Phenobarbital Use in Alcohol Withdrawal Syndrome

Alcohol withdrawal syndrome (AWS) is classified as a set of potentially fatal symptoms that can occur when a person who is physically dependent on alcohol suddenly stops drinking or drastically reduces their normal alcohol intake. Approximately 16% to 31% of patients in the intensive care unit (ICU) have alcohol use disorder or are at risk for developing AWS.¹

The mechanism behind alcohol withdrawal stems from prolonged and excessive alcohol use leading to changes in gamma-aminobutyric acid (GABA) and glutamate neurotransmitters, resulting in a downregulation of GABA receptors with an increase in glutamate. If the person suddenly stops drinking alcohol, their body is not prepared for the lack of GABA, which can lead to hyperactivity of glutamate and the potentially fatal complications we can see during withdrawal.¹

The severity of AWS can vary between individuals, ranging anywhere from mild symptoms (eg, sweating or headache) to more severe, life-threatening symptoms (eg, seizures).^2,3 When treating patients with AWS, it is important to note the timeline from when the last alcoholic drink was ingested. As seen in Table 1, patients are at highest risk for life-threatening symptoms—such as seizures and delirium tremens—between 48 and 72 hours after their last drink.¹ Knowing both this timeline and the severity of a patient's withdrawal can help determine their treatment approach, decrease their risk of severe complications, and overall improve patient outcomes. The severity of withdrawal can be assessed utilizing scoring systems, such as the Clinical Institute Withdrawal Assessment Scale Revised (CIWA-Ar) or the Minnesota Detoxification Scale (MINDS).³ Although these 2 scales are similar, CIWA-Ar requires patient responsiveness to questions, whereas MINDS does not, meaning that the latter is utilized more in the ICU setting. Whichever is used, the scales can be used to score patient severity and determine which treatment to give to prevent the patient from worsening.³

In patients experiencing AWS, it is imperative that pharmacologic therapy be initiated. The 2020 American Society of Addiction Medicine (ASAM) Clinical Practice Guidelines on Alcohol Withdrawal Management recommend benzodiazepines as the gold standard in treating patients at risk of severe alcohol withdrawal.² Benzodiazepines are utilized to minimize the risk of seizures through their effects of facilitating GABA.^4-6 Typically, they are usually dosed on a symptom-triggered (eg, based on CIWA-Ar score) or fixed-dose protocol (standing regimen with scheduled taper) when treating AWS (Table 2).^1,2 Of note, no specific benzodiazepine has been seen to be more effective than the others, but symptom-triggered protocols and long-acting benzodiazepines are more preferred.² If benzodiazepine use is not preferred or contraindicated, phenobarbital can be considered as an alternative agent.²

Phenobarbital

The use of phenobarbital has been on the rise, especially in the critical care setting, where the withdrawal symptoms are more severe. Phenobarbital is from the drug class called barbiturates and has been historically used for treating seizures because of its antiseizure properties. Phenobarbital has a dual mechanism where it can prolong opening of the GABA channel and block glutamate signaling.^8,9 Although there are other drugs in the barbiturate class, there is favoritism towards phenobarbital because of its long half-life, autotaper effect, and low addiction potential, making it the most common barbiturate used for AWS.¹ This autotaper effect is especially beneficial in AWS due to the potential risk of withdrawal symptoms lasting over the course of multiple days.⁹ These benefits have increased the usage of phenobarbital for AWS, with some studies showing decreased length of stay (LOS), ventilation demands, and significantly lower overall exposure to benzodiazepines.¹

Even with these benefits of using phenobarbital, it does have associated risks and adverse effects (AEs). This drug has been seen to cause respiratory depression and oversedation, especially with concomitant use of sedatives.¹ It has a high potential for drug-drug interactions due to its induction of CYP enzymes and has a narrow therapeutic window, requiring therapeutic drug monitoring.^8,9

Literature Selection

Studies evaluating the use of phenobarbital have been limited, most evaluating phenobarbital in conjunction with benzodiazepines, which can potentially worsen the oversedation and respiratory depression concerns. Article selection was made based on the trials’ retrospective or randomized controlled designs, population focused on patients in the ICU, and directly compared phenobarbital to benzodiazepine treatment. Ultimately, 2 retrospective cohort studies were selected based on study scope and direct comparison of treatment groups.

Literature

The first study was a retrospective, single-center, pre-post protocol, cohort study conducted by Alwakeel et al that evaluated phenobarbital versus benzodiazepine use in AWS for patients in the ICU.¹⁰ Investigators included those who were admitted to the ICU primarily for alcohol withdrawal management and excluded those who were intubated prior to ICU admission or had the presence of a serious medical or surgical diagnosis that dictated admission to the ICU. The primary outcome was ICU LOS, and secondary outcomes included hospital LOS, intubation rate, number of adjunctive agents, protocol-related AEs, and ICU readmission (Table 3).¹⁰

There were 102 patients included in the study, with 51 patients each assigned to the phenobarbital group and the benzodiazepine group.¹⁰ There were no significant differences seen in baseline characteristics between the groups. The primary outcome showed a statistically significant decrease in ICU LOS if patients received phenobarbital compared with a benzodiazepine (1.5 days [IQR, 1.2–2.4] vs 2.3 [IQR, 1.4–4.8]; p = .009). Secondary outcomes showed statistically significant decreases in hospital LOS (3 days [IQR, 2.7–4 d] vs 6 d [IQR, 4–10 d]; p < .001), use of adjunctive agents (0.7 [95% CI, 0.5–1] vs 2.5 [95% CI, 2–3]; p < 0.001), and need for intubation (1 [2%] vs 10 [19.6%]; p = .023). There were no statistically significant differences in protocol-related AEs and ICU readmission.¹⁰

Based on these results, the authors concluded that phenobarbital management of AWS is associated with shorter ICU LOS, decreased use of adjunctive agents, and decreased intubation rates. Therefore, phenobarbital can be considered an effective and safe option. Limitations of the study included a small sample size and retrospective design, with a historical comparator group.¹⁰

Another study conducted by Kessel et al was a retrospective cohort study that compared phenobarbital to benzodiazepines for the management of severe alcohol withdrawal syndrome (SAWS) for patients admitted to the ICU.¹¹ Investigators included patients who were 19 years of age or older, whose primary indication for admission was alcohol withdrawal, who had SAWS, and who received treatment within 48 hours of admission. Participants were excluded if they received overlapping phenobarbital and benzodiazepine therapy or if they were pregnant or incarcerated. The primary outcome was hospital LOS compared between the 2 groups. Some of the secondary outcomes included incidence of mechanical ventilation after treatment initiation, duration of mechanical ventilation, incidence of dexmedetomidine or antipsychotic use after treatment initiation, incidence of seizures, and in-hospital mortality.¹¹

The primary outcome included 164 patients, 76 patients in the phenobarbital cohort and 88 patients in the benzodiazepine cohort. Baseline characteristics between the groups were well matched, but more patients in the phenobarbital group had a history of seizures (85.7% vs 68.4%) and delirium tremens (79.4% vs 38.8%). The investigators found that the phenobarbital group was associated with a shorter hospital LOS compared with the benzodiazepine group (median [IQR], 2.8 [2.5–3.5] vs 4.7 [2.9–6.7] days; p < .0001). They also found a statistically significant decrease in use of dexmedetomidine (6 [4.8%] vs 53 [54.1%]; p < .0001) and antipsychotic initiation (7 [5.6%] vs 36 [36.7%]; p < .0001). Only 1 patient in the phenobarbital group required ventilation, whereas 6 patients in the benzodiazepine group required ventilation (p = .045). There were no significant differences found in duration of ventilation, incidence of seizures, and mortality.¹¹

The authors concluded that management of SAWS with phenobarbital was associated with a shorter hospital LOS than those treated with benzodiazepines. Limitations of this study included small sample size with retrospective design.¹¹

Although small and retrospective, these 2 studies provide more evidence to support the use of phenobarbital in severe AWS, especially as monotherapy. Previous studies have also shown similar benefits in decreasing LOS and the need for additional agents.^1,9-11 These 2 studies reinforce the safety and efficacy of the use of phenobarbital as monotherapy to decrease the risk of oversedation and respiratory depression.

Conclusion

Severe AWS can be challenging to manage in those who are critically ill. Although benzodiazepines are still considered the standard of care for treatment, phenobarbital continues to rise in popularity. New evidence continues to show promising results with its use in critically ill patients. Specifically, those who may be at higher risk for increased LOS, mechanical ventilation, and additional pharmacologic interventions.^10,11 Its longer half-life allows for preemptive management rather than reactive management, which can be a more beneficial and safer option for patients.¹¹ Therefore, based on the numerous advantages discussed, phenobarbital does have a role in managing these patients. With this, its use should be considered when deciding treatment for a patient.

REFERENCES

1. Dixit D, Endicott J, Burry L, et al. Management of acute alcohol withdrawal syndrome in critically ill patients. Pharmacotherapy. 2016;36(7):797-822. doi:10.1002/phar.1770

2. The ASAM Clinical Practice Guideline on Alcohol Withdrawal Management. J Addict Med. 2020;14(3S Suppl 1):1-72.

3. Gottlieb M, Chien N, Long B. Managing alcohol withdrawal syndrome. Ann Emerg Med. 2024;84(1):29-39. doi:10.1016/j.annemergmed.2024.02.016

4. Dhaliwal JS, Rosani A, Saadabadi A. Diazepam. StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; August 28, 2023. Accessed November 17, 2025. https://www.ncbi.nlm.nih.gov/books/NBK537022/

5. Ghiasi N, Bhansali RK, Marwaha R. Lorazepam. StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; May 25, 2025. Accessed November 20, 2025. https://www.ncbi.nlm.nih.gov/books/NBK532890/

6. Lingamchetty TN. Midazolam. StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; July 6, 2025. Accessed November 20, 2025. https://www.ncbi.nlm.nih.gov/books/NBK537321/

7. Freeman Recovery Center. Long-acting vs short-acting benzos. Freeman Recovery Center; September 23, 2025. Accessed November 20, 2025. https://www.freemanrecoverycenter.com/long-acting-versus-short-acting-benzos/

8. Lewis CB. Phenobarbital. StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; February 28, 2024. Accessed November 20, 2025. https://www.ncbi.nlm.nih.gov/books/NBK532277/

9. Brooks L, Reinert JP. Phenobarbital dosing for the treatment of alcohol withdrawal syndrome: a review of the literature. J Pharm Technol. 2024;40(4):186-193. doi:10.1177/87551225241249407

10. Alwakeel M, Alayan D, Saleem T, et al. Phenobarbital-based protocol for alcohol withdrawal syndrome in a medical ICU: pre-post implementation study. Crit Care Explor. 2023;5(4):e0898. doi:10.1097/CCE.0000000000000898

11. Kessel KM, Olson LM, Kruse DA, et al. Phenobarbital versus benzodiazepines for the treatment of severe alcohol withdrawal. Ann Pharmacother. 2024;58(9):877-885. doi:10.1177/10600280231221241