Alcohol withdrawal syndrome (AWS) can range from no symptoms to agitation and intense anxiety to tremors, seizures, delusions, fatal increases in body temperature, and cardiovascular collapse. Benzodiazepines are to alcohol what methadone is to heroin; that is, they provide an alcohol-like effect, relieving AWS symptoms by substituting for the alcohol that is no longer present in the system. However, benzodiazepines are similar enough to alcohol to have significant potential for intoxication, abuse and even dependence. A study in the September issue of Alcoholism: Clinical & Experimental Research examines the viability of an anticonvulsant agent called divalproex sodium as an alternative to benzodiazepines for treating AWS.
"Alcohol, benzodiazepines, and divalproex sodium all enhance gamma-aminobutyric acid (GABA) neurotransmission, one of the brain systems that becomes unbalanced during alcohol withdrawal," said Joseph P. Reoux, a psychiatrist with the Veterans Affairs Puget Sound Health Care System and lead author of the study. "More specifically, certain anticonvulsants appear to prevent the nervous system hyperexcitability that develops during alcohol withdrawal. Although an anticonvulsant like divalproex sodium enhances the same brain inhibitory system that alcohol and benzodiazepines do, it does not have the euphoria, abuse potential, or as high of a risk for cognition impairment that can occur with benzodiazepines. It also has anti-kindling properties, and tends to be better tolerated than carbamazepine (another anticonvulsant that can be used to treat alcohol withdrawal)."
"Kindling" occurs when the nervous system develops increased sensitivity to a stimulus such as withdrawal from alcohol. (Enhanced withdrawal responses are referred to as a "kindling effect" because of their similarity to the kindling of brain seizures.) When a nerve cell is repeatedly exposed to a stimulus that is initially too small to cause full nerve excitement, it can become more sensitive, or kindled, to the stimulus and begin to react at lower thresholds. This sensitivity persists over time and can become stronger with continued exposure to the stimulus. The concept of neuronal kindling is used to understand what clinicians may see during alcohol withdrawal: symptoms tend to become worse over time in people who repeatedly expose their brains to withdrawal from alcohol. Certainly kindling can complicate addiction by contributing to an individual’s unwillingness to forego alcohol, even when its ingestion is no longer a source of pleasure.
Researchers gave a primarily male inpatient population either 500 mg of the divalproex sodium formulation of divalproex sodium (also called valproate) or a placebo three times a day. Because the study participants were already experiencing withdrawal symptoms at a level that is normally medicated, they were also given a baseline dose of oxazepam (a benzodiazepine sedative) to ease their discomfort, as well as additional oxazepam if and when the severity of their withdrawal symptoms warranted it. During the seven-day study period, divalproex sodium reduced the amount of the oxazepam needed to adequately treat alcohol withdrawal. Adding divalproex sodium to the treatment regimen also appeared to stop the withdrawal symptoms from becoming worse when compared to giving oxazepam alone.
"The findings certainly support the idea that valproate is a viable treatment option for AWS," said Reoux, "although it would be more correct to say that this study showed that using divalproex sodium significantly reduces the amount of benzodiazepine needed for the treatment of AWS. One of the more important aspects of this study is that it was scientifically rigorous. Previous studies of valproate for AWS were not randomized double-blind placebo controlled trials, so this study provides the strongest evidence to date supporting the use of valproate in the treatment of alcohol withdrawal." Reoux added that larger studies in broader patient populations, including women and outpatients, would likely be necessary before valproate is accepted as a first-line treatment for AWS in the United States.
The anticonvulsant valproate has been available in Europe for treating AWS since the 1960s, but has only been marketed in the U.S. since 1978. In the U.S., benzodiazepines comprise the drug regimen of choice, despite their potential for abuse.
"Many medications are used differently in other places," explained Richard K. Ries, a professor of psychiatry and addictions at the University of Washington. "Much of this has to do with what clinicians are used to doing. Sometimes this also has to do with pharmaceutical company marketing. Or sometimes it’s due to what the federal Food and Drug Administration allows. For example, many meds are available in Europe well before they are available here, which has been true of many of the anticonvulsants."
Ries is intrigued by the study’s findings because of the potential for valproate to become a new detoxification strategy.
"AWS is an immense problem which affects patients in medical, surgical, and psychiatric settings as well as in addiction treatment populations," he said. "Yet there is a paucity of research documenting new and better ways to deal with it. This pilot study makes a good attempt to address this and highlights the need for more research.
Funding for this Addiction Science Made Easy project is provided by the Addiction Technology Transfer Center National Office, under the cooperative agreement from the Center for Substance Abuse Treatment of SAMHSA.
Articles were written based on the following published research:
Reoux, J.P., Saxon, A.J., Malte, C.A., Baer, J., & Sloan, K. (2001, September). Divalproex sodium in alcohol withdrawal: A randomized double-blind placebo-controlled clinical trial. Alcoholism: Clinical and Experimental Research, 25(9), 1324-1329.