Alcohol Withdrawal: Treatment and Application

Introduction

Alcohol was used in Egypt since the time of the pharaohs, when wine played an important part in ceremonial life. ^. Egyptian texts more than 8000-years-old made reference to alcohol abuse and its consequences. The ancient Greeks were also experienced with alcohol use disorders. They first drank as part of a religious ritual to please their gods and forget their worries. but soon realized that it caused seizures. In around 400 BCE, Hippocrates described seizures related to alcohol misuse and withdrawal, and the Romans used the term “morbius convivialis” to describe alcohol-related seizures. European physicians in the late 18th and early 19th centuries gave detailed clinical descriptions of delirium tremens and noted a 50% mortality rate. Although delirium tremens was described as early as 1787, its relationship to acute alcohol withdrawal was not firmly established until the 21st century.

Victor and Adams described a series of alcohol-dependent patients admitted to a specialist unit in the United States. They identified the now well-recognized spectrum of symptoms—including tremor, nausea, anxiety, tinnitus, muscle cramps, diaphoresis, seizures, hallucinations, and delirium tremens—that constitute the alcohol withdrawal syndrome. Severe alcohol withdrawal has a mortality rate of up to 35% if untreated; if treated early, death rates range from 5% to 15%.

Alcohol withdrawal is defined as a maladaptive behavioral change, with accompanying physiological and cognitive symptoms, that occurs in an individual whose blood- or tissue-alcohol concentrations decline following prolonged heavy use of alcohol. Withdrawal symptoms can occur when an individual who has consumed excessive alcohol daily stops drinking suddenly or reduces the quantity of alcohol. The likelihood of withdrawal symptoms increases with both the chronicity and quantity of drinking, the number of previous withdrawals, and the presence of complicating comorbid conditions. Symptoms associated with the withdrawal syndrome include anxiety, psychomotor agitation, sweating, nausea, vomiting, insomnia, tremor, and rapid heart rate. In severe cases, delirium tremens, hallucinations, grand mal seizures, and disturbances in consciousness can occur.

The goals of treatment for alcohol withdrawal include treating the immediate symptoms, preventing complications, and initiating long-term preventative therapy. The current agents of choice for the treatment of mild-to-moderate alcohol withdrawal in the outpatient setting are benzodiazepines. Although the use of benzodiazepines is supported by an extensive body of literature, their use is limited by their potential for misuse, psychomotor sedation, and cognitive impairment. Benzodiazepines may also increase alcohol craving and early relapse to alcohol use (Poulos and Zack, 2004) and increase the risk of misusing other substances in individuals with genetic predisposition to alcoholism or comorbid anxiety or personality disorder. Furthermore, benzodiazepines have significant interactions with alcohol, opioids, and other CNS depressants. If taken together, they can increase the risk for respiratory depression and cognitive impairment. Some studies have suggested that benzodiazepine use itself may be associated with the development of delirium.

Furthermore, although benzodiazepines are the standard of care for alcohol withdrawal, in clinical settings, the actual implementation varies dramatically. Some providers prefer a symptom-triggered approach, relying on elevated scores of the Clinical Institute of Withdrawal Assessment, revised (CIWA-Ar) before administering any benzodiazepine, and others prefer a standard taper of preferably longer-acting benzodiazepines for a period of 3–5 days. The former strategy runs the risk of variability in CIWA-Ar scoring, and either under- or overestimating the need for benzodiazepines, whereas the latter may prolong inpatient hospitalizations for patients with less likelihood of experiencing alcohol withdrawal for various reasons, or conversely underdosing patients with larger degrees of alcohol tolerance. Many providers use a combination of these strategies by having a standard taper supplemented with as-needed benzodiazepines for “breakthrough” withdrawal symptoms. Overall, there is poor consensus regarding the most appropriate method, and this is likely largely due to variability in patients and systematic approaches to the treatment of substance withdrawal in hospital systems.

In light of the limitations associated with benzodiazepine use, there has been a growing interest in alternative treatment options for the alcohol withdrawal syndrome. A number of recent studies suggest that anticonvulsants might provide safe and effective alternatives to benzodiazepines, especially among those with moderate to severe alcohol withdrawal symptoms. These agents have demonstrated mood-stabilizing or anxiolytic effects, or both, in addition to their anticonvulsant activity, and are widely used in psychiatric practice.

Although their mechanism of action is not completely understood, the efficacy of anticonvulsants in the alcohol withdrawal syndrome is thought to be related to their ability to reduce “kindling” and facilitate γ-aminobutyric acid (GABA) inhibitory neurotransmission. The kindling hypothesis proposes that long-term moderate to severe alcohol use disorder combined with repeated withdrawal episodes induces long-lasting neuronal and neurochemical changes in the brain. As a result of these neurobiological changes, the individual’s response to alcohol is affected, resulting in increasingly severe episodes of withdrawal. An agent that ameliorates the kindling response might therefore prevent the summative effects of repeated drinking and withdrawal.

Polycarpou et al. published a 2005 Cochrane Database review of 48 studies with 3610 participants on the utility of anticonvulsants for treating alcohol withdrawal. Compared with placebo, there was a trend for anticonvulsants to improve the participants’ global assessment of efficacy, and there was added protection against the development of seizures. Protection from seizures occurred whether anticonvulsants were given alone or in combination with other medications. In addition, anticonvulsants appeared to be superior to non-anticonvulsants at reducing the frequency of hallucinations, sweating, gastrointestinal symptoms, and sleep disorders. Furthermore, data from a subset of 12 of these studies ( N = 960) that used anticonvulsants as antiwithdrawal agents—and in which mortality was reported as an outcome—showed that no participants died. Individuals who received anticonvulsants during detoxification from alcoholism, compared with those who received either placebo or benzodiazepines, were less likely to discontinue treatment due to adverse effects. The data from which the researchers could draw any conclusions to compare the efficacy of various anticonvulsants, especially the newer agents, against one another were too limited. Nevertheless, the authors of the Cochrane Database review exercised caution with the interpretation of their results because most studies were of small sample size, outcome measures were generally heterogeneous (a recommendation was made for the CIWA-Ar scale to be used as the standard), and there was little consistency between studies on the methods and parameters for randomizing participants to treatment groups.

Anticonvulsants were found to be relatively safe and efficacious medications for treating alcohol withdrawal. Carbamazepine, the most studied medication compared with benzodiazepines, appears to confer added advantages such as fewer adverse events, no demonstrated abuse potential, and the lack of potentiation of alcohol’s psychomotor and cognitive effects. Other anticonvulsants appear to share these properties, as well as being useful for reducing the frequency of a range of other withdrawal symptoms, including hallucinations, sweating, gastrointestinal disturbance, and sleep disorders. Although the Cochrane Database review did not provide any specific recommendations based on the statistical analysis, clinical experience suggests that anticonvulsants should be considered the medication of choice among those with the potential to experience moderate to severe alcohol withdrawal symptoms and who can tolerate an oral route of administration. Adding benzodiazepines to an anticonvulsant regimen might confer some benefit patients with delirium tremens or severe agitation. This conclusion is further supported by a more recent Cochrane Database review that included 64 studies (n = 4309), evaluating benzodiazepines against placebos and other medications including anticonvulsants, and revealed that the only statistically significant finding was that benzodiazepines were more effective than placebo for preventing withdrawal seizures, but not statistically superior to anticonvulsants.

Anticonvulsants in the Treatment of Alcohol Withdrawal

New insights into the pathophysiology of alcoholism have paved the way for studies of novel pharmacological tools for treating the behavioral, cognitive, and physiological symptoms associated with alcohol use disorder. Among anticonvulsant agents evaluated for efficacy in alcohol use disorder, some studies have found that carbamazepine treatment might reduce drinks per drinking day and time to first drink after withdrawal. Small studies of valproate in alcohol-dependent individuals suggest that it might reduce relapse to heavy drinking and promote abstinence. Of interest, in a recent placebo-controlled trial among alcoholics with comorbid bipolar disorder, valproate treatment was associated with a significant reduction of heavy drinking, and with better outcomes for those with higher serum valproate levels.