Phenobarbital versus Lorazepam for the Management of Alcohol Withdrawal Syndrome (AWS) in Hospitalized Patients- A Retrospective Cohort Study

Introduction

Alcohol Use Disorder (AUD) kills over 3 million people each year globally and accounts for 6 percent of global deaths [1]. In the United States, AUD is the fifth leading risk factor for premature death and disability [2]. Alcohol Withdrawal Syndrome (AWS) manifests due to the abrupt reduction or discontinuation of long-standing alcohol use [3]. It is characterized by symptoms of autonomic hyperactivity that begin within 6 to 24 hours of abrupt cessation of alcohol use. Symptoms range in severity from mild to moderate, including irritability, tremors, fever, diaphoresis, hyperreflexia, hypertension, confusion, and agitation, to more severe life-threatening forms like seizures, hallucinations, delirium tremens, and coma [4]. These effects are mediated through ion channel adaptations and altered current flows (i.e., reduction of neuro-inhibitory gamma-aminobutyric acid (GABA) receptor sensitivity, enhanced sensitivity of neuroexcitatory glutamate receptors, and increased density of voltage-gated calcium channels [5]. Chronic alcohol overuse decreases GABA-mediated neuroinhibitory activity and increases glutamate-mediated neuroexcitatory activity. Patients may present to the hospital with clinical features of AWS or develop them after hospitalization for alternative medical conditions. In patients with AWS, 5% progress to alcohol withdrawal delirium or delirium tremens (DT), requiring ICU care [6]. Prompt recognition and timely management of AWS are essential to minimize patient morbidity and mortality.

The cornerstone of AWS management is directed at counteracting the abnormal withdrawal pathophysiology with appropriate pharmacotherapy to prevent secondary complications. Timely and effective treatment can prevent the progression to severe AWS and the associated significant morbidity and mortality. The search for a safe and effective agent with fast onset action, easy titration, negligible abuse potential, wide therapeutic window, and minor liver metabolism has been a long-term goal to treat this disorder and has resulted in extensive research and developments in the past three decades. In the mid-20th century, many hospitals used intravenous ethanol to treat and prevent the progression of AWS. However, due to ethanol’s variable and unpredictable pharmacokinetics coupled with its toxicity and narrow therapeutic index, there was a substantial need for a better treatment modality [7]. Advancements in molecular chemistry led to the discovery of benzodiazepine (BDZ) receptors on the GABAA channel complex in the 1970s [8]. BDZs allosterically bind to these receptor complexes, which leads to increased frequency of channel opening, and enhanced neuro-inhibitory GABAergic activity mitigating withdrawal signs and symptoms of AWS. Shortly after their introduction, BDZs, which were promoted heavily by the pharma industry, became the first line of treatment for AWS. Certain BDZs offer the advantages of various modes of delivery (intravenous, intramuscular, and oral) and, when needed, both rapid onset and longer duration of action [9]. BDZs, however, have a narrow therapeutic index and unpredictable pharmacokinetics and pharmacodynamics when used for AWS patients. Doses needed for control of agitation are often close to and overlap with doses resulting in central nervous system (CNS) and respiratory depression and pulmonary aspiration. In addition, serum concentrations of BDZs are not readily available and do not correlate with pharmacologic effects.

When used for AWS, BDZs are administered in one of three strategies: front-loading, fixed-dose or symptom-triggered. In most hospitals that can provide frequent monitoring of patients, symptom-triggered strategy has gained popularity [6]. The most common validated tool used to assess symptoms of AWS is 10item Clinical Institute Withdrawal Assessment for Alcohol, revised (CIWA-Ar) [10] (Table 1). Currently, BDZs remain the most widely used and preferred pharmacotherapy for AWS. Unfortunately, many patients with AWS are resistant to BDZ pharmacotherapy. Escalation of BDZ treatment can result in paradoxical agitation and enhanced delirium, yet such non-responders will have increased risks of respiratory depression and aspiration. Pharmacologically, BDZs do not function to suppress central glutamate upregulation that is present in those with AWS. Therefore, high doses of BDZs coupled with needed adjunctive pharmacologic therapy in BDZresistant AWS patients often leads to increased frequencies of ICU admissions, pulmonary aspiration, and mechanical ventilation, with a resultant long length of hospital stay [11]. Recognition of BDZ-resistant AWS patients led to a “BZ stewardship” movement seeking adjuncts to limit BDZ use. Adjunctive drugs have included baclofen, gabapentin, valproic acid, topiramate [12], and dexmedetomidine [13] but phenobarbital has demonstrated the most promising efficacy [14].