Per guidelines from the American Society of Addiction Medicine updated in 2020, in an inpatient setting, the guidelines state that phenobarbital can be used as monotherapy for patients with a contraindication to benzodiazepines who are experiencing mild to severe alcohol withdrawal. A single dose of intravenous (IV) phenobarbital 10 mg/kg in 100 mL normal saline infused over 30 minutes in addition to lorazepam in the emergency department (ED) has been shown to reduce the rate of intensive care unit (ICU) admissions without increasing the incidence of adverse events (AEs). In the case of alcohol withdrawal delirium, a retrospective cohort study showed that patients treated with 100-200 mg of phenobarbital (PO or IV) had a similar duration of symptoms and length of stay (LOS) compared to patients who received 10-20 mg of diazepam IV hourly until sedated. Additionally, phenobarbital can also be used as an adjunct to benzodiazepines as an option for patients experiencing severe alcohol withdrawal. Parenteral phenobarbital should only be used in highly supervised settings (e.g., ICU, critical care unit [CCU]) because of the risk of over-sedation and respiratory depression. Following a withdrawal seizure, benzodiazepines are the preferred option, but phenobarbital is mentioned as an option, albeit less preferred. Likewise, phenobarbital can be considered an alternative option for alcohol withdrawal delirium. Phenobarbital may also be used as an adjunct to benzodiazepines to control resistant alcohol withdrawal syndrome in settings with close monitoring. [1]
A 2024 review article synthesized findings from six key studies to evaluate the efficacy and safety of phenobarbital dosing regimens for managing alcohol withdrawal syndrome (AWS). The methodologies varied across the reviewed studies, with fixed-dose and weight-based phenobarbital regimens emerging as primary strategies. Fixed-dose protocols typically involved an initial intravenous dose of 260 mg phenobarbital, followed by 130 mg doses administered at intervals depending on symptom severity. Weight-based regimens often utilized a loading dose of 6-15 mg/kg calculated by ideal body weight, divided into multiple doses, followed by maintenance dosing based on serum phenobarbital concentrations. Fixed-dose regimens consistently demonstrated fewer ICU and hospital days, reduced adjunct medication use, and lower rates of mechanical ventilation compared to benzodiazepine-based protocols. [2]
Similarly, weight-based regimens yielded no complications of AWS and were associated with negligible adverse effects. A retrospective analysis conducted in 2020 on surgical and trauma intensive care unit (ICU) patients showcased the superiority of phenobarbital, with zero incidences of alcohol withdrawal delirium or severe withdrawal symptoms in the phenobarbital cohort when compared to benzodiazepines. Another 2022 retrospective study comparing fixed-dose and weight-based protocols found that a single larger, weight-based dose of 10 mg/kg phenobarbital resulted in lower mechanical ventilation rates and a reduced cumulative drug requirement compared to fixed dosing (see Table 1). Across various settings, including emergency departments and ICUs, phenobarbital demonstrated a favorable safety profile, rapid onset of action, and prolonged therapeutic effects. These findings suggest phenobarbital-based protocols are a viable and effective alternative to benzodiazepines for AWS, particularly in critical care or trauma settings. [2]
A 2023 retrospective cohort study published as an abstract aimed to determine if a fixed dose or weight-based phenobarbital dosing strategy would result in a reduction in cumulative benzodiazepine requirements in adults with AWS. The study was conducted at a tertiary urban academic medical center over an eight-year period in 46 adult subjects, of whom the majority were male (80.1%) and white (58.6%) with a median age of 45 years. Rates of seizures prior to phenobarbital administration were similar in both the fixed dose and weight-based arms. Subjects in both arms also received similar median lorazepam equivalent doses (25.7 vs. 38.3, respectively; p= 0.112). However, subjects in the weight-based group received significantly more phenobarbital (750 mg vs. 195 mg; p= 0.00). The highest CIWA score reported in the weight-based and fixed dose arms was similar at 20 and 19, respectively (p= 0.774). Of note, more subjects in the weight-based arm required ICU admission during hospitalization, but the difference was not statistically significant (84% vs. 61.9%; p= 0.089). Incidence of hypotension was also similar between groups. Despite patients in the weight-based arm receiving significantly more phenobarbital, it was determined that the cumulative benzodiazepines requirement, rate of ICU admission, length of stay, and CIWA scores were similar between groups. The authors determined larger studies are needed to validate these results. [3]
Another retrospective study published as an abstract in 2021 evaluated outcomes associated with a lorazepam-based symptom triggered protocol (n= 27 admissions for 21 patients) versus a weight-based, fixed-dose phenobarbital protocol (n= 24 admissions for 18 patients) for AWS. Nearly all patients in the study were men (96%) of white race (88%). Patients treated with lorazapem, however, were older on average compared to patients treated with phenobarbital (57 years vs. 51 years; p= 0.03). There were found to be no differences in safety outcomes between groups. However, ICU and hospital length of stay were significantly longer with lorazepam compared to phenobarbital (ICU: 68 vs 36.5 hours, p= 0.003; hospital: 12 vs. 5.8 days, p<0.001). Use of adjunctive agents did not differ between groups. It was determined that use of a fixed-dose phenobarbital protocol for AWS did not differ in safety outcomes compared with lorazepam alone, but improvements in ICU and hospital length of stay exist for phenobarbital. [4]
Barbiturates, such as phenobarbital, have a similar mechanism to benzodiazepines, as they are both GABA-A modulators. The difference is that phenobarbital is not only able to enhance GABA binding to the GABA-A receptor, but it also increases the duration of GABA-A-mediated inhibitory currents. At higher concentrations, barbituates may also agonize GABA-A. Each of these actions is different from that of benzodiazepines, which are known only to increase the frequency of GABA-A receptor channel opening. These pharmacologic differences allow barbiturates and benzodiazepines to be used in combination for synergistic effects in patients with severe alcohol withdrawal. The typical dose of IV phenobarbital for alcohol withdrawal is 65 to 260 mg. Despite a long elimination half-life (53-140 hours), phenobarbitol's duration of action is approximately 4 to 10 hours. [5]
A retrospective cohort study looked at whether a strategy of escalating doses of benzodiazepines in combination with phenobarbital would improve clinical outcomes of patients with severe alcohol withdrawal and DT. Doses of diazepam were escalated until agitation was controlled for ≥1 hour, and IV phenobarbital was added at the initial dose of 65 mg, then doubled up to a 260 mg maximum dose to patients who required diazepam doses of >100 mg. A dose escalation of diazepam in combination with phenobarbital yielded a significant reduction in the use of mechanical ventilation (21.9% vs. 47.3%, p= 0.008), with no differences in ICU LOS or the overall incidence of nosocomial pneumonia. [6]
Another retrospective study utilized a similar dosing of phenobarbital (65 mg IV x1, then 130 mg IV x1, then 260 mg IV until AWS symptom resolution) and compared it to the treatment with benzodiazepine (diazepam) alone in managing AWS. A total of 28 patients were included (benzodiazepine-only: n= 21; benzodiazepine and phenobarbital: n= 7). There was no difference in the primary outcome (proportion of patients with a CIWA-Ar score <10 at 24 hours after AWS treatment initiation) between the two groups (23.8% vs. 28.6%, respectively; p= 0.588). Median benzodiazepine requirements were lower in the benzodiazepine plus phenobarbital group (25 mg vs. 326 mg; p= 0.02). The median cumulative phenobarbital dose was 455 mg (interquartile range, 309 to 618 mg), which equated to a median 6.3 mg/kg dose per patient. No significant differences are noted in the safety outcome measures (e.g., requirement for intubation or ICU admission). Based on the study findings, the authors concluded that phenobarbital appears to be as safe as benzodiazepines in the treatment of alcohol withdrawal while it is effective in reducing the benzodiazepine dose requirement, especially for non-critically ill patients, and maybe benzodiazepine sparing. [7]
A prospective, uncontrolled trial performed in ED evaluated the use of IV phenobarbital for acute AWS. A total of 62 alcoholic patients received an initial phenobarbital infusion of 260 mg, followed by an additional 130 mg boluses until the endpoint of light sedation was reached or AEs (e.g., altered mental status, hypotension) were recognized. The study showed that the serum phenobarbital level rose 1.65 mcg/mL for each mg/kg of IV phenobarbital administered. Ninety-six percent showed improvement in their alcohol withdrawal tremors, and most patients were safely discharged after a mean ED stay of 3.78 hours. The IV phenobarbital was generally well tolerated, with no significant AEs. The authors concluded that IV phenobarbital is a safe and efficacious therapy for mild to moderate AWS, and IV phenobarbital may prevent alcohol withdrawal seizures. [8]