Medications to Treat Alcohol Withdrawal Syndrome & How Do They Work?

What is Alcohol Withdrawal Syndrome?

Alcohol withdrawal syndrome (AWS) refers to symptoms that may affect people who suddenly stop consuming alcohol. The symptoms usually start off mild and worsen over time. 

Around half of people with alcohol use disorder (AUD) will experience withdrawal symptoms. Seizures and more severe symptoms happen in less than 5% of alcohol-dependent people.^{1, 2}

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What Happens During Alcohol Withdrawal

Alcohol affects two brain chemicals:²

1. Glutamate: the excitatory neurotransmitter
2. Gamma-aminobutyric acid (GABA): the inhibitory neurotransmitter

Glutamate and GABA are normally balanced to keep the brain functioning properly. When a person drinks, alcohol triggers GABA’s action. 

GABA inhibits nerve excitation. This explains why people feel relaxed or sleepy after drinking. 

In chronic drinkers, alcohol continues to disrupt the GABA-glutamate balance. The body adjusts to counter alcohol’s effects and keep the brain awake. This adjustment is made by:³

• Decreasing GABA receptors to tone down GABA’s effect
• Increasing glutamate to increase nerve excitation

Chronic alcohol consumption can lead to alcohol tolerance. This is due to the further toning down of GABA’s activity. As a result, people drink more to get the same relaxing effect. 

When a chronic drinker suddenly stops drinking altogether, the body continues to adjust to a substance that’s no longer there. GABA remains low, while glutamate is left unopposed. The result: more nerve excitation. 

All of these factors lead to a hyperactive nervous system, and the person will experience withdrawal.

Repeated withdrawal episodes can lower a person’s seizure threshold and make it more likely that they will develop withdrawal seizures. This is why people who have a history of seizures are likely to experience them again during withdrawal.^{1, 3}

Timeline of Alcohol Withdrawal Symptoms

AWS consists of four stages, each varying in severity:²

Stage 1: Minor Withdrawal (6-12 hours)

Mild withdrawal symptoms may start 6 to 12 hours after the last drink. They may last up to 48 hours and include:^{1, 3, 4, 6}

• Tremors
• Excessive sweating 
• Increased heart rate
• High blood pressure
• Increased body temperature
• Abnormally rapid breathing
• Nausea
• Vomiting
• Headache
• Anxiety

At this stage, people still have clear thinking and intact orientation. 

Stage 2: Alcohol Hallucinosis (12-24 hours)

Visual, tactile, or auditory hallucinations may begin within 12 to 24 hours. Mild symptoms may persist at this stage.

Almost 25% of people with AWS experience hallucinations. However, they still have clear thinking and recognize the hallucinations as unreal.^{1, 3}

Stage 3: Withdrawal Seizures (24-48 hours)

Almost 10% of people with AWS develop alcohol withdrawal seizures. They generally start within 24 to 48 hours after the last drink.¹

Mild symptoms and hallucinations may persist at this stage.

Stage 4: Delirium Tremens (48-72 hours)

Delirium tremens (DTs) is the most severe form of AWS. It may happen 48 to 72 hours after the last drink. 

It’s accompanied by more severe symptoms like:^{1, 3}

• Tremors
• Excessive sweating 
• Increased heart rate
• Anxiety
• Hallucinations
• Agitation
• Psychosis
• Increased body temperature
• High blood pressure
• Disorientation
• Seizures
• Coma

DTs occur in approximately 5% of people with AWS. This condition can cause heart attacks, other serious medical complications, and potentially death in 1 to 5% of those affected.¹

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Medications Used to Treat Alcohol Withdrawal

Medications can treat withdrawal symptoms (particularly seizures and DTs), prevent the progression to severe withdrawal, and bridge people to other AUD treatments. 

Several medications are available for AWS:

Benzodiazepines

Benzodiazepines remain the gold standard for treating AWS. 

There are two types of benzodiazepines:

• Short-acting benzodiazepines: These include lorazepam and oxazepam. They have a half-life of 26 hours or less. After one half-life has passed, 50% of the drug is removed from the body.
• Long-acting benzodiazepines: These include chlordiazepoxide and diazepam. They have longer half-lives, reaching up to 100 hours. These drugs may facilitate a smoother withdrawal than their short-acting counterparts.

Benzodiazepines are the only medications proven to prevent seizures and DTs. Their efficacy lies in their ability to mimic alcohol’s effect and prevent GABA from further decline during withdrawal.^{1, 2, 3, 4, 5, 6}

Carbamazepine

Carbamazepine is an anticonvulsant that stimulates GABA’s effect. It prevents hyperactive symptoms in mild to moderate withdrawal cases. 

Side effects and interaction with other drugs limit carbamazepine’s use. Oxcarbazepine, a metabolite of carbamazepine, is a good alternative.

Unfortunately, carbamazepine and oxcarbazepine do not prevent DTs and seizures.^{1, 2, 5}

Gabapentin

Gabapentin is structurally similar to GABA. It amplifies the synthesis of GABA in the brain. It’s approved for adjunctive treatment of partial seizures.¹

Topiramate

Topiramate is an anticonvulsant that affects multiple neurotransmitter systems. Several studies have shown topiramate as a promising medication for reducing withdrawal seizures and other severe symptoms.¹

Barbiturates and Propofol

Combining phenobarbital (a barbiturate) and benzodiazepines can increase benzodiazepines’ effectiveness.  Both barbiturates and propofol have shown efficacy against refractory DTs. This is the type of DTs that can’t be controlled with benzodiazepines.

Propofol treatment is expensive. Its use requires clinical monitoring, intubation, and mechanical ventilation. Barbiturates are cheaper, but their use is limited due to health risks like respiratory depression and excessive sedation.^{1, 2, 5}

Baclofen

Baclofen is a muscle relaxant that’s structurally similar to GABA. There are reports that it may be as effective as diazepam (a long-acting benzodiazepine) for treating uncomplicated AWS.^{1, 2}

Valproic Acid

Valproic acid can help improve AWS symptoms, reduce the risk of seizures, and protect against more severe forms of AWS. It’s a promising outpatient drug for mild and moderate AWS. However, it can increase liver enzymes, limiting its use among people with liver disease.¹

Sodium Oxybate (SMO)

SMO is a short-chain fatty acid naturally found in mammalian brains. It is structurally similar to GABA. 

SMO has been approved in some European countries for treating AWS and preventing relapse. It’s not approved in other countries due to its addictive potential.¹

Alpha-2 Adrenergic Receptor Agonists, Beta-blockers, and Neuroleptics

Beta-blockers (like atenolol) and alpha-2 adrenergic receptor agonists (like clonidine) can reduce blood pressure, heart rate, and tremors.

Neuroleptic agents (like haloperidol) are helpful against agitation and hallucinations.

These medication classes should only be used with other AWS medications—never alone. They don’t prevent seizures or DTs. They may mask withdrawal symptoms that should be treated with benzodiazepines.^{1, 2, 5}

Nutritional Support

AWS can cause nutritional deficiencies. Thus, people with AWS are sometimes given nutritional support, particularly thiamine and folic acid.³

Thiamine supplementation can prevent the development of Wernicke’s encephalopathy (WE). This neurological condition is characterized by confusion, abnormal movement, and eye muscle paralysis. 

Magnesium supplementation is also recommended, as this mineral’s levels tend to be low during alcohol withdrawal.^{2, 3}

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Treatment for Alcohol Addiction

Treating withdrawal symptoms is just one component of AUD treatment. After withdrawal management, people should proceed with other treatments to achieve full recovery.

Here are some treatment options: 

• Inpatient treatment: For people with severe AUD or co-occurring disorders. People stay in the rehab facility where they receive 24/7 care and supervision.^{7, 8} 
• Outpatient treatment: Cheaper and less intensive than inpatient rehab. People can go home after treatment and maintain their normal routines.^{7, 8} 
• Medication-assisted therapy (MAT): It involves medications to reduce alcohol cravings or prevent relapse. The three FDA-approved medications for AUD treatment are disulfiram, naltrexone, and acamprosate.^{5, 8}
• Behavioral treatments: Involves one-on-one or group sessions with a therapist. Examples include cognitive behavioral therapy (CBT), motivational interviewing, and family therapy.⁸

Support groups: These groups can help people achieve and maintain abstinence. Examples include Alcoholics Anonymous (AA) and other 12-step programs.⁸