What causes symptoms of alcohol withdrawal?

From the Guidelines

Alcohol withdrawal symptoms are caused by the brain's adaptation to chronic alcohol exposure and subsequent rebound when alcohol is removed, leading to an imbalance in neurotransmitters and hyperarousal of the nervous system. When someone regularly drinks alcohol, their brain adjusts by increasing excitatory neurotransmitters and decreasing inhibitory ones to counterbalance alcohol's depressant effects. Upon stopping alcohol consumption, this adapted brain chemistry becomes unbalanced, with excessive excitatory activity (primarily glutamate) and reduced inhibitory activity (GABA), leading to hyperarousal of the nervous system and autonomic instability. This neurochemical imbalance manifests as withdrawal symptoms including anxiety, tremors, sweating, increased heart rate, high blood pressure, insomnia, and in severe cases, seizures or delirium tremens. The severity of symptoms typically correlates with the duration and amount of prior alcohol consumption, with symptoms beginning within 6-24 hours after the last drink, peaking at 24-72 hours, and gradually improving over 5-7 days.

Key Factors in Alcohol Withdrawal

• The brain's adaptation to chronic alcohol exposure and subsequent rebound when alcohol is removed
• Imbalance in neurotransmitters, including excessive excitatory activity (primarily glutamate) and reduced inhibitory activity (GABA)
• Hyperarousal of the nervous system and autonomic instability
• Severity of symptoms correlates with the duration and amount of prior alcohol consumption

Treatment of Alcohol Withdrawal

Treatment often involves benzodiazepines like diazepam (5-10mg) or lorazepam (1-2mg) every 4-6 hours as needed, with dosing adjusted based on symptom severity, as recommended by the EASL clinical practice guidelines 1. Thiamine supplementation (100mg daily) is also essential to prevent neurological complications like Wernicke-Korsakoff syndrome. The Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) is useful in clinical practice to assess the severity of alcohol withdrawal syndrome, with a score >8 indicating moderate AWS and a score ≥15 indicating severe AWS 1.

Management of Alcohol Withdrawal Syndrome

• Benzodiazepines are considered the 'gold standard' treatment for AWS, given their efficacy in reducing both withdrawal symptoms and the risk of seizures and/or delirium tremens 1
• Long-acting benzodiazepines (e.g. diazepam, chlordiazepoxide) provide more protection against seizures and delirium, but short and intermediate-acting benzodiazepines (e.g. lorazepam, oxazepam) are safer in elderly patients and those with hepatic dysfunction 1
• Thiamine supplementation is essential to prevent neurological complications like Wernicke-Korsakoff syndrome 1

From the FDA Drug Label

Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol)

The symptoms of alcohol withdrawal are caused by physical dependence on alcohol, which develops as a result of physiological adaptation in response to repeated alcohol use. When alcohol use is abruptly discontinued or significantly reduced, withdrawal signs and symptoms can occur. Additionally, the use of alcohol in combination with other CNS depressants, such as benzodiazepines, can increase the risk of severe adverse outcomes, including death 2 3.

• Key factors that contribute to the development of physical dependence on alcohol include:
  • Repeated alcohol use
  • Physiological adaptation
  • Abrupt discontinuation or significant reduction in alcohol use
• Severe adverse outcomes associated with alcohol withdrawal and polysubstance use include:
  • Respiratory depression
  • Overdose
  • Death

From the Research

Causes of Alcohol Withdrawal Symptoms

• Alcohol withdrawal symptoms are caused by the sudden decrease or cessation of alcohol consumption in heavy drinkers, leading to imbalances in brain chemistry and excessive neuronal activity 4.
• The brain chemistry imbalances caused by alcohol withdrawal can result in a range of symptoms, from mild to severe, including tremors, irritability, anxiety, agitation, delirium tremens, hallucinations, and seizures 4, 5.
• The severity of alcohol withdrawal symptoms can be influenced by various factors, including the amount and duration of alcohol consumption, as well as individual differences in brain chemistry and physiology 6.

Mechanisms of Alcohol Withdrawal

• Alcohol withdrawal symptoms are thought to result from the removal of alcohol's inhibitory effects on the brain, leading to an increase in neuronal activity and the release of excitatory neurotransmitters 4.
• The sudden removal of alcohol can also lead to a decrease in the activity of inhibitory neurotransmitters, such as GABA, which can contribute to the development of withdrawal symptoms 5.
• The use of benzodiazepines, such as diazepam and lorazepam, can help to alleviate alcohol withdrawal symptoms by enhancing the activity of GABA and reducing neuronal excitability 7, 8.

Risk Factors for Severe Alcohol Withdrawal

• Severe alcohol withdrawal is more likely to occur in individuals who have a history of heavy and prolonged alcohol consumption 5.
• Other risk factors for severe alcohol withdrawal include a history of previous withdrawal episodes, co-occurring medical or psychiatric conditions, and the use of other substances in addition to alcohol 6.
• The risk of severe alcohol withdrawal can be reduced by gradual tapering of alcohol consumption or the use of medications, such as benzodiazepines, to manage withdrawal symptoms 7, 8.