Phenobarbital and Alcohol Withdrawal Syndrome: A Systematic Review and Meta-Analysis

When alcohol intake is abruptly ceased, the body does not have enough time to adjust GABA and glutamate regulation, resulting in alcohol withdrawal syndrome. Symptoms of AWS begin to manifest eight hours after the last drink and peak 24 to 72 hours later. Patients initially experience nausea, sweating, headaches, shakiness, tachycardia and hypertension. Symptoms become more severe over time, leading to seizures and delirium tremens 2,3.

Phenobarbital-Based Protocol for Alcohol Withdrawal Syndrome in a Medical ICU: Pre-Post Implementation Study

It is considered to have a significant impact on the United States healthcare system. It not only has a toll on the healthcare spending but also contributes to significant morbidity and mortality. Since patients with alcohol use disorder have downregulated gamma aminobutyric acid (GABA) receptors, this often leads to benzodiazepine resistance. Here we present a systematic review and meta-analysis of the efficacy and safety of the drug. Hammond et al. reviewed nine studies in 2016 and found that the phenobarbital group had lower hospital stays, fewer ICU admissions, and decreased mechanical ventilation as compared to the benzodiazepine group 20.

Figure 3.

The initial RASS score was defined as the first RASS score recorded in the patient’s EHR immediately following the first dose of study medication administration, which was determined through a retrospective chart review. Potential limitations of this study include the retrospective design, the concurrent dexmedetomidine shortage, and medication crossover. First, the retrospective study design means that the cohorts could have been impacted by unmeasured confounders.

Phenobarbital and Alcohol Withdrawal Syndrome: A Systematic Review and Meta-Analysis

Risk factors for respiratory compromise included pneumonia, chronic obstructive pulmonary disease (COPD), asthma, interstitial lung disease, or pulmonary fibrosis. If patients had one of the above risk factors, the protocol would recommend the lower loading dose of phenobarbital, 6 mg/kg. In the United States, alcohol abuse represents a significant healthcare burden, with over 14 million Americans suffering from alcohol use disorder. In 2010, a total of $249 billion was spent in the United States on alcohol-related disorders. Despite warnings from the World Health Organization, alcohol consumption is expected to increase until at least 2025. Hospital admissions for chronic alcohol abusers are particularly dangerous since these patients are at an increased risk of developing life-threatening conditions such as alcohol withdrawal syndrome (AWS) 1.

Associated Data

Phenobarbital is a medication that doctors may prescribe to treat alcohol withdrawal syndrome (AWS). It can help reduce the severity of AWS symptoms while also reducing the risk of complications, such as delirium and seizures. A retrospective cohort study analyzing adults who received either phenobarbital or benzodiazepine‐based treatment for AWS over a 4‐year period, 2015–2019, in a community teaching hospital in a large academic medical system.

• All original studies that reported the management of AWS in the ICU setting with phenobarbital were included in the analysis.
• Sensitivity analyses were completed to control for possible covariates of type of discharge (AMA vs. planned) and BAL.
• A protocol utilizing rapidly escalating doses of PB over a short period is an effective and safe alternative to BZD in treating AWS in MICU.
• If patients had one of the above risk factors, the protocol would recommend the lower loading dose of phenobarbital, 6 mg/kg.

Figure 1. Flow diagram of the PRISMA screening process for this systematic review and meta-analysis.

Phenobarbital’s long half‐life allows for a gradual transition off therapy after the last dose is provided. Additionally, adverse effects such as bradycardia, hypotension, and mortality were examined. The only study to record bradycardia and hypotension was that of Nguyen et al., which found no incidence in the parameters of cutting back on alcohol symptoms either arm 12. Monitoring and documentation were not as effective as they could have been because the included studies were retrospective.

DATA AVAILABILITY STATEMENT

• Phenobarbital (a barbiturate) is being increasingly recommended for the treatment of patients with a contraindication to benzodiazepines 4.
• The initial RASS score was defined as the first RASS score recorded in the patient’s EHR immediately following the first dose of study medication administration, which was determined through a retrospective chart review.
• Despite warnings from the World Health Organization, alcohol consumption is expected to increase until at least 2025.

The management protocols implemented for the treatment of AWS in an ICU setting in both control and experimental groups have been described in depth in Table 2. A variety of scoring systems were used for what is Oxford House the assessment and monitoring of alcohol withdrawal. Richmond Agitation and Sedation Scale (RASS) was implemented for the monitoring of sedation 10. Oks et al., Nguyen et al., and Shah et al. used the CIWA score for the monitoring and assessment of patients admitted to the ICU for alcohol withdrawal 11,12,15. Goodberlet et al. implemented the APACHE II, Model for End-stage Liver Disease (MELD), and Confusion Assessment Method for Intensive Care Unit (CAM-ICU) scoring systems. Duby et al. used the SOFA score for the monitoring and assessment with RASS to monitor for sedation 16.

A systematic review by Mo et al. found barbiturates to be superior to benzodiazepines in cases of severe AWS or benzodiazepine resistance 21. Unfortunately, due to the lack of SD values, the heterogeneity of the data could not be evaluated. Both Tidwell et al. and Saukkonen et al. found that phenobarbital treatment reduced hospital stay in both arms.

Review

The primary outcomes were the mean length of hospital stay, mean length of ICU stay, and changes in Clinical Institute Withdrawal Assessment for Alcohol (CIWA) scale/additional scoring system scores following the implementation of phenobarbital. The secondary outcomes included complications (such as intubation) and mortality. According to the study by Tidwell et al., the phenobarbital arm showed a decreased incidence of intubation 14. Conversely, none of the five other studies were able to demonstrate such a link.