NEW YORK CITY— Several promising drugs are now in clinical trials for alcoholism, and research on genetic polymorphisms that correlate with response to alcoholism treatments may help identify patients most likely to benefit from specific approaches, according to Raye Z. Litten, PhD. Dr. Litten is the Associate Director of the Division of Treatment and Recovery Research and Co-Leader of the Medications Development Team at the National Institute on Alcohol Abuse and Alcoholism (NIAAA), Bethesda, Maryland. He discussed new drug treatments at a July 21 American Medical Association media briefing on alcohol dependence.

TARGETING MULTIPLE MECHANISMS

Alcohol dependence is complex, differs among drinkers, and may be associated with different biologic mechanisms in different patients. “The challenge in developing new medications is to be able to target these multiple mechanisms at each stage of the disease,” Dr. Litten said. The hallmarks of alcohol dependence are reward/positive reinforcement, protracted withdrawal, craving, impaired control, preoccupation with drinking, compulsive drinking, and tolerance.

Targeting brain neurotransmitter receptors is particularly important because they activate intracellular pathways inside the brain, which can turn on or turn off genes, Dr. Litten continued. “Various neurocircuits in the alcoholic brain function abnormally and need to be restored to normal function,” he said.

There are currently three medications approved for alcoholism: naltrexone, acamprosate, and disulfiram. Dr. Litten said that there is a possibility that some of these drugs also work in other addictive disorders. For example, disulfiram appears to be helping people with a cocaine addiction.

“The goal that we see in medications development is to be able to provide a menu of choices for patients and clinicians to facilitate individual treatment planning, because of this complexity. We also need to increase both our knowledge of this disease and research toward optimal medication therapy,” Dr. Litten said. Currently, the NIAAA supports one phase III trial, 33 phase II trials, and 17 phase I trials of alcoholism treatment. The phase III trial is the COMBINE (Combining Medications and Behavioral Interventions) study—one of the largest pharmacologic trials ever conducted for alcoholism, according to Dr. Litten. COMBINE has recruited 1,383 alcohol-dependent patients at 11 sites. The primary objective is to evaluate the effects of one or both of two behavioral treatments (moderate intensity and lower intensity) and one or both of two medications (naltrexone and acamprosate) or a placebo, Dr. Litten elaborated. Patients attend outpatient sessions for four months, then return for three follow-up visits over the subsequent 12 months.

REDUCING THE DESIRE TO DRINK

A new generation of medications can reduce the urge or desire to drink. Dr. Litten said that naltrexone can reduce craving and there is also evidence that it reduces the positive reinforcement of drinking. Acamprosate appears to work in a slightly different way and can reduce withdrawal symptoms that can occur for weeks or months after one has stopped drinking.

Naltrexone and acamprosate are not addictive and have no serious side effects. The most common side effects are nausea for naltrexone and diarrhea for acamprosate, and these problems typically resolve within a few weeks, Dr. Litten said. Neither drug has serious interactions with alcohol or antidepressants.

Dr. Litten said that naltrexone is not widely prescribed, “partly because practitioners such as primary care physicians are not aware that naltrexone is available.” However, he noted, “the major problem is probably that most people with alcoholism don’t seek treatment.”

THE NEUROBIOLOGY OF ALCOHOLISM

The neuroscience of alcohol seeking and drinking involves multiple neurotransmitter systems. Alcohol can interact or affect every cell in the body and can interact with neurotransmitter systems. “Over time, chronic use of alcohol can cause some of these systems to become abnormal in function,” Dr. Litten said.

Some people who are susceptible to alcoholism also have an abnormality of some of these neurotransmitter systems. “One of the strategies for developing the medications is to be able to normalize or compensate for these abnormal neurotransmitter functions. This might relieve some of the craving, improve the impaired control, reduce some of the withdrawal symptoms, and restore people so that they would not have the urge or the desire to drink.”

OFF-LABEL INDICATIONS

A number of the phase II studies sponsored by the NIAAA involve off-label drug use. “Topiramate is very promising,” said Dr. Litten. “There has been one study already. It targets the glutamate and GABA [gamma-aminobutyric acid] system. Glutamate is excitatory and GABA is inhibitory in the brain. You’d like a nice ratio between excitatory and inhibitory. During alcoholism the excitatory and inhibitory activity gets out of balance. Topiramate and gabapentin—which is also under study—bring excitation and inhibition back into balance.”

Another drug, ondansetron, affects the serotonin system, which is also involved in mood and in dysphoria. “We know ondansetron works for some subtypes of patients. Early results indicate that it works for early onset alcoholics, those who develop alcoholism before age 25, but not for those who develop alcoholism after age 25,” he said.

Other drugs under study include baclofen, rimonabant—which interacts with cannabinoid receptors—memantine, and the Chinese herbal medicine kudzu. “We’re actually doing some animal studies in isolating active components of kudzu, and they appear to be effective in reducing drinking in rats,” Dr. Litten said.

ADDITIONAL AVENUES

Increasing patient compliance is also an important area of research. “Techniques include giving patients incentives to take their pills, providing them with reminders, and reviewing side effects so that if they have a problem, they won’t panic.”

However, not everyone is able to take his or her pills daily. To facilitate compliance, long-lasting formulations may be required. “The good news is that long-acting injectable naltrexone that lasts up to 30 days has been developed. There have been two clinical trials on this, and in both, the preparations did reduce drinking in alcohol-dependent patients. One of these preparations is being reviewed by the FDA,” Dr. Litten said.

A second topic that needs more research is individual variation in response to medication. “We know these medications aren’t effective for all patients. Our goal is to be able to identify the patients who do respond to specific medication with no adverse effects. This will allow practitioners to administer the medications more safely and more effectively,” Dr. Litten said.

Some progress is being made in this area, he noted. For example, researchers have learned that people who have a family history of alcoholism seem to respond better to naltrexone. Investigators also have identified a polymorphism of the gene for the μ-opioid receptor to which naltrexone binds. “This gene can encode either aspartate or asparagine at the 40th position of the receptor. Patients with aspartate had better treatment outcome with naltrexone. This doesn’t explain all response to naltrexone, but it is a start,” Dr. Litten said.

Ultimately, he concluded, “what we’d like to do is to get a menu of behavioral treatments and medications out there for physicians and patients to choose from. If one isn’t effective, they can rely on another.”

—Janis Kelly

Suggested Reading
Boothby LA, Doering PL. Acamprosate for the treatment of alcohol dependence. Clin Ther. 2005;27:695-714.
Garbutt JC, Kranzler HR, O’Malley SS, et al. Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: a randomized controlled trial. JAMA. 2005;293:1617-1625.
Johnson BA, Ait-Daoud N, Akhtar FZ, Ma JZ. Oral topiramate reduces the consequences of drinking and improves the life of alcohol-dependent individuals: a randomized controlled trial. Arch Gen Psychiatry. 2004;61:905-912.
Johnson BA, Mann K, Willenbring ML, et al. Challenges and opportunities for medications development in alcoholism: an international perspective on collaborations between academia and industry. Alcohol Clin Exp Res. 2005;29:1528-1540.
Litten RZ, Ferrig J, Mattson M, Egli M. Development of medications for alcohol use disorders: recent advances and ongoing challenges. Expert Opin Emerg Drugs. 2005;10:323-343.
Lukas SE, Penetar D, Berko J, et al. An extract of Chinese herbal root kudzu reduces alcohol drinking by heavy drinkers in a naturalistic setting. Alcohol Clin Exp Res. 2005;29:756-762.

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