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Current trends in psychopharmacologic management of alcoholism

January 1, 2011
by William M. Glazer, MD
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According to a 2000 NIMH report to Congress, alcoholism in the United States is considered to be the third most preventable cause of accidents and deaths. That report estimated that the cost of alcoholism (excluding accidents) was $185 billion.

Individual and group counseling, as well as 12-step programs, form the foundation of the rehabilitation of patients with alcohol dependence. But research indicates that without medications to support rehabilitation interventions, almost 70 percent of those affected will be drinking again within one year1.

There are a currently a number of pharmacologic strategies for persons suffering from chronic alcoholism. The management of comorbid psychiatric conditions, such as depression, bipolar disorder or anxiety, can be discussed in other forums, but the following focuses solely on the condition of alcoholism.

Approved pharmacologic strategies for alcoholism

FDA-approved strategies for the treatment of chronic alcoholism today include antabuse (disulfiram), naltrexone (short- and long-acting formulations) and campral (acamprosate). Disulfiram, which was approved for use in 1948, is a “deterrent” drug.
When combined with alcohol, the person experiences severe hangover symptoms. These unwanted symptoms deter the alcoholic from drinking in significant amounts while taking the medicine.

Approved in 1994, naltrexone works as a competitive opiate antagonist. It is used to decrease cravings for alcohol and encourage abstinence by reducing the pleasurable effects from consuming alcohol. Campral (acamprosate) stabilizes neurotransmitter imbalance in the brain that occurs after chronic consumption. This drug works by blocking the actions of glutamate, a neurotransmitter that is hyperactive in the post-withdrawal phase.

Gaps in existing approved medications result in off-label selections

Unfortunately, these approved agents are not enough. According to Dr. Charles Silberstein, an attending psychiatrist at Martha's Vineyard Hospital in Massachusetts and a former director of the Bellevue Hospital rehabilitation and detoxification unit in Manhattan, “Nothing is foolproof.”

“Many patients experience side effects from these medications,” Silberstein says. “Relief often comes with polypharmacy or not at all.”

Disulfiram does not address cravings and the patient has to be highly motivated to quit. Also, research has indicated that for disulfiram to work, a collaborator is needed to assure that the patient takes it. On the other hand, a long-acting formulation of disulfiram is on the way and may increase the use of this approach. Interestingly, a long-acting formulation of naltrexone available under the trade name Vivitrol is available but has not been utilized by clinicians as frequently as was expected.

Dr. Silberstein, who is board certified in addiction psychiatry and treats many alcoholic patients, has “offered Vivitrol several times but there is limited interest.” It is probable that Vivitrol is underutilized for many of the same reasons that we see in the case of the long-acting antipsychotics.

While acamprosate and naltrexone have been designed to address cravings, their effectiveness has been uneven. The failure of two large, double-blind studies of acamprosate has cast doubt on its efficacy. Long-term relapse rates with all of these agents still abound-probably because none of them are effective enough at reducing cravings for alcohol-a critical factor for long-term success.

Given the limited effectiveness of FDA-approved medications, it is understandable that clinicians resort to off-label use of certain medications. But how do these medications fit into the current understanding of neurobiological mechanisms that may be associated with chronic alcoholism?

The neurobiology of alcohol dependence

A central target for pharmacologic intervention in chronic alcoholism is the phenomenon of craving. Craving is thought to result from an imbalanced reward system located in the cortico-mesolimbic dopamine loop of the brain. The more hopeful agents for the reduction of craving are those that modulate the cortico-mesolimbic dopamine system through the opioid, glutamate, aminobutyric acid (GABA), or serotonin (5-HT) systems.

Research has found that chronic alcohol intake stimulates the gamma-aminobutyric acid (GABA) (inhibitory) pathway and inhibits the glutamate (excitatory) pathway. According to Gerardo Flórez, MD, PhD, of the Addiction Treatment Unit of the Galician Health System in Ourense, Spain, “When patients try to quit or reduce their alcohol intake, their brains are left in a state of hyperexcitability and negative affect characterized by anxiety, dysphoria, and alcohol craving.”
In order to avoid these uncomfortable feelings, they drink. It is logical then to think of the anticonvulsant topiramate, which enhances GABAergic transmission and inhibits glutamatergic transmission as a remedy to the alcoholic's dilemma. A number of randomized controlled trials have demonstrated the effectiveness of topiramate over placebo for the treatment of alcohol dependence.
In a recent study, Flórez and colleagues advanced the field by conducting a randomized naturalistic trial that compared topiramate to naltrexone 2.

“Our study consisted of a six-month naturalistic, randomized and open-label trial of topiramate versus naltrexone,” said Dr. Flórez. “The study included 182 alcohol-dependent patients who had been drinking heavily during the past month, and outcome was measured using tools that assessed alcohol intake, cravings, disability, and quality of life.”

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