Sunday, February 20, 2005

Neuroscience and Substance Abuse

The Society for Neuroscience issued a press release discussing a new finding in the science of understanding substance abuse.  According to Dr. Frenois of Université Victor Segalen Bordeaux 2 (Sciences de la Vie, de l'Homme, de la Santé) memories of uncomfortable drug withdrawal can cause activation of the same brain circuits that are activated during drug withdrawal itself.  In other words, the mere act of remembering withdrawal can cause some of the same physiological anomalies that occur during the actual withdrawal. 
The team found that re-exposure to an environment associated with withdrawal reactivated part of the withdrawal neural circuitry, which can drive behavioral changes causing drug relapse. Addiction, the authors say, is a chronic, recurrent disorder involving motivation, emotion, and memory. Frenois and his team say their work is an important step in helping to determine how specific environments associated with drug withdrawal might encourage drug seeking.
The study was done in rats.  It would be hard to get humans to consent to such a study, and even harder to get an Institutional Review Board to approve it. 

The association between reminders of drug/alcohol abuse, and the occurrence of relapses, is well known.  Persons with substance abuse problems are advised to avoid situations that remind them of drinking or using drugs of abuse.  Frenois' study indicates that there may be another aspect to the role of memory in The risk of relapse.  Reminders of withdrawal may be important, tool.  If a person starts to remember an experience of withdrawal, then starts to have the same physiological effects as those produced by withdrawal, it could lead to craving, and relapse.  Finding a way to interrupt this process could be helpful.  I'm not sure that we would want to do something that interferes directly with memory, but perhaps interfering with the physiological consequences of the memory could lower the risk of relapse. 

Along the lines of the study cited above, Science Blog has a post that describes the action of drugs that can be used to treat alcohol dependence.  The author, know only as BJS, reports on a Cochrane Review of the use of opioid antagonists for alcohol dependence.  Twenty-nine randomized controlled trials of the use of naltrexone and nalmefene were included in the review.  Naltrexone was studied the most; it is what is used in the US, under the trade name ReVia

Naltrexone Structure
Morphine Structure

The authors conclude that naltrexone does have a role in the treatment of alcohol dependence, and that there is not enough evidence to recommend nalmefene.  The results with naltrexone are hardly spectacular: it reduces the risk of relapses by 36%, and the probability of attaining complete abstinence is increased only by 13%.  Still, in treatment centers, in commonly is said that alcoholism is a disease that invariably proceeds to death, unless abstinence is attained.  So a 13% decrease is worth something, at least.  Is naltrexone dangerous?  Who cares?  It is not as dangerous as alcohol is to an alcoholic.

The press release that was the basis for the Science Blog post includes the following:
Dr. Joseph Volpicelli, of the University of Pennsylvania School of Medicine, has been conducting research on naltrexone use for alcohol dependence since the early 1980s. Naltrexone blocks the brain's receptors for natural painkillers, known as opioids, which normally create the feeling of wellbeing associated with drinking.

He explains that the benefits of naltrexone lie not so much in preventing a patient from having one drink, but rather in breaking the cycle where one drink leads to many more. "Naltrexone helps people have more control over the use of alcohol. For me, that's the fundamental issue of what addiction is: impaired control."

However, this approach requires a substantial change from the abstinence-only philosophy that goes back at least as far as Prohibition. Naltrexone is most effective, says Volpicelli, in a treatment program "designed to support the notion that while one drink is not great, what you really want to stop is excessive drinking."
In the Science Blog post, BJS also mentions a drug called acamprosate, marketed as Campral.  The Corpus Callosum reviewed acamprosate in a New Year's Day post.  Acamprosate reduces the cravings for alcohol, but has no effect on the person if he or she drinks.  Neither naltrexone nor acamprosate produces an aversive reaction in the presence of alcohol, the way disulfiram (Antabuse) does.  The mechanism of action of acamprosate is unknown.  In light of the Frenois study, though, I wonder if it acts by dampening the physiological arousal caused by memories of withdrawal.  There's a paper or two in there, for anyone who is interested and has the resources to do the studies. 

The concept of abstinence vs. moderation is a hot controversy in the field.  Adherents of the AA approach insist that abstinence-based treatment is not only the best way, it is the only way to approach alcoholism.  Others agree with Dr. Volpicelli, that moderation of drinking can be a reasonable option.  The nice thing about this controversy is that both sides know that they are right.  Whatever the truth of the matter, I am not sure that the use of naltrexone requires abandoning the goal of abstinence.  In fact, I've prescribed it to persons who are dedicated to the attainment of abstinence.  My position is that abstience should be the first goal, with moderation being a fallback position. 

It is a bit of an inconsistency to tell a person, in essence, that she or he absolutely must not drink alcohol, "but if you do, it will be easier to quit gain if you are taking this drug."  However, I've always been more in favor of practicality than of philosophical purity.  I've seen people taking naltrexone relapse, but limit it to just a one-day binge, whereas in the past any relapse would go on until some catastrophe intervened.  That's not great, but it is better than the alternative.  I've prescribed acamprosate, but so far don't have any impression of its effectiveness.

This post began with a discussion of the role of the memories of withdrawal contributing to urges to relapse, which was hypothesized to play a role in the risk of relapse.  We then reviewed the action of two drugs that are known to reduce the risk of relapse: naltrexone, which acts by reducing the rewarding sensation of substance abuse; and acamprosate, which has an unknown mechanism, but which I casually postulated might act by reducing the arousal caused by memories of withdrawal.  Neither drug is resoundingly successful, though, so clearly there is more to be learned about the subject. 

It is doubtful that any pharmacological intervention alone could result in a satisfactory outcome for a person with a substance abuse disorder.  Psychosocial treatments always will be necessary.

(Note: The Rest of the Story/Corpus Callosum has moved. Visit the new site here.)
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