What is the mechanism of action of benzodiazepines (BZDs) in alcohol withdrawal and what is the evidence for their recommendation as first-line treatment?

From the Guidelines

Benzodiazepines are the first-line treatment for alcohol withdrawal syndrome due to their GABA-enhancing mechanism of action, which directly counteracts the neuronal hyperexcitability caused by alcohol withdrawal, as supported by the most recent and highest quality study 1. The mechanism of action of benzodiazepines (BZDs) in alcohol withdrawal involves binding to GABA-A receptors, enhancing the inhibitory effects of GABA in the central nervous system. When chronic alcohol use is discontinued, the brain experiences reduced GABA activity and increased glutamate activity, leading to withdrawal symptoms. Benzodiazepines effectively manage these symptoms by restoring GABA inhibition. Some key points to consider when using benzodiazepines for alcohol withdrawal include:

• Common BZDs used include diazepam, chlordiazepoxide, and lorazepam, with lorazepam or oxazepam preferred in patients with liver disease due to their shorter half-lives and lack of active metabolites, as recommended by 1.
• Treatment typically follows either a symptom-triggered approach or a fixed-schedule regimen with tapering over 3-7 days.
• The evidence supporting BZDs as first-line therapy is robust, with multiple clinical trials demonstrating their efficacy in reducing withdrawal severity, preventing seizures and delirium tremens, and decreasing mortality compared to placebo and other agents, as shown in 1.
• It is also recommended to prescribe thiamine as part of the withdrawal process to prevent the onset of Wernicke's encephalopathy, as suggested by 1. The safety profile of benzodiazepines, when properly administered, and their proven effectiveness in managing the full spectrum of withdrawal symptoms make them the standard of care for alcohol withdrawal management. In patients with advanced liver disease, a personalized prescription that is symptom-adapted and favors short-acting drugs is recommended, as stated in 1. Overall, benzodiazepines are a crucial component of alcohol withdrawal management, and their use should be guided by the most recent and highest quality evidence, such as 1.

From the FDA Drug Label

Diazepam is indicated for the management of anxiety disorders or for the short- term relief of the symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic In acute alcohol withdrawal, diazepam may be useful in the symptomatic relief of acute agitation, tremor, impending or acute delirium tremens and hallucinosis

The mechanism of action of benzodiazepines (BZDs) like diazepam in alcohol withdrawal is not explicitly stated in the label, but it is known that BZDs enhance the effect of the neurotransmitter gamma-aminobutyric acid (GABA) at the GABA_A receptor, resulting in sedative, hypnotic, anxiolytic, anticonvulsant, and muscle relaxant properties. In the context of alcohol withdrawal, BZDs like diazepam are thought to help alleviate symptoms by:

• Reducing anxiety and agitation
• Relieving tremors and muscle spasms
• Preventing or treating seizures and delirium tremens The evidence for recommendation of diazepam as a first-line treatment for alcohol withdrawal is based on its ability to provide symptomatic relief of acute agitation, tremor, impending or acute delirium tremens, and hallucinosis, as stated in the label 2. Key points about the use of diazepam in alcohol withdrawal:
• It is useful in the symptomatic relief of acute agitation, tremor, impending or acute delirium tremens, and hallucinosis
• It is a useful adjunct for the relief of skeletal muscle spasm
• The effectiveness of diazepam in long-term use has not been assessed by systematic clinical studies 2

From the Research

Mechanism of Action

• Benzodiazepines (BZDs) ameliorate or prevent the symptoms and complications of moderate to severe alcohol withdrawal by enhancing the effect of gamma-aminobutyric acid (GABA) in the brain, which helps to calm the nervous system 3.
• BZDs are cross-tolerant with ethanol, making them effective in treating alcohol withdrawal syndrome (AWS) 4.

Evidence for Recommendation

• Several studies suggest that BZDs should be the first-line treatment for alcohol withdrawal, as they decrease the risk of seizures and are safe 5, 6.
• A review of major guidelines recommends BZDs as the first-line treatment for alcohol withdrawal syndrome, with the association of anticonvulsants, adrenergic alpha-2 agonists, beta-blockers, and antipsychotics recommended for symptom reduction in severe cases 6.
• Different BZDs have varying pharmacokinetics, with diazepam having the shortest time to peak effect and longest elimination half-life, making it a preferred option for treating moderate to severe alcohol withdrawal under most circumstances 3.
• However, in patients with liver disease or the elderly, lorazepam or oxazepam may be safer options due to their metabolism being less affected by age and liver disease 4, 7.

Treatment Guidelines

• The choice of BZD depends on various factors, including the patient's medical history, liver function, and the severity of withdrawal symptoms 3, 4, 7.
• Thiamine should be administered to all patients to prevent Wernicke-Korsakoff encephalopathy, and any electrolytic imbalance should be corrected 6.
• Maintaining a high level of suspicion for alcohol withdrawal syndrome is important across all clinical settings, and it should be promptly treated 6.