Drug treatment for alcoholism today

(This article was first printed in the July 2005 issue of the Harvard Mental Health Letter. For more information or to order, please go to www.health.harvard.edu/mental.)

Finding a reliable treatment for alcoholism has been a frustrating quest. In the best studies, all common psychosocial approaches have been found equally and only moderately effective. So physicians and mental health professionals have turned to drugs in the hope of matching their success, or partial success, in the drug treatment of other psychiatric disorders.

So far the results are inconclusive, and some still hesitate to treat any substance abuse problem with a drug. But there was a time when the drug treatment of depression and schizophrenia was questioned. The search for drug treatments has also been aided by progress in understanding addiction in general and the actions of alcohol in particular. One new drug was approved in 2005 and others are being considered.

Withdrawal symptoms

Alcohol withdrawal requires drug treatment only in a minority of cases — mainly when there is a risk of delirium or seizures. There are no fundamentally new ideas about how to go about it. The best-tested approach is to substitute a safer sedative — usually a benzodiazepine, such as diazepam (Valium), chlordiazepoxide (Librium), or lorazepam (Ativan) — and gradually reduce the dose.

The main risks of these drugs are drowsiness, loss of coordination, and mild withdrawal symptoms. Propranolol (Inderal) and other beta-adrenergic blockers can help ease withdrawal by reducing tremors and lowering heart rate and blood pressure. Added antipsychotic or anticonvulsant medications have been found effective in a few studies.

Disulfiram (Antabuse) prevents the liver from metabolizing alcohol normally and causes a toxic breakdown product to accumulate. If they drink, patients taking disulfiram can become nauseated and even seriously ill; disulfiram itself can also cause hepatitis, which in rare cases is lethal. Disulfiram is supposed to deter drinking, but it does not affect the desire for alcohol, and persuading patients to continue taking it can be difficult.

There is some evidence that disulfiram may be effective for older, severely alcoholic patients who are carefully monitored by family members and professionals. But the results of controlled studies have been inconsistent, and the use of disulfiram is declining.

Only three drugs are FDA-approved for the treatment of alcoholism itself — the persistent craving for alcohol and use that persists despite unpleasant and harmful consequences long after physical withdrawal symptoms end.

Naltrexone (ReVia)

This narcotic antagonist has been approved since 1995 as a treatment for alcoholism. Taken daily in pill form, it lowers the activity of natural opioids that are stimulated by alcohol as well. It reduces the desire to drink and especially the craving that leads to relapse after a first drink. It’s recommended mainly for abstinent alcoholics who are trying to avoid relapse, but also for some who have not been able to stop drinking entirely. The popularity of naltrexone is growing. In a survey of substance abuse treatment centers in New England, use of naltrexone increased from 14% in 1997 to 25% in 2001.

The side effects, which include nausea (5%–10% of patients), depression, upset stomach, headache, and drowsiness, usually go away within a week. There is some risk of liver inflammation, but patients recover when the drug is discontinued. Compliance is a problem with naltrexone as well as disulfiram. It works only for patients with sufficient motivation to take the prescribed pills and keep their appointments with physicians and mental health professionals.

In many but not all controlled studies, patients taking naltrexone achieve longer abstinence and have fewer relapses than those taking the placebo. A meta-analysis of 29 studies in many countries found that naltrexone reduced the risk of relapse or a return to heavy drinking during the first three months after withdrawal by 36%. The effect does not persist when patients stop taking the drug. In a study reported in the New England Journal of Medicine, a year of naltrexone treatment did not help long-term alcoholic men with severe symptoms.

To prolong the effects of naltrexone and reduce the temptation to skip taking a pill, investigators are considering a once-a-month injection for gradual release of the drug. In a six-month study, researchers at Harvard Medical School compared this treatment to a placebo (both groups of patients also had psychosocial therapy). They found that intramuscular injection of naltrexone reduced heavy drinking by about 25% and raised the rate of abstinence.

Nalmefene, a longer-acting opiate antagonist related to naltrexone, has been found effective in two small controlled studies, but this research is preliminary.

Acamprosate (Campral)

Acamprosate has been used widely throughout the world in alcoholism treatment since the 1980s, but it was approved by the FDA only in 2004. It lowers the activity of receptors for the excitatory neurotransmitter glutamate, possibly steadying a nerve circuit in the brain of an alcohol-dependent person. Acamprosate takes about a week to work; the main side effects are diarrhea and occasional headache.

Acamprosate is approved “for the maintenance of abstinence from alcohol in patients with alcohol dependence who are abstinent at treatment initiation” and who are also receiving psychosocial therapy. The FDA adds that it “may not be effective in patients who are actively drinking or those who abuse other substances in addition to alcohol.” The theory is that only abstinence brings the hypersensitivity of glutamate receptors that acamprosate reduces.

Several large studies have found acamprosate to be effective. In European trials, abstinence rates were two to three times greater in patients taking acamprosate than in those taking a placebo. In some of those studies, the effect seemed to persist even after the patients stopped taking the drug.

Compliance is still a problem; alcoholic patients will usually not continue to take acamprosate unless they are supervised and committed to abstinence.

Topiramate and other anticonvulsants

Anticonvulsant drugs are used routinely in the treatment of bipolar disorder and schizophrenia as well as epilepsy. Interest is growing in other uses, including alcoholism. Prospects are best for topiramate (Topamax), an anticonvulsant that stimulates the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and, like acamprosate, reduces the activity of glutamate. It may also slow the release of dopamine in the brain’s reward system, which is promoted by alcohol and other addictive substances.

The main potential side effects are dizziness, tingling in the hands and feet, weight loss, and temporary loss of memory or concentration.

Topiramate has been found effective as a short-term treatment for abstaining alcoholics who also receive behavioral therapy. In a three-month placebo-controlled study reported in 2004, it reduced binge drinking, increased the abstinence rate, and improved overall well-being in alcoholic patients. A large controlled study on its effects in drinking alcoholics is under way.

Two other anticonvulsants, carbamazepine (Tegretol) and valproate (Depakote), have also shown some promise. In a six-month study, valproate reduced alcohol consumption in patients with bipolar disorder who were also taking lithium.

Other drug treatments

The antinauseant ondansetron in combination with other drugs may help some alcoholic patients. In early research, a skin patch containing mecamylamine has shown some promise; this drug is now used to help smokers quit. Baclofen, another drug that increases GABA activity, has been found to reduce alcohol consumption and craving in some animal experiments and human trials.

Drug treatment for related disorders

Alcoholic patients have high rates of other psychiatric disorders, especially depression, anxiety disorders, attention deficit disorder, and drug addictions. Some of these symptoms can be treated with standard psychiatric drugs. In alcoholic patients with major depression, antidepressants and psychosocial therapy usually improve depressive symptoms but have little effect on drinking.

Antidepressants are all equally effective; selective serotonin reuptake inhibitors such as fluoxetine (Prozac) and sertraline (Zoloft) are preferred because on average their side effects have been better tolerated. SSRIs also reduce alcohol consumption in some animal experiments, although not in most human studies. But in one trial, sertraline reduced drinking in patients with no family history of alcoholism and relatively mild symptoms.

For people with alcoholism and an anxiety disorder, some physicians will prescribe a benzodiazepine for a few weeks, although others consider that risky. The alternative anti-anxiety drug buspirone (BuSpar) has been found effective for the anxiety symptoms of alcoholics in a few studies. In one small controlled study, fluoxetine reduced drinking in alcoholic patients with social anxiety disorder (social phobia).

The antipsychotic drug clozapine may reduce heavy drinking in schizophrenic patients. But it has serious side effects, including weight gain, drowsiness, and a 1% risk of a potentially lethal blood disorder that requires constant monitoring. Researchers are also looking at the antipsychotic drug aripiprazole (Abilify), which has a unique mechanism of action and may be freer of side effects than the alternatives.

The future

As of 2005, studies are also looking into combinations of naltrexone and acamprosate. The hope is that they will complement each other because they have different biological mechanisms and may be effective at different stages of the disorder. Naltrexone is supposed to reduce cravings in a person who is still drinking, while acamprosate diminishes the conditioned craving that may plague an abstinent alcoholic at the sight of a bar or bottle or the first sip.

It’s not clear whether this distinction is legitimate. The COMBINE (Combining Medications and Behavioral Interventions) study, completed but not yet analyzed as of mid-2005, may provide some answers. More than 1,300 patients were divided into groups and assigned at random to four months of treatment with naltrexone alone, acamprosate alone, both medications, or a placebo along with one of several psychosocial therapies. The outcome will be measured by the rate of abstinence and the amount of binge drinking.

There is also much other research activity. As of 2005, nearly two dozen drugs already available for other purposes are being tested for their effects on alcoholism. Other drugs are in earlier stages, undergoing animal testing.

Drawing conclusions from these trials may be difficult, though. Several months is not long enough to gauge long-term effects, and alcoholics can relapse even after many years.

Another problem is that when people with other psychiatric disorders are excluded from clinical trials, the results may not apply fully to the majority of alcoholics. For example, there is still little research on drug treatment for people who have bipolar disorder or attention deficit disorder along with alcohol abuse problems.

The complexity of alcohol’s effects on the body and brain creates further difficulties. Alcohol influences almost every neurotransmitter system in the brain and has a specific affinity for none. It may also cause long-term changes in neuronal gene expression (activation). Different types of alcoholism — early-onset and late-onset, severe and mild, with and without a family history — may be different genetically and respond differently to drugs and psychosocial treatments. It is unlikely that any single approach will ever work for all alcoholics. These complications make the potential availability of more drug treatments especially welcome.

(This article was first printed in the July 2005 issue of the Harvard Mental Health Letter. For more information or to order, please go to www.health.harvard.edu/mental.)

	Click to enlarge		Harvard Mental Health Letter The Harvard Mental Health Letter is a unique resource that covers a wide range of mental health issues and concerns. It presents the latest thinking, treatment options, therapies and debate of interest to both mental health care professionals and the concerned public. Read more 12 monthly issues (Print+Electronic) $59.00 12 monthly issues (Electronic Only) $55.00