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Journal Scan: Phenobarbital as Adjunct to Benzodiazepines Shows Promise for Alcohol Withdrawal

Rouhani, Amir A. MD; Lovato, Luis M. MD

doi: 10.1097/01.EEM.0000433397.62925.4c
Journal Scan

Dr. Rouhani is an assistant professor at the David Geffen School of Medicine at UCLA and the director of continuing and critical care for emergency medicine at Olive View-UCLA Medical Center. Dr. Lovato is an associate professor at the David Geffen School of Medicine at UCLA, the director of medical informatics for emergency medicine at Olive View-UCLA Medical Center, and the chair of the Emergency Medicine Best Practices Committee for the Los Angeles County Department of Health Services.

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Alcohol-related disease and acute alcohol withdrawal syndrome are among the most frequently encountered illnesses in the emergency department. Nearly two million people experience symptoms each year in the United States (Am Fam Physician 2004;69[6]:1443), and more than 500,000 of these episodes are significant enough to require pharmacologic management. (N Engl J Med 2003;348[18]:1786.)

The relationship between alcohol and the syndrome was first described in a 1955 study that illustrated that the severity of clinical manifestations is dependent on several factors, including dose and duration of ethanol consumption. (Q J Stud Alcohol 1955;16[1]:1.)

Acute alcohol withdrawal syndrome is classically associated with the abrupt cessation of ethanol intake, but it can actually occur any time the blood alcohol level begins to decrease. Once this occurs, the physiologic and clinical manifestations of withdrawal develop, ranging from mild withdrawal with irritability, mild tremor, and insomnia to major withdrawal heralded by diaphoresis, disorientation, hallucinosis, and autonomic dysfunction.

Delirium tremens is the most severe form of acute alcohol withdrawal syndrome, with a mortality rate of up to five percent. It consists of gross tremor, agitation, confusion, seizures, and severe autonomic instability. Acute alcohol withdrawal syndrome usually develops between six and 24 hours after blood alcohol levels decline, and may last from two to seven days. (J Gen Intern Med 1989;4[5]:432.)

Prompt and aggressive ED management of the syndrome is critical given the potential for rapid progression to life-threatening DTs. These patients generally require pharmacologic management of their syndrome in addition to supportive care. Benzodiazepines are the preferred treatment of acute alcohol withdrawal syndrome because of their safety, efficacy, and many ideal pharmacologic properties. (JAMA 1997;278[2]:144.) Among the most important of these is long half-life, which allows for decreased rebound manifestations and a smoother treatment course overall.

The revised Clinical Institute Withdrawal Assessment for Alcohol scale is a 10-item assessment tool that has been validated for assessing the severity of the syndrome and to monitor and guide pharmacologic management. (Am J Addict 2000;9[2]:135.) The use of this score and the development of symptom-triggered benzodiazepine regimens have resulted in more streamlined management of acute alcohol withdrawal syndrome with less total medication requirements and shorter duration of treatment. (Arch Intern Med 2002;162[10]:1117.)

Yet perhaps there is still room for improvement. Phenobarbital has long been considered an alternative or second-line agent for managing acute alcohol withdrawal syndrome, although prospective study data are limited.

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Phenobarbital for Acute Alcohol Withdrawal: A Prospective Randomized Double-Blind Placebo-Controlled Study

Rosenson J, Clements C, et al

J Emerg Med


This prospective, randomized, double-blind, placebo-controlled study of ED patients with a primary admission diagnosis of acute alcohol withdrawal syndrome enrolled patients based on provider judgment of clinical need for placement on the institutional lorazepam-based protocol, clinical evidence of the syndrome, and provider judgment of the anticipated need for hospital admission. Patients were then randomized to receive either a single dose of intravenous phenobarbital (10 mg/kg in 100 mL normal saline) or placebo (100 mL normal saline). All patients were then placed on the institutional symptom-guided lorazepam-based alcohol withdrawal protocol using the Clinical Institute Withdrawal Assessment for Alcohol scale.

The primary outcome measure was the initial level of care required at hospital admission (ICU, telemetry, or floor). The authors hypothesized that the study regimen would result in decreased ICU admission rates. The study took place in an urban, teaching ED with an annual census of 85,000 patients. The ED was staffed by residents and midlevel practitioners, and all patient care was supervised by an attending emergency physician. Randomization occurred using a random-number generator program in the pharmacy, and all investigators, providers, and research assistants were blinded to group allocation. The study assessed 460 patients who presented to the ED with possible acute alcohol withdrawal syndrome from January 2009 to March 2010. A total of 262 were excluded because they did not meet inclusion criteria. Randomization proceeded with 198 patients, with 100 allocated to the phenobarbital group and 98 to the placebo group. Baseline characteristics and severity were similar in both groups.

Patients receiving phenobarbital had fewer ICU admissions (8% vs. 25%, difference 17% [95% CI, 4% to 32%]). No differences were found in adverse events, such as intubation, seizure, falls, or requirement of mechanical restraints. The patients receiving phenobarbital also required less total dose of lorazepam, and fewer patients needed continuous lorazepam infusion to control their symptoms. No study patients were transferred to a higher level care, and no deaths were reported in either group.

Almost half of the patients randomized (96), however, were excluded from analysis because consent was not obtained, data were incomplete, the patient was discharged home, or the primary admission diagnosis was other than acute alcohol withdrawal syndrome. That such a large proportion of randomized patients was excluded from analysis threatens the external validity of this study's findings (attrition bias). One can no longer guarantee that conclusions arising from the analyzed population can be applied to patients meeting the original inclusion criteria.

It is promising despite the limitations, however, that the decision to add a single IV dose of phenobarbital, with an estimated cost of only $18, resulted in fewer ICU admissions and a decreased need for benzodiazepines. This study may offer some support for using phenobarbital as an adjunct to benzodiazepine therapy for acute alcohol withdrawal syndrome, but larger studies with fewer limitations are needed before incorporating phenobarbital into routine first-line acute alcohol withdrawal syndrome regimens.

A symptom-guided benzodiazepine-based regimen will remain the mainstay of therapy in the meantime, but phenobarbital has the potential to reduce ICU admissions and the need for benzodiazepine drips. Coupled with its relatively low cost and its good safety profile, emergency physicians treating patients on the severe end of the syndrome spectrum should seriously consider adding phenobarbital to standard therapy in these selected patients.

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