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Abstract
For years, addiction specialists could only dream of medications to cut craving, reduce withdrawal, and lower the odds of relapse. American clinicians have long emphasized the idea that drug addiction and alcoholism are diseases - but, even now, most treatment is nonmedical, primarily support for 12-step self help (like Alcoholics Anonymous) or counseling.
| New drugs fight addiction by reducing craving. |
Recently, however, medication development efforts, funded largely by the National Institute on Drug Abuse (NIDA) and the National Institute on Alcohol Abuse and Alcoholism, have begun to pay off. There are now medications that reduce alcohol craving (acamprosate, naltrexone), lower the risk that one drink will lead to a binge (naltrexone), cut relapse among those with the severest form of alcoholism (ondansetron), and reduce heroin relapse (buprenorphine, methadone). Some promising medications for cocaine abuse are also in development (most notably, vigabatrin and baclofen).
However, moving these medications from lab to clinic has been harder than most "technology transfer" problems. While doctors say that you can tell what year someone graduated from medical school by her medication preferences, there are additional barriers to new medications for addiction. The most difficult is the underlying moralism that pervades the field.
| Society says addiction treatments shouldn't feel good. |
In most areas of medicine, drugs that make patients feel better are desirable - but not here. Addicts are believed to get too much pleasure while using; treatments, therefore, should deny pleasure. Though research shows that addicts commonly have lives that are less pleasurable than others (due to factors like depression and childhood abuse), they are frequently labeled as selfish and hedonistic. Too often, science takes a back seat to moral sentiment.
Charles Schuster is the former director of the National Institute on Drug Abuse. "I remember when a congressman told me he was backing our medication development program," Schuster says. "He said, 'I want something so that when they take cocaine, they suffer.' He regarded addicts as despicable, not [medically] sick."
| "What addicts will accept is not acceptable to the culture." |
Sociologist Robin Room, now professor and director of the Centre for Social Research on Alcohol and Drugs, Stockholm University, agrees. "We've got a cultural dilemma. On the one hand, we want a pill that is not fun for addicts and is resistant to anything that might be in any way pleasurable. On the other hand, if it [doesn't provide any psychological benefit], you have a compliance problem. What the culture wants makes it unappealing to those who will take it. What the addicts will accept is not acceptable to the culture."
This theme dominates the history of addiction medication. The most widely accepted drug in alcoholism treatment, for example, is Antabuse, which can kill, or, at least, make alcoholics who drink while taking it wish they were dead. This medication has been marketed for alcoholism treatment since 1948, but it does not improve recovery rates. Those who are highly motivated will take it, but those who most need help stop using it if they feel like drinking.
| "Clinicians accept Antabuse because if you drink, you get punished." |
Says Joseph Volpicelli, senior research scientist at the University of Pennsylvania Health System, "It's fair to say that clinicians accept Antabuse because if you drink, you get punished." Adds Room, "Giving up drinking itself serves several social functions. First, of course, you can't have a drinking problem if you are not drinking. But second, total abstinence is a way of showing that you are serious. By giving up something that you valued more than anything else, it's a way that people who have lost social credit can regain it."
Naltrexone, developed by Volpicelli and approved in 1994, is superior to Antabuse. When used in combination with counseling and other social support, it can cut relapse by 50 percent compared to a placebo, by reducing the chances that someone who has one drink will go on to a full-fledged alcoholic binge. This property, however, makes many treatment providers anxious, because it means that some could use it to "have just one" and avoid lifetime abstinence.
| Naltrexone has a PR problem: allowing moderate drinking. |
"One difficulty with getting naltrexone accepted," says Room, "is that it goes fairly well with a moderate drinking goal, but that is not allowed in the American situation." Room believes that the strong resistance to treatment that doesn't demand abstinence results from fear that this will lower the social standing of those who have recovered by giving up alcohol altogether.
In fact, nonabstinence options are so controversial that when a famous abstinence-only treatment provider, the Smithers Center in New York, revealed that it had begun offering heavy drinkers help with moderation in addition to abstinence, its director was fired and the policy reversed after an outcry from supporters of Alcoholics Anonymous.
| "There's still a bias that addiction is a personal failing." |
Because of its pharmacological action, naltrexone seemed more acceptable than it proved to be. Naltrexone works by blocking the brain's opiate receptors, thereby reducing the high from drinking. This could be seen as punishing. But because of the "benefit" of allowing potential moderate drinking, it's not enough. Says Volpicelli, "A medication that takes away the high is not as attractive [to the public and clinicians] as one that makes you sick. There's still a bias that addiction is a personal failing, not a medical disorder." As a result of the difficulties in gaining acceptance for it, naltrexone is not actively marketed by its makers.
Another new alcoholism medication, acamprosate, was developed in Europe and has been used by over 1 million patients abroad. Says Stephanie O'Malley, professor of psychiatry at Yale University School of Medicine, "[Acamprosate's] primary effect is to increase abstinence - so it is consistent with the philosophy of most American programs." Acamprosate is believed to work by reducing the activity of excitatory amino acid neurotransmitters in the brain. These may be overactive following heavy alcohol use, because alcohol itself activates a counterbalancing neurotransmitter system. Acamprosate may be most useful for people who suffer protracted withdrawal symptoms. A phase III clinical trial, with 601 patients, conducted by Barbara Mason of the University of Miami School of Medicine, found that Acamprosate increased abstinence rates by 10 to 25 percent. It is not yet FDA approved.
| Ondansetron helps early onset alcoholics. |
Also, in August, the Journal of the American Medical Association published results of an intriguing study by University of Texas Health Science Center researcher Bankole Johnson. His group studied ondansetron, which may help alcoholics who are most difficult to treat: those who start drinking at a very young age. Already approved for treating nausea, ondansetron blocks one of the brain's serotonin receptors, the 5HT3A receptor.
Early-onset alcoholics tend to have the most intractable problems. They are impulsive, may have antisocial tendencies, and tend to repeatedly drop out of treatment. In this group, ondansetron increased the number of days abstinent by 20 percent. In a smaller study, ondansetron combined with naltrexone was even more effective with this population. Since depression and aggressive behavior are often linked with serotonin system dysfunction, as well as with alcohol problems, it's not surprising that a drug that acts on this system could be helpful.
| A pill puts the doctor in charge. |
As newer and more effective medications are developed, it will become increasingly difficult for treatment providers to avoid offering them. Says Johnson, "Medications have not traditionally been used - it's a new vista for treatment programs." Adds Room, "People talk about alcoholism as a disease, but the truth is, most of the people who treat it are not doctors. Suddenly, with a pill, the doctor is going to be in charge. Medications have a lot of pluses and minuses for many different actors in the field."
The addictions field also seems to be recognizing its mistakes, which can be seen most prominently in heroin addiction treatment. Methadone is the most effective treatment for heroin. It gives addicts the opiate comfort they seek, without the drawbacks of an illegal, short-acting drug that causes chaotic shifts from an altered to a normal state of consciousness. However, because methadone is not punishing, it is stigmatized as "not real" recovery even when addicts lead productive lives. Its effectiveness is hampered by regulations requiring addicts to pick it up, at least twice a week, from grungy clinics.
| Buprenorphine has mixed effects on opiate receptors. |
The FDA is preparing to approve a new medication for opiate addiction that won't be restricted this way. Buprenorphine is an unusual opiate - it has mixed effects on opioid receptors. At lower doses, it produces an opiate receptor-agonist effect like methadone; at high doses, it produces the opiate-blocking effects of naltrexone. Researchers say that at an agonist dose, most patients cannot distinguish it from methadone. (Interestingly, naltrexone is approved as a treatment for opiate addiction, but, because it doesn't provide the anxiety-reducing effects of opiate agonists, it is not as effective as methadone.)
Congress has just passed legislation allowing any doctor with training in addictions to prescribe buprenorphine - addicts won't have to venture to ghetto areas or give up freedom to get it. And because it has antagonist effects if addicts try to take extra or use street drugs on top of it, it offers some satisfaction for those who want a drug to punish.
| The FDA nixed trials of Vigabatrin, due to vision side effects. |
On the cocaine front, an epilepsy drug approved in Canada called gamma-vinyl-GABA (vigabatrin/Sabril) decreases cocaine-seeking in animals. The drug seems to work by increasing levels of the neurotransmitter GABA - this is believed to cut cocaine craving by reducing levels of another transmitter, dopamine, which is involved with anticipating and experiencing pleasure. According to Eliott Gardner, a researcher at NIDA's Division of Intramural Research Medications Discovery Research Branch, anecdotal reports suggest the drug may help humans. Unfortunately, because of a side effect involving constriction of the field of vision, the FDA currently "won't permit trials," says Gardner. Another drug which works on the GABA system via a different mechanism, baclofen, is also being studied and has the advantage of being FDA-approved.
Taboos against "drugs to fight drugs" are unusually resistant to change. Any medication that potentially evokes pleasure - even if it improves lives radically - is met with skepticism. A new medication to replace arduous physical therapy following injury would be greeted enthusiastically, but one that avoids the struggle of talk therapy for depression or addiction is seen as "cheating." Science has yet to defeat the mind/body problem - or those who view psychological problems as failures of will and values. But, if addiction science comes up with a blockbuster drug like Prozac, the terms of the debate will shift. After all, if a medication can end addiction, one of the main reasons to avoid recreational use disappears.
Maia Szalavitz is a health/science journalist who has written for the New York Times, the Washington Post, Newsday, New York Magazine, Salon, and other major publications.
Andrzej Krauze is an illustrator, poster maker, cartoonist, and painter who illustrates regularly for HMS Beagle, The Guardian, The Sunday Telegraph, Bookseller, and New Statesman.
Web of Addictions - a centralized resource for information on drug addiction, with links to sites for patients and professionals.
Principles of Drug Addiction Treatment - a research-based guide from the NIDA.
Role of Serotonin and Serotonin-Selective Pharmacotherapy in Alcohol Dependence - an overview of treatments, including ondansetron. From CNS Spectrums 2000, 5(2):33-46
Endogenous Morphine - a review of morphine's endogenous functions. From Trends in Neurosciences, 2000, 23(9):436-442. Full text available from BioMedNet.
The Dopamine Hypothesis of Reward: Past and Current Status - examines this neurotransmitter's role in addiction. From Trends in Neurosciences, 1999, 22(11):521-527. Full text available from BioMedNet.
Dopaminergic Agents for the Treatment of Cocaine Abuse - focuses on small-molecule-based approaches to discovering therapies. From Drug Discovery Today, 1999, 4(7):322-332. Full text available from BioMedNet.
The Genetics of Alcoholism - considers results from human and animal studies. From Current Opinion in Genetics & Development, 1998, 8:282-286. Full text available from BioMedNet.
Rational Treatment of Addiction - includes discussion of naltrexone and acamprosate. From Current Opinion in Chemical Biology, 1998, 2:541-547. Full text available from BioMedNet.
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