Current trends in psychopharmacologic management of alcoholism

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.

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.”

At the six-month evaluation, patients taking topiramate had significantly lower scores on scales that rated craving, quality of life and alcohol-related disability. Dr. Flórez concluded from this study “topiramate at a mean dose of 200 mg/day was better than naltrexone at a mean dose of 50 mg/day at reducing alcohol intake and cravings.”

Two other available compounds have interested researchers and clinicians trying to address the problem of alcohol craving by impacting on the cortico-mesolimbic dopamine mediated reward loop in the brain. The muscle relaxant baclofen (aka Lioresal or Baclo) works as an agonist at presynaptic GABA-B receptors that modulate potassium channels resulting in the suppression of cortico-mesolimbic dopamine system neurons.
Usually prescribed for post-operative nausea and vomiting or as a treatment for nausea induced by chemotherapy, ondansetron is a serotonin 5-HT3 receptor antagonist that works on both peripheral and central nerves. However, ondansetron (Zofran or Zupienz) it is not clinically available at the necessary dose for alcoholism treatment.

Individualizing pharmacologic treatments in alcoholic patients

The study by Flórez and colleagues is one of a handful of comparative studies in alcoholic populations. The largest effort to date has been the “COMBINE project” supported by the National Institute of Alcohol Abuse and Alcoholism (NIAAA). The study found that naltrexone was superior to acamprosate in general and the combination of naltrexone and acamprosate was not superior to naltrexone alone. The authors concluded that “Naltrexone with medical management could be delivered in healthcare settings, thus serving alcohol-dependent patients who might otherwise not receive treatment.” ³

“There's not enough research on combining or selecting treatments for different types of alcoholism,” said Dr. Flórez. “The general rule is to use medications for the more severely affected alcoholic patients. Medication combinations are of interest because they would target several neurotransmitters simultaneously, but the evidence base is only just beginning.”

Dr. Bankole A. Johnson, a researcher from the Department of Psychiatry and Neurobehavioral Sciences at the University of Virginia, wrote a recent clinical discussion that suggested that medications could be selected for different types of alcoholism⁴. Johnson identified three important subtypes:

• Early-onset, which exhibits persistent symptoms and “a strong biological predisposition to the disease;
• Late-onset, which is thought to emerge out of psychosocial triggers and associated with mood symptoms; and
• Binge drinking patterns.

Further research will be needed before specific psychopharmacologic agents can be aligned with these kinds of subtypes. Until then, it is interesting to see how clinicians individualize treatments in their alcoholic patients.
Dr. Flórez favors acamprosate and topiramate for alcohol craving, naltrexone for the purpose of reducing the “priming” phenomenon (in which some patients experience an increased desire for alcohol after a single drink) and disulfiram for reducing alcohol intake. In contrast, Dr. Silberstein prefers disulfiram “for the highly motivated in therapy with other team members who can administer it” and topiramate for “severe craving.” For “acute relief,” Dr. Silberstein prefers gabapentin (Neurontin), explaining that it has demonstrated “some success with people who take it at the cocktail hour.”
The role of drugs such as gabapentin used to treat alcohol withdrawal was discussed in the article published in the June 2010 issue of Behavioral Healthcare titled “ Anticonvulsants can help, but how?” ⁵

Neurobiological mechanisms such as those that underlie alcohol craving are beginning to inform decision-making at the point of care. Hopefully, continued research efforts will generate best practice algorithms for the characterization and pharmacological management of persons suffering from chronic alcoholism.

Questions? Comments? Ideas?

Behavioral Healthcare wants to know. E-mail Dennis Grantham at dgrantham@vendomegrp.com.

References

1. Swift RM:Drug therapy for alcohol dependence. N Engl J Med 1999; 340:1482-1490
2. Gerardo Flórez G Saiz PA, García-Portilla P, et al.: Topiramate for the Treatment of Alcohol Dependence: Comparison with Naltrexone Eur Addict Res 2011; 17:29-36).
3. Anton RF, O'Malley SS, Ciraulo DA, et al.: Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA. 2006 May 3; 295 (17): 2003-17.
4. Johnson BA:Medication Treatment of Different Types of Alcoholism Am J Psychiatry 167:630-639, June 2010.
5. Anticonvulsants can help, but how? Behavioral Healthcare, June 2010 www.behavioral.net/glazer0610.

Behavioral Healthcare 2011 January-February;31(1):46-47