Alcohol withdrawal overview

# Overview
Alcohol withdrawal occurs with sudden discontinuation of alcohol intake after consumption of large quantities of alcohol for more than two weeks. The incidence of alcohol dependence is approximately 8 million individuals, annually, in the United States, and about 50% of them experience alcohol withdrawal symptoms with decreased or discontinuation of alcohol consumption. Common symptoms of alcohol withdrawal may include loss of appetite, nausea, vomiting, agitation, anxiety, irritability, insomnia, headache, diaphoresis, tremor, and the most severe symptoms in alcohol withdrawal include hallucinosis, seizures, and delirium tremens (DT). Symptoms of alcohol withdrawal usually resolve within seven days of alcohol intake discontinuation. Most patients with alcohol withdrawal have mild symptoms and may be treated with outpatient management. 5% of patients with alcohol withdrawal will present with severe alcohol withdrawal characteristics including seizures and delirium tremens (DT). The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria is used to diagnose alcohol withdrawal. The Clinical Institute Withdrawal Assessment for Alcohol (CIWA-A) scale is used to assess the severity of alcohol withdrawal. Benzodiazepines are currently the gold standard treatment of alcohol withdrawal such as diazepam, chlordiazepoxide, lorazepam, and oxazepam. Other drugs that may be used are phenobarbital, propofol, and dexmedetomidine. Thiamine is usually administered for prevention of Wernicke encephalopathy (prior to glucose administration).

# Historical Perspective
The term 'alcoholism' was first used in medical texts by Magnus Huss in 1894.

# Classification
Stages of Alcohol Withdrawal Syndrome (AWS) may be classified as:
- Uncomplicated withdrawal (first 6 hours)
- Alcohol hallucinosis  (8-12 hours)
- Alcohol withdrawal seizures (12-24 hours)
- Alcohol withdrawal delirium (24-72 hours)

# Pathophysiology
Under normal conditions in the brain, there is a balance between excitatory neurotransmitters such as glutamate and inhibitory neurotransmitters such as  gamma-aminobutyric acid (GABA).
Chronic alcohol intake and acute discontinuation of alcohol intake affect the balance of the neurotransmitters and cause many of the symptoms observed in alcohol withdrawal.  
Acute Alcohol Consumption
- Increases the GABA neurotransmitter and sensitivity of GABA-A receptor subtypes, which in turn, increases inhibitory neurotransmission.
- Prevents the effects of glutamate (an excitatory neurotransmitter) on the N-methyl-d-aspartate (NMDA) receptors by inhibiting the binding of glycine to the NMDA receptors.
Chronic Alcohol Consumption
- Causes tolerance and compensation by downregulation GABA-A receptors and upregulating NMDA receptors, and requires higher blood levels of alcohol to cause the same effect.
Alcohol Withdrawal in Chronic Alcohol Consumption
- Exposes the downregulation of GABA-A receptors and the upregulation of NMDA receptors, resulting in hyperexcitability of the neurons that lower the threshold for seizures.
- Upregulation of noradrenergic and dopaminergic receptors cause the autonomic hyperactivity and hallucinations that are seen in patients with alcohol withdrawal.
- Kindling is increased excitability and sensitivity of the neurons after repeated events of alcohol withdrawal, and is suggested to be the reason for progressing from milder to more severe symptoms of alcohol withdrawal in some patients.

# Causes
Alcohol withdrawal occurs with sudden discontinuation of alcohol intake after consumption of large quantities of alcohol for more than two weeks.

# Differentiating Alcohol Withdrawal from Other Diseases
Alcohol withdrawal must also be differentiated from other diseases including:
- Diabetic ketoacidosis
- Essential tremor
- Hypoglycemia
- Sedative, hypnotic, or anxiolytic withdrawal

# Epidemiology and Demographics
- The incidence of alcohol dependence is approximately 8 million individuals, annually, in the United States, and about 50% of them experience alcohol withdrawal symptoms with decreased or discontinuation of alcohol consumption.
- The prevalence of alcohol withdrawal is approximately 50% of middle-class individuals with alcohol use disorder.
- The prevalence of alcohol withdrawal is approximately 80% of hospitalized or homeless individuals with alcohol use disorder.
- 5% of patients with alcohol withdrawal will present with severe alcohol withdrawal symptoms including seizures and delirium tremens (DT). 5% of patients with alcohol withdrawal and delirium tremens (DT) die from various complications such as cardiovascular, metabolic, infections, and trauma.
- Alcohol withdrawal is rare in patients <30 years old, and the severity increases with more age.
- It is estimated that about 20% of men and 10% of women have alcohol use disorder, and in about half of them alcohol withdrawal symptoms will be observed with a decrease in alcohol intake.

# Risk Factors
Risk factors for alcohol withdrawal include:
- Quantity and frequency of alcohol consumption
- Family history of alcohol withdrawal
- Prior withdrawals
- Sedative, hypnotic, or anxiolytic drugs

# Natural History, Complications, and Prognosis
- Symptoms of alcohol withdrawal usually resolve within seven days of alcohol intake discontinuation.
- Most patients with alcohol withdrawal have mild symptoms and may be treated with outpatient management.
- 5% of patients with alcohol withdrawal will present with severe alcohol withdrawal characteristics including seizures and delirium tremens (DT).
- 5% of patients with alcohol withdrawal and delirium tremens (DT) die from complications such as cardiovascular, metabolic, infections, and trauma.

# Diagnosis

## Diagnostic Criteria
- The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria is used to diagnose alcohol withdrawal.
- The Clinical Institute Withdrawal Assessment for Alcohol (CIWA-A) scale is used to assess the severity of alcohol withdrawal.

## History and Symptoms
The most common symptoms of alcohol withdrawal include:
- Loss of appetite, anorexia
- Craving for alcohol
- Nausea, vomiting
- Agitation
- Anxiety
- Irritability
- Hypervigilance
- Insomnia
- Vivid dreams
- Headache
- Diaphoresis
- Tremor
The most severe symptoms in alcohol withdrawal include 
- Hallucinosis
- Seizures
- Delirium tremens (DT)

## Physical Examination
Signs to consider in the physical examination of patients with alcohol withdrawal may include:
- Anxiety
- Nausea, vomiting
- Tremors
- Autonomic hyperactivity (tachycardia, hypertension, and hyperthermia)
- Hallucinations (auditory, visual, tactile, gustatory, and olfactory)
- Delusions
- Confusion
- Seizure
- Delirium tremens (DT)

## Laboratory Findings
Routine laboratory tests should include:
- Blood or breath alcohol concentration
- Complete blood count (CBC)
- Electrolytes
- Glucose
- Liver function tests
- Renal function tests
- Urinalysis
- Urine toxicology

## CT scan
- There are no CT scan findings associated with alcohol withdrawal.
- However, it has been suggested that in linear CT scan measurements in patients that are dependent on alcohol and have a history of delirium tremens, the maximum width of the anterior interhemispheric fissure (MIF) and the maximum width of the Sylvian fissure (MSF) are significantly larger compared to those patients that did not have delirium tremens and controls.

## Other Imaging Findings
- There are no MRI findings associated with alcohol withdrawal.
- Studies have suggested a decrease in hippocampal volume on a MRI may represent brain atrophy in patients with chronic alcoholism, however, a decrease in hippocampal volume has been suggested to have no association with seizures during alcohol withdrawal.

## Other Diagnostic Studies
- There are no other diagnostic studies associated with alcohol withdrawal.
- However, studies with neurochemical brain imaging  have shown the neurochemical (GABA, glutamate, and dopamine) effects during alcohol dependence and withdrawal such as:
Downregulation of dopamine D2/D3 receptor
Higher glutamate levels during acute alcohol withdrawal followed by fluctuating concentrations
Potential detrimental effects on the GABA system by smoking
- Downregulation of dopamine D2/D3 receptor
- Higher glutamate levels during acute alcohol withdrawal followed by fluctuating concentrations
- Potential detrimental effects on the GABA system by smoking

# Treatment

## Medical Therapy
The medical management of alcohol withdrawal includes:
- Supportive and nonpharmacological therapy:
Airway protection
Monitoring of vital signs
Assessment of adequate hydration
- Airway protection
- Monitoring of vital signs
- Assessment of adequate hydration
- Vitamin and electrolyte replacement:
Thiamine for prevention of Wernicke encephalopathy (prior to glucose administration)
Folate supplementation
Electrolyte imbalances may be seen in alcohol withdrawal due to inadequate nutrition and hydration:
Hypokalemia (may be corrected with potassium supplementation)
Hypomagnesemia (routine supplementation of magnesium is not recommended)
Hypophosphatemia (in asymptomatic and  moderate hypophosphatemia, correction with proper nutrition is preferred)
- Thiamine for prevention of Wernicke encephalopathy (prior to glucose administration)
- Folate supplementation
- Electrolyte imbalances may be seen in alcohol withdrawal due to inadequate nutrition and hydration:
Hypokalemia (may be corrected with potassium supplementation)
Hypomagnesemia (routine supplementation of magnesium is not recommended)
Hypophosphatemia (in asymptomatic and  moderate hypophosphatemia, correction with proper nutrition is preferred)
- Hypokalemia (may be corrected with potassium supplementation)
- Hypomagnesemia (routine supplementation of magnesium is not recommended)
- Hypophosphatemia (in asymptomatic and  moderate hypophosphatemia, correction with proper nutrition is preferred)
- Benzodiazepines (currently the gold standard treatment of alcohol withdrawal): diazepam, chlordiazepoxide, lorazepam, and oxazepam
- Phenobarbital
- Propofol (an agonist at the GABA-A receptor)
- Dexmedetomidine (-2 adrenergic receptor agonist)

## Surgery
Surgical intervention is not recommended for the management of alcohol withdrawal.

## Primary Prevention
Refraining from sudden and abrupt discontinuation of alcohol intake in individuals with alcohol dependence may be considered in the primary prevention of alcohol withdrawal.

## Secondary Prevention
Long-term abstinence may be considered in the secondary prevention of alcohol withdrawal. Abstinence requires enrollment in long-term treatment programs in order to reduce the risk of relapse, such as:
- Group meetings
- Counseling
- Medications

## Cost-Effectiveness of Therapy
- Outpatient detoxification and treatment are more cost-effective in patients with mid-to-moderate alcohol withdrawal symptoms. 
- Outpatient treatment costs are about $175 to $388 per patient.
- Inpatient treatment costs are about $3,319 to $3,665 per patient.

## Future or Investigational Therapies
Further studies are required for:
- Investigating the exact molecular and genetic mechanisms that cause the different symptoms of withdrawal
- Kindling and the risk factors that cause severe withdrawal
- The most appropriate treatment
- Methods that help the patients in relapse prevention
- Methods that improve the physician recognition of alcohol dependence
- Methods that improve receiving evidence-based treatment