Helping alcoholic patients maintain long-term sobriety is "where the [research] action really is these days," said Enoch Gordis, M.D., director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA).
Over the past decade, research on pharmacotherapy for
alcoholism treatment has burgeoned.
NIAAA allocated $19 million for medications development in 1998 and
$23.5 million in 1999. While symptoms of acute alcohol withdrawal are
important, they generally can be managed with benzodiazepines and other
medications, Gordis said in an interview.
"Up until recently, there wasn't much you could do [to help people stay sober except for the behavioral therapies," he said, adding that such therapies are important.
Opioid Antagonists
Naltrexone (ReVia) was approved by the U.S. Food and Drug
Administration in 1994 as an adjunct treatment for alcoholism. It was the first such drug so approved
in the United States since introduction of disulfiram (Antabuse). Naltrexone antagonizes the opioid system. The original work on naltrexone, Gordis said, was conducted at Yale University School of Medicine by O'Malley et al. (1992, 1996a, 1996b), and at the University of Pennsylvania by Volpicelli et al. (1992).
Naltrexone seems to interfere with the craving for alcohol that abstinent people feel, Gordis explained. "The most striking finding with naltrexone is that it seems to abort the likelihood of a bender if a person slips and takes a drink...Among the people who did do that on naltrexone, a smaller fraction of them ended up on a bender [than did those on placebo]," he added.
A more recent study (Anton et al., 1999) involved 131
newly abstinent outpatients who were treated with 12 weekly sessions of
manual-guided cognitive-behavioral therapy (CBT) and either 50 mg/day of
naltrexone (n=68) or placebo (n=63).
Naltrexone-treated subjects drank less, took longer to relapse and had
more time between relapses. They also exhibited more resistance to, and control
over, alcohol-related thoughts and urges. The therapeutic effects of CBT and
naltrexone may be synergistic, the researchers concluded.
Use of naltrexone for alcoholism treatment has only a few
limitations. In a 12-week open-label safety study of naltrexone, there were no
serious adverse effects; the most common were nausea (9.8%) and headaches
(6.6%) (Croop et al., 1997).
A newer opioid antagonist being evaluated is nalmefene. Although structurally similar to
naltrexone, nalmefene offers the advantages of greater oral bioavailability and
longer duration of antagonist action. As shown in animal studies, nalmefene
binds more competitively with µ and
κ receptors, which are believed to reinforce alcohol consumption
(Emmerson et al., 1994; Mason et al., 1999).
Nalmefene also may have less risk for liver toxicity than naltrexone, Gordis said. "In the early days of using naltrexone for obesity, very big doses (300 mg/day) caused some liver problems," he said. The conventional dose-about 50mg/day-is not hepatotoxic, Gordis added.
Mason et al. (1999) conducted a 12-week, double-blind,
placebo-controlled clinical trial of nalmefene with patients meeting DSM-III-R criteria for alcohol dependence. Investigators found that patients on
placebo were 2.4 times more likely to relapse to heavy drinking than those who
received nalmefene, while those on nalmefene had fewer subsequent heavy-drinking
episodes. Patients on nalmefene showed no evidence of medically serious adverse
drug experiences, although those taking the drug reported significantly more
nausea than those taking placebo. No patient skipped the medication or
discontinued treatment because of nausea. The nalmefene and placebo groups did
not differ in rates of abstinent days or self-reported craving severity (Mason
et al., 1999).
Nalmefene is not yet available commercially in tablet
form; an injectable form (Revex) is available to treat opiate overdose. The FDA has not yet approved nalmefene
for use in alcohol dependence, but Gordis said some companies are interested in
manufacturing it.
Acamprosate
Acamprosate (calcium acetyl homotaurinate), developed and extensively studied in Europe, is in a different drug category for alcohol dependence, Gordis said. Although the precise mechanism of action or cellular target of acamprosate is unknown, it seems to involve primarily the restoration of normal N-methyl-D-aspartate (NMDA) receptor tone in the glutamate system (Mason and Ownby, 2000). "It probably does more to relieve the discomfort of not having alcohol, rather than interfering with the reward that results from taking alcohol," Gordis added.
Several studies have demonstrated the efficacy of
acamprosate. One such study of acamprosate involved 4,000 patients in 10 European countries (Spanagel and Zieglg & nsberger, 1997). The double-blind, placebo-controlled trial showed that acamprosate was efficacious for the treatment of alcoholism, with long-term benefits.
A review of 16 double-blind, placebo-controlled trials
found that acamprosate made a significant difference in alcohol-dependent
patients (Mason and Ownby, 2000).
Acamprosate was found to be equally effective in maintaining abstinence
across four major psychosocial concomitant treatment programs in a
multinational open-label study involving 1,281 alcohol-dependent individuals.
The medication also lowered rates of consumption during periods of
relapse. Gordis said that the drug doesn't seem to have any appreciable toxicity; the most common side effect in clinical trials has been diarrhea, affecting about 10% of the patients (Mason and Ownby, 2000).
Lipha Pharmaceuticals Inc., New York, is applying for FDA
approval of acamprosate in treatment of alcohol dependence. Gordis said the application is based on
the European experience and on a multisite trial of the drug conducted in the
United States.
To assess the efficacy of combined behavioral and
pharmacologic interventions in the treatment of alcohol dependence, NIAAA is
helping to launch Project COMBINE, a prospective, multicenter clinical trial,
Gordis said. "It is going to be a trial of a combination of behavioral (verbal therapies) on one hand, and either naltrexone or acamprosate, or both together," Gordis said. "They have just completed the pilot safety trial to show no side effects in giving the drugs together."
Other Pharmaceuticals
NIAAA is also looking at the use of more conventional
drugs for alcoholism treatment, according to Gordis. "The antidepressants, primarily serotonin reuptake inhibitors, do not appear to be as effective as naltrexone or acamprosate, but they may be helpful in treating subpopulations of alcoholics, especially those with depression [Litten and Allen, 1998]," Gordis said.
A three-month trial of fluoxetine (Prozac) in patients
(n=51) suffering from both alcoholism and major depression found that the
medication had a significant effect on both conditions (Cornelius et al.,
1997). Patients were randomly assigned to either fluoxetine, at dosages of 20
mg to 40 mg/day, or placebo. Each week, the patients received supportive
psychotherapy and met with a psychiatrist expert in the treatment of comorbid
patients. Several other trials of
antidepressants alone or combined with naltrexone for depressed alcoholics have
been initiated (Litten and Allen, 1998).
"There is a European drug called amperozide which George F. Koob, Ph.D., [at the Scripps Research Institute in La Jolla, Calif.] has studied in animals. It was originally introduced in Europe for psychiatric indications without great success, but it turns out that it modulates alcohol drinking in animals pretty impressively [Roberts et al., 1998]," Gordis said. "And there is a descendent of amperozide (FG 5974). It has the advantage in that, unlike amperozide, it only interferes with alcohol. It doesn't interfere with any other ingestive behaviors such as food or water, which amperozide does a little in the animals."
Neuroscience and Genetics
Gordis explained that drugs such as naltrexone and acamprosate are important not only because they are useful, but also because, "They signal a new era in which good products of neuroscience are going to produce new treatments for alcoholism."
For example, a first step in developing medications to
treat alcoholism is determining the specific neurotransmitters and receptor
subtypes that may be involved in the development and effects of alcoholism.
"Unlike the other drugs of abuse, which tend to focus on one or several transmitters, there is no single neurotransmitter that alcohol functions on," Gordis said. "It functions on virtually every neurotransmitter system that has been measuredÉthe opioid system, the GABA system, the NMDA glutamate system and serotonin. Beyond that, we have ATP [adenosine triphosphate] and all sorts of subtypes of these receptors which may differ in vulnerable people or which may change as a result of drinking. We are learning the unifying theoretical features by which all these actions on neurotransmitters are linked, and we are learning from structural chemistry and molecular biology what are the essential parts of neurotransmitters that alcohol reacts with."
Moreover, in his introduction to Principles of
Addiction Medicine, 2nd ed.
(American Society of Addiction Medicine, 1998), Gordis explained that
scientists from the Collaborative Project on the Genetics of Alcoholism, a
multisite study, have located several loci in the chromosomes that have been
shown to have a high probability of containing genes relating to vulnerability
to alcoholism. Alcohol dependence may be linked with chromosomes 1, 2 and 7
(Reich et al., 1998), while chromosome 4 may be linked to resilience to alcohol
(Long et al., 1998). There have also been tentative identifications of
locations for genes linked to the expression of evoked potential responses, a
high-risk marker for alcoholism (Polich et al., 1998).
Psychotherapy and Prevention
"The drugs don't work alone. It seems they have to be combined with capable counseling, and that means research-based methods of counseling," Gordis said.
Several forms of verbal therapy have roughly equal
effects, he noted. One is based on the 12-Step principles of Alcoholics
Anonymous: not just going to AA meetings but working through the principles
with trained professionals, he explained. The second is cognitive-behavioral
therapy that seeks to undo such maladaptive behavior as drinking in response to
stressful situations. The third is a briefer, motivational interviewing
approach.
Prevention is just as important as the pharmacotherapeutic
and psychotherapeutic treatment approaches, Gordis emphasized. The NIAAA is sponsoring several
prevention efforts, such as studying college-age drinking and determining
effective interventions for reducing drinking among teen-agers. They are also
exploring the effects of social and legislative controls such as blood alcohol
limits for driving and controlling the density of liquor outlets in
neighborhoods. "We have research which is largely focused on preventing the problem from developing," he said, "which, as in many areas of health, is the best treatment of all."
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