Carley’s mini note: I’ll be quick here, Joe has a note of his own for us! I just have to say, every time I read a Joe post, I find myself completely ready to delve back into as much clinical learning as possible, don’t you? Anyways, amaze us again, Joe!

Joe’s Note: Back in 2018, we posted an article that went over alcohol use disorder. In case you need a refresher, you can find that post here. In that post, we briefly touched base on alcohol withdrawal but didn’t go super in-depth because we promised you its own full article. Well, it’s now 2025. Yes, it’s been 7 years. Yes, you can probably judge us. But we’re human too. We’ve been so busy pumping out new content that we forgot all about it. But hey, better late than never, am I right? Today, we make good on our promise to you and review everything you need to know about alcohol withdrawal. Who's ready to get started? I know I am.

How Common Is Alcohol Withdrawal Syndrome?

Would you believe me if I told you that alcohol use disorder is the most common substance use disorder in the United States? What if I said that as many as 2 million Americans experience alcohol withdrawal symptoms each year? Or what about the fact that there were an estimated 8,566,725 emergency department visits related to alcohol between January 2021 through September 2023. As you can tell, alcohol withdrawal is an extremely important topic that you will definitely come across. So let's get you comfortable managing this disease state to ensure the best possible care for your patients.

Pathophysiology of Alcohol Withdrawal Syndrome

Believe it or not, the pathophysiology of alcohol withdrawal is actually pretty straightforward. However, to get a better understanding, we need to review some background information first.

Throwing it back to pathophysiology 101, we were taught that GABA is the main inhibitory neurotransmitter in the brain, while glutamate is the main excitatory neurotransmitter in the brain. GABA binds to GABA receptors and leads to sedation, reduced anxiety, and slowed breathing. Glutamate binds to NMDA receptors and leads to excitotoxicity, agitation, hallucinations, psychosis, hypertension, and tachycardia. Well, our body likes to maintain a balance between these two neurotransmitters. When GABA and glutamate are in equal balance, we are just right. Not overly sedated and not overly excited. Just dandy. This balance is called homeostasis.

Do you remember the term homeostasis? If not, homeostasis is the process by which the body maintains a stable internal environment despite changes in the external environment. Our body loves to maintain homeostasis because it is essential for survival and optimal functioning. It’s how the body compensates for external stress or change and maintains stability. This stability helps optimize cellular function, prevent diseases, and allows for survival. So remember, homeostasis is king. More on homeostasis in a little bit.

Okay, so now back to alcohol. Alcohol is a central nervous system depressant that works primarily on GABA receptors. In other words, alcohol is a form of exogenous GABA. We already have endogenous GABA neurotransmitters in our brains. So excessive consumption of alcohol leads to excessive GABAergic activity in the brain, leading to a chronic state of sedation.

Remember what we just said, though? Homeostasis is king, meaning that our body will always compensate to maintain equilibrium because it does not want us to be chronically sedated. So what happens when our exogenous GABA concentration increases? Our body compensates by increasing endogenous levels of glutamate to maintain that equal balance between GABA and glutamate.

Now comes alcohol withdrawal. Let’s say your patient has been a chronic drinker for years. They continue to provide the body with exogenous GABA (alcohol). As a result, their endogenous glutamate levels rise to match those of GABA and maintain equilibrium. Now, for one reason or another, let’s say the patient abruptly stops boozing altogether. What do you think is going to happen?

Their GABA levels are going to plummet rapidly while their endogenous glutamate levels remain elevated for a short period of time. Eventually, the endogenous glutamate production will decrease to regain equilibrium with GABA. However, that natural decrease of glutamate takes a couple of weeks to match, leaving this patient with high levels of glutamate for a brief period of time. This excess glutamate is what causes the severe symptoms associated with alcohol withdrawal.

I know, that was a lot of words. For my visual learners, here is a picture that helps better describe what we just went over. In the end, it’s all about balance. (Image)

Signs And Symptoms of Alcohol Withdrawal

Signs and symptoms of alcohol withdrawal are all secondary to excess glutamate and low GABA levels. Since glutamate is the main excitatory neurotransmitter in the brain, we can now understand why patients who come in with acute alcohol withdrawal are generally anxious, agitated, hallucinating, tachycardic, hypertensive, and delirious. Without treatment, symptoms of alcohol withdrawal generally begin within 6 to 24 hours of the last drink.

The Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) is a tool used to assess the severity of alcohol withdrawal symptoms. A CIWA-Ar score of 0-9 generally indicates minimal to mild withdrawal, 10-15 moderate withdrawal, and 16 or higher indicates severe withdrawal. Severe scores may indicate impending delirium tremens. To get a better idea of how a CIWA-Ar score is calculated, use this MDCalc calculator that can be found here.

Going back to delirium tremens for a second. Why do we actually care about delirium tremens? Because delirium tremens is caused by sympathetic overdrive and can progress to cardiovascular collapse and death. Unlike most other substance withdrawal syndromes, alcohol withdrawal is extremely dangerous if left untreated, and mortality can be high.

Benzodiazepines for Alcohol Withdrawal

If we understand the pathophysiology of alcohol withdrawal, then treatment is simple. We have two options. We can either increase exogenous levels of GABA to regain equilibrium with glutamate. Or, we can reduce glutamate levels to regain equilibrium with GABA. To sum it up, our goal is to balance that pendulum again and ensure that GABA and glutamate levels are equal.

Let’s start with the first option: increase exogenous levels of GABA to regain equilibrium with glutamate. How can we do that? Intravenous GABAergic medications, of course. Specifically benzodiazepines.

There are three intravenous benzodiazepines available: midazolam, diazepam, and lorazepam. Let’s compare them.

A couple of things to note here. As you can see, midazolam is the shortest-acting. It’s very quick on but also very quick off. The short duration of action of midazolam makes it less attractive when treating alcohol withdrawal, as symptoms will likely recur fairly rapidly, requiring the nurse to continue administering repeat doses very often. This can cause medication error or medication delay, and can lead to seizures and delirium tremens. Therefore, longer-acting benzodiazepines such as lorazepam and diazepam are generally preferred for the treatment of alcohol withdrawal.

Another thing to note. Each institution will have its own specific benzodiazepine dosing policy for alcohol withdrawal. Some institutions will follow a symptom-triggered regimen while others may implement a fixed-dose regimen. Both regimens have their advantages and disadvantages. Symptom-triggered regimens work retrospectively and only treat withdrawal after the patient has already experienced symptoms. Fixed-dose regimens work more proactively and help prevent withdrawal symptoms before they happen. The symptom-triggered approach is usually more labor-intensive for hospital personnel, but fixed regimens may lead to prolonged hospital stay and excess sedation. Like I said, they both have their advantages and disadvantages. Please refer to your specific institution's protocol regarding benzodiazepine dosing for alcohol withdrawal. That being said, the takeaway here is to remember that longer-acting IV benzodiazepines such as lorazepam and diazepam are recommended for the treatment of alcohol withdrawal.

Phenobarbital for Alcohol Withdrawal

Okay, on to option #2. My personal favorite. Like we said earlier, to treat alcohol withdrawal, we can either increase exogenous GABA activity or reduce endogenous glutamate activity to achieve equilibrium between the two neurotransmitters. Would you believe me if I told you that we have a medication that works on both GABA and glutamate? Please welcome phenobarbital.

I love phenobarbital for multiple reasons. First, much like benzodiazepines, phenobarbital also exhibits GABAergic activity. However, unlike benzodiazepines, phenobarbital also antagonizes NMDA receptors, leading to the inhibition of glutamate activity. So on paper, it’s literally perfect for alcohol withdrawal.

The second reason I love phenobarbital is for its pharmacokinetic profile. It has a very quick onset of action but a crazy long half-life. When given intravenously, phenobarbital has an onset of action of 5 minutes with a half-life of ~80 hours. That means if you appropriately load the patient with phenobarbital, that one dose may be enough to get a patient through the withdrawal stage and avoid seizures/delirium tremens. I mean, that’s pretty sick if you ask me.

In regard to dosing, much like benzodiazepines, it’s going to be institution and provider-specific. Some protocols are more aggressive than others. Generally speaking, the important detail is not to exceed 15 mg/kg of IV phenobarbital within 24 hours to avoid excessive sedation and respiratory depression. Some protocols will load a patient with 5-10 mg/kg and give the remaining doses only if needed.

One really important thing to remember. You generally want to avoid mixing benzodiazepines and phenobarbital. If your patient recently received benzodiazepines, then phenobarbital is generally not recommended because of the increased risk for respiratory depression. If phenobarbital is to be started, it is generally recommended to be given as monotherapy with close monitoring to avoid oversedation and respiratory compromise.

Benzodiazepines vs Phenobarbital: What the Evidence Says

So on paper, phenobarbital sounds like a much better option for the acute management of alcohol withdrawal given its dual mechanism of action and favorable pharmacokinetic profile. However, what does the literature say? This has been an ongoing battle for years now. Overall, I would say phenobarbital has gained more popularity over the last few years.

The first study I want to review can be found here. This retrospective cohort study aimed to determine the clinical impact of phenobarbital versus benzodiazepines for severe alcohol withdrawal syndrome (SAWS). They included a total of 224 patients (126 phenobarbital and 98 benzodiazepine). Their results showed that patients treated with phenobarbital had a shorter median ICU and hospital length of stay versus those treated with benzodiazepines (2.8 vs 4.7 days; P <0.0001). Additionally, they found that the phenobarbital group had a lower incidence of supplemental dexmedetomidine and antipsychotic initiation (P < 0.0001). Lastly, fewer patients in the phenobarbital group received new mechanical ventilation (P = 0.045), but the median duration of mechanical ventilation was similar (1.2 vs 1.6 days; P = 1.00).

The second study I want to review can be found here. This was also a retrospective cohort study that aimed to assess the clinical impact of phenobarbital versus benzodiazepines for alcohol withdrawal in hospitalized patients. A total of 300 patients met the inclusion criteria (148 lorazepam and 152 phenobarbital). Their results showed significant differences between lorazepam and phenobarbital in terms of:

ICU admission (13.5% vs 5.3%, P = 0.014)
Mechanical ventilation rate (9.5% vs 0.7%, P = 0.0004)
Need for adjunctive dexmedetomidine (9.5% vs 1.3%, P = 0.0016), and
Mean length of hospital days (6.16 vs 4.89 days, P = 0.004) and ICU days (1.07 vs 0.21 days, P value = 0.003).

Therefore, the authors concluded that their results support the growing evidence of the efficacy of phenobarbital over lorazepam as the primary treatment for acute alcohol withdrawal syndrome.

Metabolic Disturbances in Alcohol Withdrawal

Chronic alcoholism can lead to metabolic disturbances due to a combination of poor nutritional intake and organ damage (especially the liver and pancreas). These metabolic disturbances are generally secondary to:

Poor nutritional intake:
- Mechanism: chronic alcoholics often consume alcohol instead of solid food, leading to vitamin and mineral deficiencies
- Deficiency: thiamine, folate, magnesium, zinc, potassium
Gastrointestinal malabsorption:
- Mechanism: alcohol damages the stomach lining and small intestine, leading to nutrient malabsorption
- Deficiency: Vitamins A, B, D, E, K, and electrolytes
Liver Dysfunction:
- Mechanism: chronic alcoholism leads to liver damage, leading to impaired glucose storage and protein synthesis
- Deficiency: glucose, albumin
Pancreatic Damage:
- Mechanisms: chronic alcoholism leads to pancreatic damage, leading to poor insulin secretion and nutrient digestion
- Deficiency: insulin, absorption of fat, protein, and vitamins

Correcting all of these metabolic deficiencies is crucial in treating alcoholism. The specific metabolic disturbances that I want to focus on are thiamine and folic acid. Why are these so important? Because deficiency in these vitamins can lead to a life-threatening neurological condition called Wernicke’s encephalopathy. Wernicke’s encephalopathy is generally characterized by a triad of symptoms such as confusion, nystagmus, and ataxia.

So how do we prevent Wernicke’s encephalopathy? By supplementing thiamine and folic acid. Prophylactic dosing is as follows:

Thiamine (IV, Oral, IM): 100 to 200 mg once daily for 3 to 5 days
Folic Acid (Oral, IV): 400 mcg to 1 mg daily until no longer at risk

There is a really important clinical pearl that I want to review regarding thiamine administration. As you can see from the bullet points I have above, chronic alcoholism can lead to glucose and thiamine deficiencies. Therefore, it is very common to have to replenish both glucose and thiamine in these patients. But why does this matter?

Well, believe it or not, glucose metabolism requires thiamine. Without adequate thiamine, the body may not be able to efficiently utilize glucose, leading to a buildup of harmful byproducts such as lactic acid. This can further exacerbate existing neurological symptoms such as Wernicke's encephalopathy. Therefore, replenishing thiamine before administering glucose is generally recommended to avoid all the harmful things I said above. However, this practice should only be done “when able”. Ideally, thiamine should be given before dextrose. However, the real world isn’t always ideal. Hypoglycemia is a life-threatening condition that needs to be treated ASAP. Therefore, it is very essential to correct severe hypoglycemia regardless of thiamine levels. We should NOT withhold dextrose while waiting for thiamine to be administered. If anything, you can co-administer them together at the same time.

The tl;dr of Alcohol Withdrawal Syndromes

Well folks, that’s all she wrote. I hope this was worth the 7-year wait. And in case you need a quick summary of everything we talked about, take a look below:

GABA is the main inhibitory neurotransmitter in the brain, while glutamate is the main excitatory neurotransmitter in the brain

GABA binds to GABA receptors and leads to sedation, reduced anxiety, and slowed breathing
Glutamate binds to NMDA receptors and leads to excitotoxicity, agitation, hallucinations, psychosis, hypertension, and tachycardia

The human body achieves homeostasis by maintaining a constant equilibrium between the GABA and glutamate neurotransmitters
Alcohol is a central nervous system depressant that works primarily on GABA receptors
Chronic alcoholism leads to excessive levels of exogenous GABA, which causes an increase in endogenous glutamate to maintain homeostasis
Abrupt cessation of alcohol causes a rapid decrease in exogenous GABA, followed by a much slower decrease in endogenous glutamate. During this short period of regaining equilibrium, alcohol withdrawal patients are left with excessive levels of glutamate, leading to excitotoxicity
Without treatment, symptoms of alcohol withdrawal generally begin within 6 to 24 hours of the last drink
The Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) is a tool used to assess the severity of alcohol withdrawal symptoms

CIWA-Ar score 0-9: mild alcohol withdrawal
CIWA-Ar score 10-15: moderate alcohol withdrawal
CIWA-Ar score 16 or higher: severe alcohol withdrawal

Treatment of acute alcohol withdrawal can be achieved by regaining equilibrium between GABA and glutamate neurotransmitters
Longer-acting intravenous benzodiazepines such as lorazepam and diazepam are commonly used as first-line treatment agents for alcohol withdrawal syndrome, given their GABAergic activity
Intravenous phenobarbital may be a preferred agent given its dual mechanism of action and favorable pharmacokinetic profile
Recent literature comparing benzodiazepine versus phenobarbital use for alcohol withdrawal syndrome found that phenobarbital was associated with decreased ICU and hospital length of stay, reduced need for adjunct sedative medications, and decreased need for mechanical ventilation
Chronic alcoholism can lead to metabolic disturbances due to a combination of poor nutritional intake and organ damage (especially liver and pancreas)
Thiamine and folic acid deficiency can lead to Wernicke’s encephalopathy. Therefore, supplementation with thiamine and folic acid is generally recommended in chronic alcoholics to avoid this disease state

What Every Pharmacist Should Know About Alcohol Withdrawal Syndrome