcohol Withdrawal Risk Scale ^[24]

• Evaluate for other disease that may have contributed to precipitation of withdrawal ^[4]

  • Consider presence of concomitant condition or complication of long-term alcohol use, especially in the presence of severe withdrawal (eg, delirium) ^[2]

    • Withdrawal is often precipitated in patients with comorbid medical or surgical conditions during periods of abstinence when illness or surgery prevents alcohol intake ^[6]

    • 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 workup by 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 approximately one-third of patients and diagnosis is missed in up to 80% of cases ^[4]

• Evaluate for other substance use ^[21]

• 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) ^[6][12]

  • Obtain finger stick glucose measurement for all patients with altered mental status or seizures ^[18]

  • Most experts order the following:

    • Metabolic panel with serum electrolyte, magnesium, phosphate, and glucose levels, plus renal function testing ^[18]

    • CBC ^[18]

    • Liver function tests, including INR and serum AST, ALT, bilirubin, and ammonia ^[18]

  • Consider the following:

    • Head CT or other brain imaging for patients with seizures: only attribute seizure to alcohol withdrawal if there is recent cessation or marked reduction in alcohol consumption ^[16][21]

    • 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 patients

    • Screening for hepatitis, HIV, and tuberculosis ^[21]

• Refer to regionally specified protocols to guide evaluation strategy ^[25]

Laboratory

• Serum blood alcohol concentration

  • 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 ^[2]

    • Anticipate worsening of withdrawal manifestations as ethanol concentration falls in patients presenting with alcohol withdrawal and an elevated ethanol concentration ^[4]

• Metabolic panel with serum electrolyte (including magnesium) and glucose levels ^[26]

  • Abnormal findings are common in long-term alcohol use and may include: ^[27]

    • Hypoglycemia

    • Hypokalemia

    • Hypomagnesemia

    • Hypophosphatemia

• Renal function tests (BUN, creatinine)

  • Renal insufficiency can guide choice of doses in treatment ^[28]

• Liver function testing

  • Evaluation of hepatic transaminases and synthetic liver function (eg, prothrombin time, INR) may help guide medication choice and assess for alcohol-related hepatic injury ^[28]

Imaging

• Head CT

  • May be indicated to exclude alternate causes of manifestations or with concern for trauma

• Chest radiograph

  • May be indicated to assess for acute pneumonia or other concurrent pulmonary disease

Other diagnostic tools

• DSM-5-TR clinical diagnostic criteria

  • Alcohol withdrawal syndrome ^[2]

    • 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 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

      • Nausea or vomiting

    • C: signs and symptoms in criterion B cause clinically significant distress or impairment in social, occupational, or other important areas of functioning

    • D: 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

    • Confusion or change in consciousness is not a core criterion for alcohol withdrawal; however, delirium may be present ^[2]

  • Criteria for alcohol withdrawal delirium ^[29]

    • Alcohol withdrawal delirium diagnosis should be made instead of alcohol withdrawal when symptoms in criteria A and C predominate in the clinical picture and when they are sufficiently severe to warrant clinical attention

    • A: disturbance in attention (ie, reduced ability to direct, focus, sustain, and shift attention) and awareness (reduced orientation to 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: disturbance in criteria 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 no evidence from 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

  • Validated for use in outpatient setting ^[12]

    • 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) ^[22]

  • Objectively measures severity of withdrawal and determines likelihood of progressing alcohol withdrawal syndrome; clinical uses may include: ^[6]

    • Determination of need for medically supervised withdrawal management

      • Initial score higher than 10 is correlated with risk of developing severe withdrawal; requires further evaluation and development of admission goals of therapy ^[6]

    • Monitor course of withdrawal and guide symptom-triggered treatment when alcohol use history is known

      • Patients with scores less than 10 do not usually need additional medication ^[12]

      • Patients requiring treatment with scores of 15 or less are likely to respond to moderate benzodiazepine doses ^[11]

      • Patients with scores higher than 15 require close monitoring and aggressive treatment to avoid seizures and alcohol withdrawal delirium ^[11]

  • 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 ^[4]

  • Scores are altered by pain, other medical and surgical issues, and administration of sedation agents ^[6]

  • Scoring-based severity is variably reported and not rigorously standardized; refer to regional protocol to guide symptom-triggered treatment based on specific score

    • 1 source suggests the following: ^[12]

      • Absent or very mild withdrawal: score of 8 or less

      • 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, less than 8, 0 to 8 ^[30][11][16]

      • Moderate: 10 to 18, 8 to 15, 9 to 15 ^[30][11][16]

      • Severe: 19 or higher, higher than 15, 16 or higher ^[30][11][16]

• Richmond Agitation-Sedation Scale ^[6][23]

  • Use to assess effectiveness of sedation in patients who lack 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; awakens 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; moves in response to voice, without eye contact

    • −4: patient is deeply sedated; moves 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) ^[4]

• Prediction of Alcohol Withdrawal Severity Scale may predict complicated withdrawal among hospitalized patients ^[10][24]

  • Score of 4 or higher suggests high risk for developing moderate to severe withdrawal ^[18]

    • Sensitivity is approximately 93% and specificity is approximately 99% ^[10]

  • Scoring questions are as follows: ^[31]

    • 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, heart rate above 120 beats per minute, tremor, sweating, agitation, nausea)?

Differential Diagnosis

Most common

• Sedative-hypnotic medication withdrawal ^[32][33]

  • Withdrawal from chronically used sedative-hypnotic medications, including benzodiazepines, barbiturates, baclofen, or γ-hydroxybutyrate (GHB) ^[34][35]

  • May present with symptoms similar to those of alcohol withdrawal syndrome (eg, anxiety, restlessness, tremor, tachycardia, delirium, hallucinations, seizures)

  • Sedative-hypnotic medication withdrawal and alcohol withdrawal are virtually indistinguishable from a clinical standpoint

  • History of long-term alcohol use may point toward 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 show fulfillment of benzodiazepine prescriptions

• Stimulant intoxication ^[36]

  • 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 (eg, picking at objects [real or imagined] on skin or bed sheets, 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 ^[37]

  • Chronic psychiatric disorder characterized by faulty perceptions and withdrawal from reality that may present similarly to alcohol withdrawal with delusions and hallucinations

  • Onset is typically in adolescence or young adulthood and may be more gradual than onset of alcohol withdrawal syndrome

    • While substance use is common among patients with schizophrenia, 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-TR criteria ^[38]

• Encephalitis ^[39]

  • 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 ^[6]

  • 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 ^[40]

  • 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 are 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 are present in thyrotoxicosis

• Epilepsy ^[41]

  • 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 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 ^[42][43]

  • Patients with cranial trauma may have confusion, altered mental status, and seizures; physical signs of trauma to 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 (eg, 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 ^[44]

  • 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 typically occurs in older adults with critical illness and is associated with more adverse prognosis

  • While delirium tremens presents with a hyperactive delirium, ICU delirium is typically of a mixed or hypoactive subtype ^[6]

  • Diagnosis of delirium is clinical and based on DSM-5-TR diagnostic criteria ^[45]

Treatment

Goals

• Monitor withdrawal course and provide symptomatic treatment with aim to normalize vital signs, relieve anxiety, and halt progression to severe withdrawal ^[1]

• Manage severe withdrawal (eg, seizures, delirium) and monitor for complications (eg, respiratory depression, pneumonia, rhabdomyolysis) ^[1]

• Address and manage other comorbid or concurrent medical, surgical, traumatic, toxicologic, or psychiatric issues ^[6]

• Arrange for substance use disorder treatment and encourage long-term abstinence ^[1]

Disposition

General criteria for outpatient management ^[12]

• Mild to moderate withdrawal and:

  • No serious psychiatric problems (eg, suicidal ideation, psychosis), medical comorbidity, or acute illness

  • No significant laboratory abnormalities, when obtained

  • No concurrent substance use disorder

  • Low risk for development of delirium tremens

  • No history of significant alcohol withdrawal (eg, withdrawal seizure)

  • Ability to take oral medications

  • Commitment to frequent follow-up visits

  • Presence of friend or relative who can monitor patient and administer medications

  • Aged 16 years or older ^[25]

General criteria for discharge with referral for outpatient alcohol dependence treatment program:

• Clinical Institute Withdrawal Assessment for Alcohol (Revised) score less than 8 to 10 ^[4][6][46]

• No current intoxication (alcohol or other drugs) ^[4]

• No history of complicated alcohol withdrawal syndrome (ie, seizures, hallucinosis, delirium tremens) ^[4]

• No significant medical or psychiatric comorbidity or suicidal ideation ^[4][46]

• Ability to maintain regular outpatient visits and therapy ^[4]

General criteria for outpatient detoxification:

• Clinical Institute Withdrawal Assessment for Alcohol (Revised) score 15 or less ^[4]

• Lack of symptoms or history of delirium tremens or alcohol withdrawal seizures ^[4][46]

• Ability to take oral medications ^[4]

• Presence of a family member or close contact who can stay with the patient ^[4]

• Lack of unstable medical condition ^[4]

• Lack of psychosis or suicidality ^[4]

• Ability to commit to daily medical visits and adequate follow-up ^[4]

Admission criteria

Admission criteria to medical unit or inpatient medically supervised detoxification center ^[6]

• Patients with more than mild alcohol withdrawal plus all of the following:

  • Lack of underlying medical or surgical condition requiring ICU-level care ^[4]

  • Normalization or near-normalization of vital signs within emergency department ^[4]

  • Clear sensorium ^[4]

  • Response to 10 to 20 mg diazepam and toleration of 2 to 4 hours between benzodiazepine doses ^[4]

• Clinical Institute Withdrawal Assessment for Alcohol (Revised) score higher than 15 ^[46]

• Clinical Institute Withdrawal Assessment for Alcohol (Revised) score of 8 to 15 and history of delirium tremens or alcohol withdrawal seizures ^[46]

• Patients at high risk for progression to worsening stage of withdrawal (ie, mild withdrawal despite detectable ethanol concentration, concomitant use of benzodiazepines, history of severe withdrawal )^[18]

• Patients with concomitant major electrolyte disorder, decompensated medical illness, psychiatric illness, or pregnancy ^[46][18]

• Presence of medical or psychiatric condition or suicidal ideation requiring inpatient admission ^[4]

Criteria for ICU admission

• Intubation or other respiratory support requirement ^[6]

• Severe hemodynamic abnormalities ^[6]

  • Significant tachycardia or hypotension

• Persistent fever higher than 39 °C ^[6]

• Severe, or advanced stage 2 or greater, withdrawal ^[6]

  • Delirium

  • Recurrent seizures

  • Requirement for large or escalating doses of benzodiazepines or barbiturates ^[1][4]

  • Moderate to severe withdrawal despite elevated blood alcohol concentration ^[4]

• Consider for patients with:

  • Significant medical or surgical comorbidities (eg, cardiac disease, respiratory disease, renal insufficiency, acute serious infection, trauma) ^[4][6]

  • Evidence of significant alcohol-related complications (eg, hepatic insufficiency, pancreatitis, gastrointestinal bleeding, rhabdomyolysis) ^[4]

  • History of complicated alcohol withdrawal or severe withdrawal course ^[4]

  • Marked fluid or electrolyte abnormalities ^[6]

  • Need for treatment of suspected Wernicke encephalopathy ^[4]

  • Older age ^[18]

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) ^[9][11]

• Consult a medical toxicologist or addiction medicine specialist for patients with benzodiazepine-resistant withdrawal and severe withdrawal for further diagnostic and treatment recommendations

Treatment Options

Resuscitation and stabilization is first aspect of care while assessing need for treatment of concurrent medical conditions ^[4][8]

• Manage airway and administer oxygen as indicated clinically ^[18]

• Initiate fluid resuscitation and start IV fluids when clinically indicated ^[18]

• Treat concurrent medical conditions ^[18]

• Treat hypoglycemia; it is preferable to begin thiamine administration before administration of glucose, but treatment of hypoglycemia should not be delayed ^[5][16]

Determine level of care and setting necessary for appropriate management

• Patients with very mild withdrawal (ie, Clinical Institute Withdrawal Assessment for Alcohol [Revised] score lower than 8-10 with isolated stage 1) do not require pharmacologic management or admission if there is no progression or complicating factors ^[6][11]

  • May be managed with supportive care alone, carbamazepine, or gabapentin ^[21]

  • Some experts consider prescribing brief lorazepam regimen as needed for 3 to 5 days ^[46]

• Patients with mild to moderate manifestations without significant comorbidity or significant risk of developing severe withdrawal may be managed in either: ^[6][12][19]

  • Outpatient setting with oral medications and daily follow-up when environment is conducive to recovery

    • Benzodiazepines are the first line treatment; carbamazepine or gabapentin can be alternatives or adjunctive agents ^[47][48]

  • Residential detoxification centers when home environment is unstable or not conducive to recovery

    • Centers may be medically managed by nursing staff with consulting physician or nonclinically managed by social workers and counselors

• Stabilization in an emergency setting and medically monitored inpatient or residential admission is appropriate for patients presenting with: ^[12]

  • Moderate to severe manifestations ^[6]

  • Significant comorbid psychiatric, medical, or surgical conditions ^[6]

  • Risk for severe withdrawal ^[19]

Regional protocols are available to guide management strategy for both inpatient and outpatient treatment ^[25]

Standard inpatient alcohol withdrawal treatment with medical assistance ^[1]

• Sedative hypnotics are the cornerstone of initial management ^[5]

  • Goal of initial treatment is rapid sedation with normalization of vital signs ^[1]

    • Consider alternative or concurrent diagnosis if appropriate sedation is achieved without normalization of vital signs ^[18]

    • Appropriately sedated patient is calm and sleepy but arousable without active hallucinations or seizures ^[23]

    • Early and adequate treatment minimizes morbidity; administration of adequate benzodiazepine dose based on high withdrawal score (Clinical Institute Withdrawal Assessment for Alcohol [Revised]) is indicated regardless of blood alcohol concentration

  • Benzodiazepines are first line treatment ^[1][41][49]

    • Treat psychomotor agitation and prevent progression to more serious withdrawal symptoms (eg, seizures, delirium tremens)

    • Act as GABA-A agonist to overcome loss of central nervous system GABA-A inhibitory effects ^[4]

    • Preferred methods of administration include:

      • IV route for severe symptoms; oral route for less severe symptoms ^[4]

      • Front-loading (loading dose) of benzodiazepines ^[50]

        • Decreases rate of seizures, achieves earlier symptom control, and decreases total cumulative dose of medication needed

        • Involves high initial doses repeated frequently (eg, every 2-3 hours)

        • Often a long-acting agent is used (eg, diazepam)

      • Rapid and repeated escalating dosing (ie, double subsequent doses if control not achieved) of benzodiazepines

        • Reduces risk of seizures, delirium tremens, and need for mechanical ventilation in patients with severe withdrawal ^[4]

        • Titrate based on sequential sedation scale scores ^[6]

        • No maximum dose of benzodiazepines exists for treatment of alcohol withdrawal ^[4]

        • Dose required to control manifestations is highly variable among patients ^[11]

    • Debate exists regarding which benzodiazepine is the best treatment option ^[4]

      • Some clinicians prefer IV diazepam or lorazepam for acute severe symptom control ^[4]

        • Diazepam has shorter onset of action when compared to lorazepam, which may allow more rapid determination of dose response and more frequent dose titration with less risk of dose stacking ^[4][5]

          • Lorazepam has a slower time to peak effect than diazepam; therefore, dose stacking may occur if re-dosed before peak effect

        • Longer duration of action with diazepam may allow for smoother downward titration compared to lorazepam ^[4][5]

          • Lack of active metabolites for lorazepam results in shorter half-life compared to diazepam, which has active metabolites ^[4]

        • Diazepam may require dose adjustment in patients with renal failure because active metabolites are eliminated by kidneys; avoid in patients with liver disease ^[5]

        • Lorazepam may be safer in patients with liver dysfunction and those at high risk of serious medical consequences after sedation (eg, older patients, those with severe pulmonary dysfunction) because lack of active metabolites leads to lower risk of overdose ^[9]

      • Midazolam has the most rapid onset of action (1-2 minutes) but short duration of action

      • Exercise caution with routine use of more than 1 type of benzodiazepine in combination; experts recommend use of only a single benzodiazepine ^[9]

        • Use of 2 different benzodiazepines may be required in select scenarios including: ^[51]

          • Transitioning to tapering phase of treatment

          • Initial stabilization phase of treatment, particularly in patients with severe withdrawal

            • Some experts maintain that alternating doses of lorazepam and diazepam in patients with severe withdrawal may be more effective at arresting withdrawal than use of lorazepam alone and leads to less postwithdrawal sedation than use of diazepam alone

  • Benzodiazepine equivalents: diazepam 5 mg = lorazepam 1 mg = chlordiazepoxide 25 mg = oxazepam 15 mg ^[16]

  • Second line adjunct treatments for withdrawal resistant to benzodiazepines alone include phenobarbital and/or propofol ^[4][21]

    • Can work synergistically with benzodiazepines on the GABA-A receptor ^[1][52]

      • Limited data suggest that a single dose of IV phenobarbital combined with symptom-triggered benzodiazepine treatment of acute withdrawal decreases rates of ICU admission without significant adverse effects ^[53]

    • Respiratory and cardiac depressant effects are more common than with benzodiazepines alone

    • Emerging adjunct treatments include dexmedetomidine and ketamine ^[4]

    • Carbamazepine, phenobarbital, or gabapentin may be used when benzodiazepines are contraindicated ^[21]

• Continued inpatient alcohol withdrawal management with medical assistance

  • Dosing regimens

    • Symptom-triggered (as needed) dosing of benzodiazepines is preferred to scheduled dosing after initial stabilization of symptoms for most inpatients ^[21][50][54]

      • Symptom-triggered dosing based on severity scales allows for individualized dosing and results in shorter duration of therapy and lower cumulative medication doses ^[4][5]

      • Numerous regional guidelines outline individual treatment protocols with a great deal of variability among them; insufficient evidence is available to recommend 1 individual protocol above another

        • Refer to individual hospital-driven and regional protocols for specific dosing recommendations ^[9][18]

    • Fixed-tapering-dose regimen may be best suited for outpatient detoxification and for patients in whom sedation scales cannot be accurately applied (eg, severe comorbid illness)

    • Front-loading is recommended for patients having severe withdrawal ^[21]

    • Examples of dosing regimen are described in ASAM guideline on alcohol withdrawal management ^[21]

  • Use objective measurement of symptom severity to determine frequency of administration targeted to treatment goals ^[4]

    • Several scales assess severity of withdrawal

      • General target treatment goals include prevention of withdrawal seizures and delirium tremens, normalization of vital signs, and reduction or elimination of sensory disturbances (eg, agitation, anxiety, hallucinations)

      • Clinical Institute Withdrawal Assessment for Alcohol (Revised) is most commonly used ^[4]

        • Goal of treatment is a calm awake state ^[16]

        • Suggested treatment response to score ^[9]

          • Lower than 10: no need for pharmacotherapy

          • 11 to 20: clinical judgment is necessary regarding need for pharmacotherapy

          • Higher than 21: requires pharmacotherapy

        • Not validated for patients requiring ICU level of care ^[5]

      • ICU sedation scales are often used for patients with severe withdrawal or withdrawal requiring intubation ^[4]

        • Richmond Agitation-Sedation Score is most commonly used ^[6]

          • Score of 0 to −2 indicates patient is in a calm, arousable state ^[4]

  • Tapering

    • Usually benzodiazepines can be tapered down from peak dosing after approximately 48 to 72 hours ^[9]

    • General guideline is to taper by approximately 20% of total daily benzodiazepine equivalent dose ^[51]

    • Some experts prefer chlordiazepoxide for scheduled tapering protocol; other experts prefer lorazepam given by a symptom-triggered tapering strategy ^[51]

• Manifestation-specific treatment

  • Seizures

    • Benzodiazepines are first line treatment ^[4]

    • Barbiturates and propofol are second line treatment options for seizures recalcitrant to benzodiazepines ^[55]

    • Avoid other anticonvulsants (eg, carbamazepine, phenytoin, valproic acid, levetiracetam) for treatment or prophylaxis of seizures because most seizures are self-limited and inconsistently responsive to anticonvulsants other than benzodiazepines and barbiturates ^[4]

    • Long-term anticonvulsant therapy is not necessary unless patient has underlying seizure disorder or epilepsy ^[6]

    • Refractory status epilepticus may require management in consultation with specialists (eg, medical toxicologist, neurologist) and infusion of phenobarbital, pentobarbital, propofol, or midazolam ^[3]

  • Alcoholic hallucinosis

    • Benzodiazepines are first line treatment ^[4]

    • Avoid routine use of antipsychotics (eg, phenothiazines, butyrophenones) because they lower seizure threshold, often have anticholinergic effects (eg, worsening hypertension, tachycardia), mask symptoms of worsening withdrawal, and increase risk of respiratory complications ^[18][4][6]

      • May be beneficial for patients with known or suspected thought disorders (eg, schizophrenia) ^[4]

      • May be used in outpatient setting to diminish craving

  • Autonomic hyperactivity

    • Adjunct medications that may be useful to diminish symptoms but do not prevent seizures or delirium tremens include: ^[6]

      • β-blockers

        • May diminish symptoms such as tremor, tachycardia, cardiac arrhythmias, hypertension, and craving

      • Clonidine (α₂ agonist)

        • May diminish severity of symptoms in mild to moderate withdrawal

  • Delirium and severe agitation

    • Management requires aggressive sedation ^[6]

      • Extremely high benzodiazepine dosing may be required to achieve sedation goals

      • Titrated IV infusion may be required

      • Adjunct measures for benzodiazepine-resistant withdrawal may be required

    • Potential need for endotracheal intubation and mechanical ventilation is high ^[6]

    • Maintain high awareness for potential complications (eg, development of pneumonia and sepsis) ^[6]

    • Physical restraints may be temporarily required; however, take care to avoid prolonged physical restraints without appropriate sedation owing to increased risk for rhabdomyolysis ^[1][16]

    • Intermittent verbal reorientation to time, place, and date are important after stabilization ^[5]

• Benzodiazepine-resistant withdrawal

  • Clear definition is lacking; many experts define as lack of symptom control after the following doses:

    • At least 40 to 50 mg diazepam or 8 to 10 mg lorazepam within the first hour of treatment ^[4][5]

    • More than 200 mg diazepam or 40 mg lorazepam within 3 hours of treatment ^[4]

  • If rapid escalation of benzodiazepines fails to control symptoms, adjunct treatment options include phenobarbital, propofol, ketamine, and dexmedetomidine ^[4][56]

    • Phenobarbital is effective when used in combination with benzodiazepines for resistant withdrawal and delirium tremens ^[4][57]

      • Paucity of data exists for phenobarbital use as monotherapy; therefore, monotherapy should only be considered in a patient whose condition is refractory to benzodiazepines ^[5][57][58]

      • Patients requiring phenobarbital may require intubation and mechanical ventilation

    • Reserve propofol for severe withdrawal refractory to benzodiazepine therapy in patients requiring intubation and mechanical ventilation ^[5]

    • Dexmedetomidine and ketamine use has not been studied as much as phenobarbital and propofol use ^[4]

      • Adjunct treatment with dexmedetomidine may lower benzodiazepine requirements and decrease need for mechanical ventilation in patients with severe, refractory withdrawal ^{[5][59][60][61][62]}

        • Clinical effects of dexmedetomidine include sedation, anxiolysis, analgesia, and sympatholysis; incidence of respiratory depression is lower compared with other adjunct agents available for severe, refractory withdrawal ^[5]

        • Dexmedetomidine does not prevent or treat withdrawal seizures and may increase rate of delirium, although available data are conflicting ^[5]

      • Very limited data demonstrate safety of ketamine when used as an adjunctive therapy for patients with benzodiazepine-resistant withdrawal; may reduce benzodiazepine dose requirements ^[5][47][63]

    • Antipsychotic agents may be used as an adjunct to benzodiazepines; not recommended as monotherapy ^[21]

  • Consider alternative or concurrent diagnosis ^[18]

  • Refractory withdrawal and delirium tremens may require intubation and mechanical ventilation ^[4]

  • Most experts do not recommend treating with ethanol or baclofen (selective GABA-B receptor agonist) ^{[18][4][21][64]}

• Treat concurrent acute illness and comorbid conditions in standard manner

  • May include treatment of other pathologic processes leading to alcohol withdrawal such as: ^[4]

    • Infection (eg, pneumonia, sepsis, meningitis/encephalitis)

    • Gastrointestinal disease (eg, pancreatitis, hepatitis, alcoholic gastritis, bleeding esophageal varices)

    • Trauma (eg, head trauma)

    • Metabolic derangements (eg, hypoglycemia, electrolyte abnormalities)

    • Intracerebral hemorrhage

    • Acute coronary syndrome

    • Drug overdose

Outpatient alcohol withdrawal treatment with medical assistance

• Aggressive counseling and rehabilitation are essential adjuncts to medication-assisted withdrawal to sustain recovery process and prevent relapse and subsequent episodes of withdrawal

• Options include oral benzodiazepines, anticonvulsants, β-blockers, and α₂-adrenergic agonists ^[4][12]

  • Benzodiazepines

    • Choice of specific benzodiazepine

      • Long-acting benzodiazepines (eg, diazepam, chlordiazepoxide) are preferred in most patients ^[12]

      • Intermediate-acting benzodiazepines (eg, lorazepam, oxazepam) are also effective and preferred in patients with liver dysfunction owing to lack of active metabolites ^[12]

      • Chlordiazepoxide and oxazepam have less misuse potential than diazepam and lorazepam and may be preferred in patients at high risk for substance use disorders ^[12]

    • Stress importance of abstinence from alcohol intake during treatment with benzodiazepine ^[12]

      • Increased risk of respiratory depression and death is associated with alcohol and benzodiazepine coingestion

    • Administration technique

      • Either fixed-dose or symptom-triggered schedule may be used ^[12]

        • Administration of dose during symptom-triggered management should be given for: ^[12]

          • Short Alcohol Withdrawal Score of 12 or higher, or

          • Clinical Institute Withdrawal Assessment for Alcohol (Revised) score higher than 9

      • Front-loading (loading dose) is not routinely recommended ^[12]

    • Tapering

      • In general, doses can be gradually tapered down when Clinical Institute Withdrawal Assessment for Alcohol (Revised) score is lower than 10 or Short Alcohol Withdrawal Score is lower than 12 until eventual discontinuation ^[12]

      • Symptoms usually resolve by day 7 after last alcohol use ^[12]

  • Anticonvulsants

    • Data are limited; carbamazepine, valproic acid, and gabapentin may be used to reduce craving and prevent early relapse ^[65][12][66]

    • Anticonvulsants do not prevent withdrawal seizures or delirium tremens ^[12][67]

    • Conflicting evidence regarding whether adjunctive gabapentin use reduces benzodiazepine dose requirements ^[68][69][70]

      • Misuse has been reported with gabapentin and caution should be taken especially in patients with substance use disorder ^[71][72]

  • β-blockers and α₂-adrenergic agonists

    • Atenolol and clonidine may be used as adjunct medications in combination with benzodiazepines to reduce adrenergic symptoms ^[12][62][73]

    • β-blockers and α₂-adrenergic agonists do not prevent withdrawal seizures or delirium tremens

Counseling and rehabilitation

• Cornerstone to recovery and adjunct to medication-assisted withdrawal

• Refer all patients with alcohol withdrawal for alcohol use disorder treatment (eg, alcohol abstinence counseling, long-term rehabilitation) ^[6]

• ASAM placement criteria can guide placement after detoxification process ^[18][74]

• Provide patient with resources for assistance in long-term abstinence such as:

  • Alcoholics Anonymous ^[75]

  • National Council on Alcoholism and Drug Dependence (local affiliates)

  • National Institute on Alcohol Abuse and Alcoholism ^[76]

  • Substance Abuse and Mental Health Services Administration ^[77]

Drug therapy

• Benzodiazepines

  • Diazepam

    • Non-severe alcohol withdrawal

      • Oral

        • Fixed-dose

          • Diazepam Oral tablet; Adults: 10 mg PO every 6 hours on day 1, then 10 mg PO every 8 hours on day 2, then 10 mg PO every 12 hours on day 3, then 10 mg PO once daily at bedtime on days 4 and 5.

        • Symptom-triggered

          • Diazepam Oral tablet; Adults: 10 mg PO every 4 hours as needed on day 1, 10 mg PO every 6 hours as needed on days 2 and 3, and then 10 mg PO every 12 hours as needed on days 4 and 5.

      • Intravenous

        • Diazepam Solution for injection; Adults: 10 to 20 mg IV or 10 mg IM as a single dose, initially, then 5 to 10 mg IV or IM in 3 hours if needed.

    • Severe alcohol withdrawal

      • Diazepam Solution for injection; Adults: 10 mg IV every 5 to 10 minutes for 2 doses, then 20 mg IV every 5 to 10 minutes for 2 doses, then 40 mg IV every 5 to 10 minutes for 3 doses as needed.

      • 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 ^[4]

  • Lorazepam

    • Non-severe alcohol withdrawal

      • Fixed-dose

        • Lorazepam Oral tablet; Adults: 2 mg PO every 8 hours on days 1 and 2, then 1 mg PO every 8 hours on day 3, then 1 mg PO every 12 hours on day 4, and then 1 mg PO once daily at bedtime on day 5.

      • Symptom-triggered

        • Lorazepam Oral tablet; Adults: 2 mg PO every 6 hours as needed on days 1 and 2, then 1 mg PO every 8 hours as needed on day 3, and then 1 mg PO every 12 hours as needed on days 4 and 5.

    • Severe alcohol withdrawal

      • IV bolus

        • Lorazepam Solution for injection; Adults: 4 mg IV every 15 to 20 minutes for 2 doses, then 8 mg IV every 15 to 20 minutes for 2 doses, then 16 mg IV every 15 to 20 minutes for 3 doses as needed.

        • Extremely high doses may be required for management of manifestations

      • Continuous IV infusion

        • For use in patients requiring frequent treatment

        • Lorazepam Solution for injection; Adults: 1 to 20 mg/hour continuous IV infusion. Titrate dose to target clinical score. Average dose: 14 mg/hour.

        • Infusion carries risk of propylene glycol toxicity and excessive accumulation of drug (ie, dose stacking)

  • Chlordiazepoxide

    • Fixed-dose

      • Chlordiazepoxide Hydrochloride Oral capsule; Adults: 25 to 100 mg PO every 4 to 6 hours on day 1, then 25 to 100 mg PO every 6 to 8 hours on day 2, then 25 to 100 mg PO every 8 to 12 hours on day 3, and then 25 to 100 mg PO once daily at bedtime on days 4 and 5.

    • Symptom-triggered

      • Chlordiazepoxide Hydrochloride Oral capsule; Adults: 25 to 100 mg PO every 4 to 6 hours as needed on day 1, then 25 to 100 mg PO every 6 to 12 hours as needed on days 2 and 3, then 25 to 100 mg PO every 12 to 24 hours as needed on days 4 and 5.

  • Midazolam

    • Midazolam Solution for injection; Adults: 0.02 to 0.1 mg/kg/hour continuous IV infusion, initially. Titrate dose to achieve target clinical score. Usual dose range: 1 to 20 mg/hour.

  • Oxazepam

    • Oxazepam Oral capsule; Adults: 15 to 30 mg PO 3 to 4 times daily.

Nondrug and supportive care

Electrolytes

• Electrolyte abnormalities are common in patients with long-term alcohol use and those with severe withdrawal; correct in standard manner when indicated ^[27]

  • 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 ^[4]

  • Hypomagnesemia and hypophosphatemia may occur; usually result from dietary deficiency

    • Routine supplementation is not recommended ^[5]

    • Supplementation may be required, especially when symptomatic, given supporting laboratory evidence of severe deficiency

    • Self-correction with proper nutrition is preferred treatment for patients with asymptomatic, mild to moderate deficiency

    • IV repletion is not routinely required ^[4]

Fluids

• 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 ^[1]

Nutrition ^[6]

• Thiamine

  • Thiamine is a critical cofactor in carbohydrate metabolism; deficiency results in decreased glucose utilization ^[4]

  • Thiamine deficiency is often present and increases risk of Wernicke encephalopathy (eg, altered mental status, ophthalmoplegia, ataxia) ^[4]

  • Administer prophylactic dose for presumed thiamine deficiency to all patients presenting in withdrawal ^[4][16]

  • Administer treatment dose to any patients with concerning manifestations for Wernicke encephalopathy ^[4]

  • Administer thiamine before (preferred) or with glucose administration ^[5]

• Folate

  • Supplementation is recommended owing to low dietary folate intake, which may lead to megaloblastic anemia in patients with long-term alcohol use disorder ^[4]

  • Multivitamins containing daily recommended allowance of folic acid are often used ^[5]

• Provide nutritional support to those with long-term alcohol use to prevent and/or treat ketoacidosis

  • Route of administration is individualized ^[6]

    • Enteral is preferred (oral, nasogastric, or nasoduodenal)

    • Parenteral may be required

• Glucose

  • Some patients may require glucose supplementation for hypoglycemia because of increased metabolic requirements in the setting of diminished glycogen stores ^[1]

  • Untreated hypoglycemia can lead to alcoholic ketoacidosis (hyperketonemia with anion gap metabolic acidosis without significant hyperglycemia), complicating withdrawal management ^[27]

  • Avoid glucose administration alone (without thiamine administration) in patients at risk for Wernicke encephalopathy

Procedures

Comorbidities

• Liver failure

  • 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 ^[1][4]

  • Duration of any benzodiazepines may be significantly prolonged in patients with hepatic dysfunction; dose adjustment may be required ^[4]

• Renal insufficiency

  • Most benzodiazepines and their metabolites are eliminated by the kidneys; dose adjustment may be necessary, particularly in agents with active metabolites ^[1]

• Wernicke encephalopathy

  • Administer treatment dose of thiamine for duration of 3 to 5 days to any patients with concerning manifestations for Wernicke encephalopathy ^[4][11]

  • Administer thiamine before (preferred) or with glucose administration to avoid precipitating Wernicke encephalopathy in patients at risk ^[5][11]

Special populations

• Pregnant patients

  • There are no structured guidelines or high-level studies regarding optimal treatment of alcohol withdrawal in pregnancy ^[79]

  • As maternal health is vitally important to fetal health, benzodiazepines should still be considered first line treatment; barbiturates are also considered safe ^[21]

  • Manage in consultation with specialist (eg, substance misuse medicine, high-risk obstetrician)

• Trauma patients ^[80]

  • Alcohol withdrawal affects 8% to 40% of patients admitted to surgical ICU after trauma

  • Assess patients for risk of alcohol withdrawal with a validated screening tool such as Alcohol Use Disorders Identification Test (AUDIT) or Prediction of Alcohol Withdrawal Severity Scale (PAWSS)

  • Patients at risk for severe or complicated alcohol withdrawal benefit from empiric prophylactic treatment with benzodiazepines or phenobarbital

Monitoring

• Admitted patients with alcohol withdrawal syndrome and patients at risk for developing alcohol withdrawal syndrome

  • Serial measurements using a validated withdrawal severity scale are required to guide symptom-triggered treatment ^[6]

    • Frequency of scoring depends on stage of management and degree of symptom control

      • Frequent evaluations (eg, every 10-15 minutes) may be required during initial stages of treatment ^[4]

      • Scoring evaluations may be spaced to hourly once treatment goals are reached ^[4]

  • Maintain awareness and assess for other coexistent conditions and alternate medical causes for patient decompensation other than worsening or recalcitrant withdrawal ^[4]

  • Monitor for adequacy of airway protection, frequent vital signs, and hydration status ^[5]

• Outpatient monitoring for patients requiring treatment

  • Guide monitoring type and frequency based on symptom severity and characteristics of individual patient and environment ^[12]

  • Daily reassessments are required in most patients until symptoms abate, including: ^[12]

    • Measurement of vital signs

    • Random alcohol breath analysis

    • Withdrawal symptom severity scale assessment (eg, Short Alcohol Withdrawal Score, Clinical Institute Withdrawal Assessment for Alcohol [Revised])

  • Refer for long-term outpatient treatment when symptoms are minimal, benzodiazepines are no longer required, and patient has abstained from alcohol intake for at least 3 days ^[12]

  • Refer to addiction medicine specialist or inpatient treatment program if patient does not adequately respond to benzodiazepine therapy, misses an appointment, or resumes drinking alcohol ^[12]

• Refer to regional protocols to guide monitoring strategy ^[25]

Complications and Prognosis

Complications

• Death

  • Cause of death usually results from hyperthermia, cardiac arrhythmias, complications of withdrawal seizures, or concomitant medical disorders (eg, pneumonia, acute coronary syndrome ) ^[9][11]

• Aspiration pneumonia and/or respiratory depression requiring tracheal intubation and mechanical ventilation

  • May result from oversedation

• Rhabdomyolysis

  • May result from severe agitation, hyperthermia, prolonged seizures, and/or prolonged use of physical restraints

• Wernicke encephalopathy

  • Alcohol use disorder may result in chronic thiamine deficiency characterized by cell damage to the mammillary body, thalamus, and hippocampus ^[16]

    • Wernicke encephalopathy is the acute presentation and is reversible with prompt treatment ^[27]

    • Delayed treatment or repeated episodes may lead to the permanent amnestic syndrome or Korsakoff encephalopathy ^[27]

  • Prevalence may be as high as 3% ^[9]

  • Classically presents with confusion, ataxia, and ophthalmoplegia; less than 33% of patients have all 3 findings ^[27]

  • Glucose administration without thiamine replacement can precipitate syndrome in patients with thiamine deficiency ^[16]

  • Diagnosis may be missed if nystagmus and ataxia are not appreciated; mental status changes may be attributed to delirium tremens ^[9]