The 2023 National Survey on Drug Use and Health demonstrated that approximately 10% of the U.S. population meets the diagnostic criteria for alcohol use disorder (AUD). Additionally, one in eight deaths among U.S. adults aged 20 to 64 is attributed to excessive alcohol consumption, highlighting the severity and scope of this public health issue.
The pathophysiology of alcohol withdrawal extends well beyond the foundational concepts of tolerance, dependence, and acute withdrawal. It involves a complex interplay among multiple neurotransmitter systems. The earliest and most extensively studied mechanism—and originally the cornerstone of treatment—involves the disruption of gamma-aminobutyric acid (GABA) and glutamate homeostasis. GABA functions as the primary inhibitory neurotransmitter in the central nervous system, and alcohol enhances GABAergic activity by binding to the GABAA receptor, producing sedative and anxiolytic effects. Conversely, glutamate serves as the brain’s major excitatory neurotransmitter. With chronic alcohol use, the brain adapts by upregulating glutamatergic activity to counterbalance persistent GABAergic stimulation.
Upon abrupt cessation of alcohol, this imbalance contributes to the excitatory symptoms of withdrawal. The body’s neuroadaptive response to prolonged alcohol exposure is intricate, engaging numerous neural circuits and biochemical pathways that are only partially understood. These include: modulation of monoamines such as dopamine, norepinephrine, and serotonin; activation of the hypothalamic-pituitary-adrenal axis; involvement of neuropeptides; and alterations in various ion channels and receptor subtypes.1 Emerging research into these mechanisms is paving the way for a more nuanced, multi-modal approach to treating patients with significant alcohol withdrawal symptoms.
Despite the significant impact of alcohol use and the complexity of its withdrawal mechanisms, many clinical studies are limited by small sample sizes, variability in patient populations, and diverse treatment protocols across healthcare institutions.
The Prediction of Alcohol Withdrawal Severity Scale, or PAWSS, has emerged as the first validated tool designed to assess the risk of severe alcohol withdrawal syndromes (AWS). In contrast to the more commonly used Clinical Institute Withdrawal Assessment for Alcohol, or CIWA, scale, the Prediction of Alcohol Withdrawal Severity Scale is designed to identify at-risk patients before the onset of withdrawal symptoms, allowing for the implementation of a proactive, multimodal management strategy, which can be crucial in reducing complications and improving patient outcomes.
Although benzodiazepines have long been the cornerstone of treatment, guidelines from the American Society of Addiction Medicine (ASAM) now recognize the effectiveness of emerging multimodal approaches in the inpatient setting. Increasing evidence has highlighted the adverse effects associated with benzodiazepines, including paradoxical agitation, delirium, increased risk of falls, and prolonged hospital stays.
Alternative agents, particularly gabapentin, have been increasingly studied. These medications modulate voltage-gated sodium and calcium channels and offer an additional route for symptom control with a potentially better safety profile. Small-scale studies have also demonstrated the potential efficacy of carbamazepine and valproic acid in managing withdrawal symptoms in selected patient groups.
To reduce sympathetic overactivity by decreasing the release of norepinephrine and glutamate, alpha-2 adrenergic agonists like clonidine have shown clinical benefit in some AWS cases. Current ASAM guidelines recommend the use of long-acting benzodiazepines for moderate to severe withdrawal, typically when the Clinical Institute Withdrawal Assessment for Alcohol scores exceed 19. These medications are administered to achieve rapid symptom control, followed by a structured tapering protocol. However, these recommendations are largely based on small-scale trials, many of which include fewer than 100 patients.
In line with the concept of “front-loading,” phenobarbital has emerged as an alternative therapeutic agent. It works by activating GABA receptors and inhibiting glutamate, with a long half-life of approximately 100 hours. Some studies suggest that phenobarbital-based strategies, when compared to benzodiazepine-driven approaches, may reduce intensive care unit admissions, rates of intubation, duration of hospital stay, and the incidence of delirium.2,3 However, like many benzodiazepine studies, the evidence for phenobarbital is largely derived from small observational trials without standardized dosing regimens, limiting definitive conclusions. Utilization of medications such as naltrexone or acamprosate was not covered in depth during this discussion of acute inpatient management.
The 2020 ASAM guidelines advise against the use of phenobarbital monotherapy due to its side effect profile, which includes serious risks such as bradycardia, coma, hypotension, and respiratory depression. The 2024 Academic Emergency Medicine guidelines offer a conditional recommendation for the use of phenobarbital in patients experiencing moderate to severe AWS. However, they emphasize that the supporting evidence is of low to very low certainty and highlight the need for further high-quality research to better define its role in treatment protocols. Given how widespread the use of phenobarbital has become in clinical practice, especially in emergency and inpatient settings, additional studies are urgently needed in the near future to inform evidence-based guidelines.
Key Takeaways
- Benzodiazepines remain the most evidence-based approach for acute withdrawal symptoms.
- Benzodiazepines are problematic medications, leading to attempts to find novel approaches with other agents such as anti-convulsants, alpha blockers, and barbiturates, among others.
- “Front-loading” patients and using a multi-modal approach for those who are at high risk for severe and complicated alcohol withdrawal symptoms helps reduce mortality and length of stay.
Dr. Singh is an associate professor at the University of New Mexico-Sandoval Regional Medical Center in Rio Rancho, N.M., and currently serves as the past president for SHM’s New Mexico chapter.
References
- Becker HC, Mulholland PJ. Neurochemical mechanisms of alcohol withdrawal. Handb Clin Neurol. 2014;125:133-56. doi:10.1016/B978-0-444-62619-6.00009-4.
- Goodberlet M, et al. Evaluation of a phenobarbital-based protocol for severe alcohol withdrawal in critically ill patients. Hosp Pharm. 2021;56(5):550-559. doi:10.1177/0018578720931464.
- Malone D, et al. Phenobarbital versus benzodiazepines in alcohol withdrawal syndrome. Neuropsychopharmacol Rep. 2023;43(4):532-541. doi: 10.1002/npr2.12347.