Alcohol Withdrawal

Key Points

• 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 ^r1r2
• Alcohol withdrawal can start as early as 6 hours from the last drink and early manifestations are characterized by sympathomimetic symptoms, tremor, anxiety, insomnia, nausea, and vomiting ^r3
• Manifestations may worsen without treatment; progression to severe symptom manifestations including seizures and delirium tremens occurs in up to 5% of patients ^r4
• Withdrawal is a clinical diagnosis and a diagnosis of exclusion; DSM-5-TR diagnostic criteria define the diagnosis ^r2
• Ancillary testing does not usually aid in diagnosis; obtain routine baseline studies (eg, metabolic panel, liver function testing) to evaluate for concurrent problems in patients with moderate to severe withdrawal manifestations requiring admission
• Obtain individualized studies based on presentation to identify concurrent conditions that may have contributed to precipitation of withdrawal
• Outpatient alcohol withdrawal treatment with medical assistance may be used for select patients with mild to moderate withdrawal without significant comorbidity
• Inpatient alcohol withdrawal treatment with medical assistance is required for patients with severe withdrawal and patients at risk for progression to severe withdrawal
• Sedative hypnotics (ie, benzodiazepines) are the cornerstone of initial management ^r5
• With effective treatment, progression of disease and development of delirium tremens may be avoided
• Administer thiamine and folate supplementation in patients presenting in withdrawal; replenish potassium to correct hypokalemia ^r4
• Refer all patients with alcohol withdrawal for alcohol use disorder treatment (eg, alcohol abstinence counseling, long-term rehabilitation) ^r6
• Overall prognosis is best among patients without other acute medical problems ^r6
• Morbidity and mortality are increased among patients with comorbidity, concurrent disease related to alcohol use disorder that complicates management,^r6 and older age^r7
• Prevention of withdrawal may be possible with screening, early identification, and rehabilitation of patients with alcohol use disorder

Urgent Action

• Early and aggressive treatment of alcohol withdrawal halts progression to more severe forms of withdrawal
• Treat moderate to severe withdrawal aggressively with rapid escalating doses of benzodiazepines initially
• Terminate seizures with benzodiazepines (first line); second line agents include barbiturates and/or propofol
• Wernicke encephalopathy requires urgent treatment doses of thiamine

Pitfalls

• Patients may develop manifestations of withdrawal despite a detectable serum alcohol concentration
  • Consider diagnosis even in patients who are not abstinent from alcohol because decreased consumption can lead to withdrawal
  • Early and aggressive treatment of withdrawal manifestations is a key measure to diminish morbidity when indicated regardless of detectable blood alcohol concentration
• Consider alcohol withdrawal diagnosis in patients admitted to hospital for other reasons if manifestations consistent with withdrawal develop
  • Up to 8% of patients admitted to hospitals with nonalcohol-related diagnoses exhibit signs of withdrawal ^r7
  • Early recognition and aggressive treatment decrease morbidity
• Inadequate initial treatment of withdrawal symptoms may lead to worsening withdrawal
  • Treat aggressively to targeted treatment goals for sedation
• Accurate diagnosis is key to appropriate management of manifestations
  • For example, benzodiazepines are the treatment of choice for alcoholic hallucinosis; administration of antipsychotics can be detrimental if hallucinations are considered attributable to a psychiatric illness rather than withdrawal
• Acute illness may precipitate withdrawal episode
  • Maintain awareness for need to identify and treat any acute illness that occurs concurrently with withdrawal
• Monitor for other coexistent conditions and alternate medical causes for patient decompensation or recalcitrant withdrawal ^r4
  • For example, persistent tachycardia may be a manifestation of alternate disease (eg, hypovolemia, sepsis, heart failure, thyrotoxicosis) rather than withdrawal alone
  • Failure to consider alternative and coexisting diagnoses may lead to increased morbidity and mortality
• Subsequent episodes of alcohol withdrawal tend to increase in severity
  • Encourage treatment and counseling for alcohol use disorder after an episode of acute withdrawal to prevent recurrent withdrawal episodes
• Prophylactic thiamine replacement is important to avoid increased risk of Wernicke encephalopathy ^r4
  • Maintain high suspicion for Wernicke encephalopathy in patients presenting with suspicious manifestations (eg, ataxia, ophthalmoplegia) because mortality is high and diagnosis is frequently missed
  • Treatment thiamine dosing is higher and longer than prophylactic dosing for patients presenting with concern for Wernicke encephalopathy
  • Administer thiamine before (preferred) or with glucose administration in patients at risk for Wernicke encephalopathy because supplemental administration of glucose alone can precipitate encephalopathy

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 ^r1r2
• Severe symptom manifestations (eg, seizures, delirium tremens) may develop in up to 5% of patients ^r4

Classification

• Based on severity: ^r8
  • 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 ^r9
      • 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^r10 if withdrawal does not progress to major alcohol withdrawal syndrome ^r3
    • 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 ^r3
  • Complicated or severe alcohol withdrawal
    • Up to 5% of patients develop a more complicated syndrome ^r4r11
    • Withdrawal manifestations progress and worsen, usually approximately 24 hours after onset of initial manifestations ^r3
    • 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 ^r3
    • Manifestations often peak around 50 hours before gradual resolution or may continue to progress to severe (complicated) withdrawal, particularly without treatment ^r3
    • Rigorous definition is lacking ^r5
    • Many experts define by presence of any of the following:
      • Withdrawal seizures ^r4r5
      • Delirium tremens
      • Clinical Institute Withdrawal Assessment for Alcohol (Revised) score higher than 20 ^r12
      • Major alcohol withdrawal syndrome manifestations refractory to high-dose benzodiazepines ^r5
• Based on progressive stages: ^r6
  • Stage 1
    • Minor symptoms not usually associated with significantly abnormal vital signs ^r12
  • Stage 2
    • Mild to moderate symptoms associated with abnormal vital signs and possibly alcoholic hallucinosis ^r12
  • 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 ^r12

Clinical Presentation

Characteristic withdrawal syndrome develops within hours to days after cessation or reduction of heavy and prolonged alcohol use ^r2c1

• Probability of developing withdrawal rises with increasing quantity and frequency of alcohol consumption ^r2
  • Most affected patients are drinking daily for multiple days and consuming large amounts (ie, more than 8 drinks/day for multiple days) ^r2r5
• Symptoms typically begin after sharp decline in blood alcohol concentration ^r2
• Reduction or cessation in alcohol use may not always be intentional ^r6r13
  • Inability to acquire or pay for alcohol
  • Gastrointestinal illness characterized by decreased oral intake
  • Hospital admission for another medical issue ^r7
    • Up to 8% of patients admitted to hospitals with nonalcohol-related diagnoses exhibit signs of withdrawal

Earlier medical history may be significant for: ^r6

• Alcohol use disorder ^c2c3
  • 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 ^r9r11
  • Suspect alcohol dependence in female patients who: ^r12
    • 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)^r14
  • Suspect alcohol dependence in male patients who: ^r12
    • 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)^r14
• History of prior withdrawal ^c4
  • Course of prior alcohol withdrawal episodes is the most reliable predictor of subsequent episodes ^r15

Psychiatric history

• Alcohol may cause several psychiatric conditions such as alcohol-induced mood, anxiety, or psychotic disorder ^r6c5c6c7
• Underlying psychiatric disorders (eg, antisocial personality disorder, schizophrenia, major anxiety disorders, bipolar disorder) or other drug use disorder and dependence may be present ^c8c9c10c11

Factors that may modify withdrawal symptoms or course

• Relief of symptoms can occur by administration of alcohol or benzodiazepines ^r2c12c13
• Concurrent use of medication for other underlying disorders (eg, β-blockers, α₂-adrenergic agonists) may blunt typical abnormalities noted in vital signs at presentation. ^r4

Presence of comorbidity

• Patients with underlying psychiatric disorders may use alcohol to alleviate psychiatric symptoms (eg, anxiety, depression) ^r6
• Acute medical or surgical disorder may precipitate withdrawal ^r6
• Poorly controlled medical comorbidity may precipitate withdrawal ^r6

Acute withdrawal may progress in stages ranging in severity from mild to severe ^r16

• Manifestations during stages may overlap and may not progress in a precise sequential pattern ^r6
• Early withdrawal: symptoms of central nervous system stimulation typically occurring within 48 hours of drinking cessation ^r9
  • Stage 1 (hangover stage)
    • Initial broad withdrawal manifestations begin 6 to 8 hours after last drink and may include: ^r4
      • Sympathomimetic symptoms (eg, diaphoresis, palpitations) ^c14c15
      • Mild tremor ^c16
      • Insomnia and anxiety ^c17c18
      • Gastrointestinal (eg, nausea, vomiting) ^c19c20
      • Headache ^c21
    • If withdrawal does not progress, these manifestations may resolve within 24 to 48 hours ^r4
  • Stage 2 (alcoholic hallucinosis stage)
    • Develops approximately 24 to 48 hours after last drink, but may be up to 8 days later ^r6
    • Worsening sympathomimetic symptoms (eg, diaphoresis, fever), marked tremors, worsening hyperactivity, and insomnia ^{c22c23c24c25c26}
    • Sensorium is lucid but nightmares or illusions are not uncommon ^c27c28
    • Hallucinations may develop
      • Most commonly occur 12 to 24 hours after last drink ^r4
      • Occur in 7% to 8% of untreated patients with withdrawal ^r4
      • Can be visual, auditory, or tactile ^r4
        • Isolated visual hallucinations are most common ^{r12r17c29c30c31}
      • May occur in isolation without other broad withdrawal manifestations
      • Sensorium is normal (ie, delirium is absent; patient is aware that hallucinations are not real) ^r9c32
  • Stage 3 (tonic-clonic seizure stage)
    • Similar to stage 2 with development of tonic-clonic seizures ^{r6c33c34c35c36c37}
    • Withdrawal seizures (rum fits)
      • Commonly occur 12 to 48 hours after last drink ^r4
      • May occur in up to 10% of patients ^r1
        • Alcohol withdrawal represents 1 of the most common causes of adult-onset seizures ^r3c38
      • Commonly consist of isolated, short-duration, generalized tonic-clonic seizures with short or absent postictal period ^{r1c39c40c41c42}
        • May occur in clusters^r6r18 and may be recurrent in a minority of patients ^r6r9
        • Prolonged seizures and status epilepticus are relatively uncommon ^r6c43c44
      • Seizures impart increased risk for complications (eg, aspiration pneumonia, rhabdomyolysis) ^r6c45c46
      • 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 ^r9
  • Stage 4 (delirium tremens stage)
    • High likelihood that a concurrent, clinically relevant medical condition exists when delirium develops ^r2
      • May include liver failure, pneumonia, gastrointestinal bleeding, head trauma, hypoglycemia, electrolyte imbalance, and postoperative state ^{c47c48c49c50c51c52}
    • 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: ^r5
          • Lack of attention and awareness ^c53c54
          • Memory loss and disorientation ^c55c56
          • Hallucinations ^c57
          • Agitation ^r9c58
      • 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 ^r4r6
        • Rarely, may develop as early as 8 hours after last drink ^r4
      • Often associated with cardiovascular, respiratory, and metabolic abnormalities ^r6
      • Occurs in 1% to 5% of hospitalized patients with withdrawal ^r4r6
      • Risk is significantly increased in patients with concurrent acute medical illness ^r6

Causes and Risk Factors

Diagnostic Procedures

Differential Diagnosis

Goals

• Monitor withdrawal course and provide symptomatic treatment with aim to normalize vital signs, relieve anxiety, and halt progression to severe withdrawal ^r1
• Manage severe withdrawal (eg, seizures, delirium) and monitor for complications (eg, respiratory depression, pneumonia, rhabdomyolysis) ^r1
• Address and manage other comorbid or concurrent medical, surgical, traumatic, toxicologic, or psychiatric issues ^r6
• Arrange for substance use disorder treatment and encourage long-term abstinence ^r1

Disposition

General criteria for outpatient management ^r12

• 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 ^r25

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 ^r4r6r46
• No current intoxication (alcohol or other drugs) ^r4
• No history of complicated alcohol withdrawal syndrome (ie, seizures, hallucinosis, delirium tremens) ^r4
• No significant medical or psychiatric comorbidity or suicidal ideation ^r4r46
• Ability to maintain regular outpatient visits and therapy ^r4

General criteria for outpatient detoxification:

• Clinical Institute Withdrawal Assessment for Alcohol (Revised) score 15 or less ^r4
• Lack of symptoms or history of delirium tremens or alcohol withdrawal seizures ^r4r46
• Ability to take oral medications ^r4
• Presence of a family member or close contact who can stay with the patient ^r4
• Lack of unstable medical condition ^r4
• Lack of psychosis or suicidality ^r4
• Ability to commit to daily medical visits and adequate follow-up ^r4

Treatment Options

Resuscitation and stabilization is first aspect of care while assessing need for treatment of concurrent medical conditions ^r4r8

• Manage airway and administer oxygen as indicated clinically ^r18
• Initiate fluid resuscitation and start IV fluids when clinically indicated ^r18
• Treat concurrent medical conditions ^r18
• Treat hypoglycemia; it is preferable to begin thiamine administration before administration of glucose, but treatment of hypoglycemia should not be delayed ^r5r16

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 ^r6r11
  • May be managed with supportive care alone, carbamazepine, or gabapentin ^r21
  • Some experts consider prescribing brief lorazepam regimen as needed for 3 to 5 days ^r46
• Patients with mild to moderate manifestations without significant comorbidity or significant risk of developing severe withdrawal may be managed in either: ^r6r12r19
  • 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 ^r47r48
  • 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: ^r12
  • Moderate to severe manifestations ^r6
  • Significant comorbid psychiatric, medical, or surgical conditions ^r6
  • Risk for severe withdrawal ^r19

Regional protocols are available to guide management strategy for both inpatient and outpatient treatment ^r25

Standard inpatient alcohol withdrawal treatment with medical assistance ^r1

• Sedative hypnotics are the cornerstone of initial management ^r5
  • Goal of initial treatment is rapid sedation with normalization of vital signs ^r1
    • Consider alternative or concurrent diagnosis if appropriate sedation is achieved without normalization of vital signs ^r18
    • Appropriately sedated patient is calm and sleepy but arousable without active hallucinations or seizures ^r23
    • 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 ^r1r41r49
    • 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 ^r4
    • Preferred methods of administration include:
      • IV route for severe symptoms; oral route for less severe symptoms ^r4
      • Front-loading (loading dose) of benzodiazepines ^r50
        • 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 ^r4
        • Titrate based on sequential sedation scale scores ^r6
        • No maximum dose of benzodiazepines exists for treatment of alcohol withdrawal ^r4
        • Dose required to control manifestations is highly variable among patients ^r11
    • Debate exists regarding which benzodiazepine is the best treatment option ^r4
      • Some clinicians prefer IV diazepam or lorazepam for acute severe symptom control ^r4
        • 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 ^r4r5
          • 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 ^r4r5
          • Lack of active metabolites for lorazepam results in shorter half-life compared to diazepam, which has active metabolites ^r4
        • Diazepam may require dose adjustment in patients with renal failure because active metabolites are eliminated by kidneys; avoid in patients with liver disease ^r5
        • 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 ^r9
      • 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 ^r9
        • Use of 2 different benzodiazepines may be required in select scenarios including: ^r51
          • 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 ^r16
  • Second line adjunct treatments for withdrawal resistant to benzodiazepines alone include phenobarbital and/or propofol ^r4r21
    • Can work synergistically with benzodiazepines on the GABA-A receptor ^r1r52
      • 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 ^r53
    • Respiratory and cardiac depressant effects are more common than with benzodiazepines alone
    • Emerging adjunct treatments include dexmedetomidine and ketamine ^r4
    • Carbamazepine, phenobarbital, or gabapentin may be used when benzodiazepines are contraindicated ^r21
• 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 ^r21r50r54
      • Symptom-triggered dosing based on severity scales allows for individualized dosing and results in shorter duration of therapy and lower cumulative medication doses ^r4r5
      • 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 ^r9r18
    • 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 ^r21
    • Examples of dosing regimen are described in ASAM guideline on alcohol withdrawal management ^r21
  • Use objective measurement of symptom severity to determine frequency of administration targeted to treatment goals ^r4
    • 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 ^r4
        • Goal of treatment is a calm awake state ^r16
        • Suggested treatment response to score ^r9
          • 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 ^r5
      • ICU sedation scales are often used for patients with severe withdrawal or withdrawal requiring intubation ^r4
        • Richmond Agitation-Sedation Score is most commonly used ^r6
          • Score of 0 to −2 indicates patient is in a calm, arousable state ^r4
  • Tapering
    • Usually benzodiazepines can be tapered down from peak dosing after approximately 48 to 72 hours ^r9
    • General guideline is to taper by approximately 20% of total daily benzodiazepine equivalent dose ^r51
    • Some experts prefer chlordiazepoxide for scheduled tapering protocol; other experts prefer lorazepam given by a symptom-triggered tapering strategy ^r51
• Manifestation-specific treatment
  • Seizures
    • Benzodiazepines are first line treatment ^r4
    • Barbiturates and propofol are second line treatment options for seizures recalcitrant to benzodiazepines ^r55
    • 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 ^r4
    • Long-term anticonvulsant therapy is not necessary unless patient has underlying seizure disorder or epilepsy ^r6
    • Refractory status epilepticus may require management in consultation with specialists (eg, medical toxicologist, neurologist) and infusion of phenobarbital, pentobarbital, propofol, or midazolam ^r3
  • Alcoholic hallucinosis
    • Benzodiazepines are first line treatment ^r4
    • 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,^r18 and increase risk of respiratory complications ^r4r6
      • May be beneficial for patients with known or suspected thought disorders (eg, schizophrenia) ^r4
      • 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: ^r6
      • 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 ^r6
      • 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 ^r6
    • Maintain high awareness for potential complications (eg, development of pneumonia and sepsis) ^r6
    • Physical restraints may be temporarily required; however, take care to avoid prolonged physical restraints without appropriate sedation owing to increased risk for rhabdomyolysis ^r1r16
    • Intermittent verbal reorientation to time, place, and date are important after stabilization ^r5
• 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 ^r4r5
    • More than 200 mg diazepam or 40 mg lorazepam within 3 hours of treatment ^r4
  • If rapid escalation of benzodiazepines fails to control symptoms, adjunct treatment options include phenobarbital, propofol, ketamine, and dexmedetomidine ^r4r56
    • Phenobarbital is effective when used in combination with benzodiazepines for resistant withdrawal and delirium tremens ^r4r57
      • Paucity of data exists for phenobarbital use as monotherapy; therefore, monotherapy should only be considered in a patient whose condition is refractory to benzodiazepines ^r5r57r58
      • 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 ^r5
    • Dexmedetomidine and ketamine use has not been studied as much as phenobarbital and propofol use ^r4
      • Adjunct treatment with dexmedetomidine may lower benzodiazepine requirements and decrease need for mechanical ventilation in patients with severe, refractory withdrawal ^{r5r59r60r61r62}
        • 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 ^r5
        • Dexmedetomidine does not prevent or treat withdrawal seizures and may increase rate of delirium, although available data are conflicting ^r5
      • Very limited data demonstrate safety of ketamine when used as an adjunctive therapy for patients with benzodiazepine-resistant withdrawal; may reduce benzodiazepine dose requirements ^r5r47r63
    • Antipsychotic agents may be used as an adjunct to benzodiazepines; not recommended as monotherapy ^r21
  • Consider alternative or concurrent diagnosis ^r18
  • Refractory withdrawal and delirium tremens may require intubation and mechanical ventilation ^r4
  • Most experts do not recommend treating with ethanol^r18 or baclofen (selective GABA-B receptor agonist) ^r4r21r64
• Treat concurrent acute illness and comorbid conditions in standard manner
  • May include treatment of other pathologic processes leading to alcohol withdrawal such as: ^r4
    • 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,^r4 β-blockers, and α₂-adrenergic agonists ^r12
  • Benzodiazepines
    • Choice of specific benzodiazepine
      • Long-acting benzodiazepines (eg, diazepam, chlordiazepoxide) are preferred in most patients ^r12
      • Intermediate-acting benzodiazepines (eg, lorazepam, oxazepam) are also effective and preferred in patients with liver dysfunction owing to lack of active metabolites ^r12
      • Chlordiazepoxide and oxazepam have less misuse potential than diazepam and lorazepam and may be preferred in patients at high risk for substance use disorders ^r12
    • Stress importance of abstinence from alcohol intake during treatment with benzodiazepine ^r12
      • 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 ^r12
        • Administration of dose during symptom-triggered management should be given for: ^r12
          • 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 ^r12
    • 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 ^r12
      • Symptoms usually resolve by day 7 after last alcohol use ^r12
  • Anticonvulsants
    • Data are limited;^r65carbamazepine, valproic acid, and gabapentin may be used to reduce craving and prevent early relapse^r12r66
    • Anticonvulsants do not prevent withdrawal seizures or delirium tremens ^r12r67
    • Conflicting evidence regarding whether adjunctive gabapentin use reduces benzodiazepine dose requirements ^r68r69r70
      • Misuse has been reported with gabapentin and caution should be taken especially in patients with substance use disorder ^r71r72
  • β-blockers and α₂-adrenergic agonists
    • Atenolol and clonidine may be used as adjunct medications in combination with benzodiazepines to reduce adrenergic symptoms ^r12r62r73
    • 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) ^r6
• ASAM placement criteria can guide placement after detoxification process ^r18r74
• Provide patient with resources for assistance in long-term abstinence such as:
  • Alcoholics Anonymous ^r75
  • National Council on Alcoholism and Drug Dependence (local affiliates)
  • National Institute on Alcohol Abuse and Alcoholism ^r76
  • Substance Abuse and Mental Health Services Administration ^r77

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 ^{r6c211c212c213c214c215c216}
    • 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 ^r4
      • Scoring evaluations may be spaced to hourly once treatment goals are reached ^r4
  • Maintain awareness and assess for other coexistent conditions and alternate medical causes for patient decompensation other than worsening or recalcitrant withdrawal ^r4
  • Monitor for adequacy of airway protection, frequent vital signs, and hydration status ^{r5c217c218c219}
• Outpatient monitoring for patients requiring treatment
  • Guide monitoring type and frequency based on symptom severity and characteristics of individual patient and environment ^r12
  • Daily reassessments are required in most patients until symptoms abate, including: ^r12
    • Measurement of vital signs ^c220
    • Random alcohol breath analysis ^c221
    • Withdrawal symptom severity scale assessment (eg, Short Alcohol Withdrawal Score, Clinical Institute Withdrawal Assessment for Alcohol [Revised]) ^c222
  • 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 ^r12c223
  • 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 ^{r12c224c225c226}
• Refer to regional protocols to guide monitoring strategy ^r25

Complications

• Death
  • Cause of death usually results from hyperthermia, cardiac arrhythmias, complications of withdrawal seizures, or concomitant medical disorders (eg, pneumonia, acute coronary syndrome^r9) ^{r11c227c228c229c230c231}
• Aspiration pneumonia and/or respiratory depression requiring tracheal intubation and mechanical ventilation ^d8
  • May result from oversedation ^c232c233
• Rhabdomyolysis ^d9
  • May result from severe agitation, hyperthermia, prolonged seizures, and/or prolonged use of physical restraints ^{c234c235c236c237}
• Wernicke encephalopathy ^c238d7
  • Alcohol use disorder may result in chronic thiamine deficiency characterized by cell damage to the mammillary body, thalamus, and hippocampus ^r16
    • Wernicke encephalopathy is the acute presentation and is reversible with prompt treatment ^r27
    • Delayed treatment or repeated episodes may lead to the permanent amnestic syndrome or Korsakoff encephalopathy ^r27
  • Prevalence may be as high as 3% ^r9
  • Classically presents with confusion, ataxia, and ophthalmoplegia; less than 33% of patients have all 3 findings ^r27
  • Glucose administration without thiamine replacement can precipitate syndrome in patients with thiamine deficiency ^r16
  • Diagnosis may be missed if nystagmus and ataxia are not appreciated; mental status changes may be attributed to delirium tremens ^r9

Prognosis

• Overall prognosis is best among patients without other acute medical problems ^r6
• Morbidity and mortality are increased among patients with comorbidity, concurrent disease related to alcohol use disorder that complicates management,^r6 and older age^r7
  • Failure to identify an underlying medical or surgical issue leading to decreased alcohol intake places patient at increased risk for morbidity and mortality
• Mortality among hospitalized patients with delirium tremens is approximately 1% to 4% ^r4
• Long-term mortality among patients who experience seizures or delirium tremens associated with withdrawal episode is guarded
  • Up to 50% of patients die within 10 years ^r5
• Clinical course
  • Symptoms of acute withdrawal usually improve markedly by several days after abstinence ^r2
  • Persistent symptoms (eg, anxiety, insomnia, autonomic dysfunction) may occur in some patients for up to 3 to 6 months ^r2
    • Symptoms occur at lower level of intensity than during acute withdrawal
  • Approximately 5% of patients who develop acute withdrawal will progress to severe withdrawal without treatment ^r81
  • Approximately one-third of patients who develop seizures will progress to delirium tremens without treatment ^r4
  • Average length of hospitalization for acute withdrawal
    • General inpatients: approximately 5.4 days ^r6
    • ICU patients: approximately 12.5 days ^r6
  • Patients who develop delirium
    • Delirium usually subsides within a few days; rarely persists for up to 2 weeks ^r6
    • Return to baseline mental status may require several weeks for some patients ^r6
  • Long-term abstinence from alcohol among patients with alcohol use disorder ^r12
    • First step is successful treatment of withdrawal
    • Enrollment in a long-term treatment program greatly increases likelihood of long-term abstinence
• Recurrent withdrawal
  • Subsequent episodes of alcohol withdrawal tend to increase in severity ^r82

Screening

Prevention ^r83

• Treat hospitalized patients considered at risk for severe alcohol withdrawal with prophylactic benzodiazepines before onset of symptoms ^r84
  • Also give thiamine supplementation to malnourished patients with alcohol dependency
• Counsel patients with frequent alcohol use to limit consumption to a safe level ^c239c240
• Consider referral to an alcohol or substance use specialist if patient cannot self-limit alcohol intake ^c241
• Enrollment in long-term treatment program after an episode of withdrawal decreases likelihood of relapse and future episodes of withdrawal ^r12c242