Alcohol Withdrawal and Flumazenil: Not for the Faint of Heart

Abstract

It is almost paradoxical that medical toxicologists are frequently involved with the management of patients with alcohol withdrawal, given that this syndrome is due to the absence, not the presence of a toxin. Because of our understanding of the pharmacologic underpinnings of both the syndrome and its treatment, medical toxicologists typically recommend a goal-directed treatment of this disease at its early stages, with full understanding that this carries consequences, such as prolonged sedation, that are easily offset by the improvement in outcome [1]. Our experience breeds expertise that guides the management of this complex clinical problem not just in the ED, but during the patient’s entire course in the hospital. This is well illustrated in the paper published in this issue by Moore et al., which looked at the concluding steps in the treatment of such patients [2]. The alcohol withdrawal syndrome (AWS), the constellation of signs and symptoms that alcoholics suffer upon cessation or reduction of alcohol intake, remains to be a century-old clinical challenge faced by health-care providers. Despite the millennia-long use of ethanol, we have a remarkably limited understanding of the pathophysiology of both drunkenness and AWS. Until as recently as the 1950s, the cause of the tremors and delirium associated with ethanol discontinuation was actually believed to be the excessive alcohol consumption itself along with nutritional deficiency, not the act of cessation. In 1953, Victor and Adams observed in exquisite detail the clinical consequences of abstinence in 206 alcoholic patients hospitalized at Boston City Hospital [3]. This was followed by the “landmark,” and quite unethical by today’s standards, study in 1955 by Isbell that supported the burgeoning understanding that there was a dose-response relationship of ethanol to the severity of AWS [4]. In this study, ten prisoners, who were all former morphine addicts, were assigned to consume large amounts of alcohol for periods of time varying from 1 week to several months. Consumption was abruptly discontinued at the end of these time periods, and the subjects were monitored for signs of AWS. Not surprising to any current reader, but novel in 1955, the longer the period of consumption, the more severe the withdrawal. Subsequently, in 1964, the work by Mendelson and Mello provided the first controlled experimental evidence that withdrawal was directly related to drinking cessation [5]. Despite a lack of understanding of the reasons for withdrawal, as early as the turn of the twentieth century, alcohollike drugs, such as paraldehyde and chloral hydrate, were introduced into clinical practice for its management. In the 1950s, phenothiazines were introduced with checkered success, followed by the barbiturates and benzodiazepines through the 1960s and 1970s. Some centers used, and some amazingly continue to use, ethanol either orally or by infusion to prevent and treat AWS, particularly in trauma patients [6]. In the 1990s, the approach to AWS underwent a paradigm shift, with the acceptance of symptom-triggered therapy [7]. It is now clear that AWS is best treated by administering benzodiazepines using a symptom-triggered approach, meaning the next dose is administered when the patient begins to feel or display recrudescent AWS (such as a rising CIWA, RASS, or Riker score). Using this approach, a reduction in the total dose of benzodiazepines required and the length of stay have been demonstrated in controlled trials [8]. However, the responsiveness to individual doses of benzodiazepine varies widely among patients [1]. The reasons for this are unknown, but there may be, in part, a genetic determinant [9]. Regardless of the reason, the relative resistance to benzodiazepines displayed by some patients has led to the administration of escalating, and sometimes massive, doses of drug, in what amounts to a pharmacologic game of cat and mouse [10]. It is not uncommon for a patient with AWS to receive several L. S. Nelson (*) New York University School of Medicine, New York, NY, USA e-mail: lewis.nelson@nyumc.org DOI 10.1007/s13181-014-0392-5 J. Med. Toxicol. (2014) 10:123–125