Alkermes, a Cambridge biotech firm, has developed an injection that may allow alcoholics to drink moderately.

To some, the drug represents the triumph of science over superstition. To others, it's a heresy.

By Chris Wright

When John K. started taking the drug disulfiram, he felt like he was dying. Pain pulsed through his head and neck. His skin prickled. His vision blurred. His heart jackhammered. His saliva calcified and his shirt sopped with acrid sweat. He vomited profusely. He was dizzy, muddled, barely able to breathe.

Satisfied with the results, his doctors gave him more.

The miseries John K. endured on disulfiram were not unfortunate side effects of the drug. A person taking it is supposed to feel awful—if, that is, he takes it in conjunction with alcohol.

Sold as Antabuse and first approved for use in alcoholics in 1951, the drug is a classic example of aversion therapy—an electrified cookie-jar lid for drunks. John K., a middle-aged college professor with a decades-old addiction to whiskey, endured this grim regimen for the same reason as all alcoholics who take it. He had run out of options.

The way the drug works is simple. By hindering the breakdown of alcohol, Antabuse leaves the system teeming with hangover-causing toxins. A single dry martini will inflict an immediate and profoundly miserable morning after.

The logic, too, is simple: You drink on Antabuse, you suffer, therefore you stop drinking. The problem is, for many alcoholics the logic gets skewed: You drink, you suffer, therefore you stop medicating. Or you do what John K. did. "He drank through it," says a friend, "and eventually it killed him."

Whatever the potential benefits of Antabuse, the drug amounts to a harsh, punitive therapy. Alcohol dependency has long been viewed as a kind of moral failing, even a kind of possession, and its treatment has reflected this view—the disease is to be managed through force of will (with help from a "higher power"), as with Alcoholics Anonymous; or, as with Antabuse, it is beaten out of you.

Neither option, however, is seen as a cure. The prevailing wisdom is that once the demon booze gets its claws into a victim, it never lets go. Either you stop drinking entirely, or you are consumed by your addiction.

Now, however, that dogma is facing a challenge. Alkermes, a mid-sized biotech company in Cambridge, has developed a drug that offers alcoholics an alternative to do-or-die abstinence, and possibly the opportunity to drink moderately.

Along the way, the drug will rekindle a debate that has often seethed with religious intensity. Vivitrol, says David Gastfriend, Alkermes's vice president of medical affairs, will mark the moment when "the myth of the demon falls."

LOCATED IN A spacious, modern, unnervingly quiet building, Alkermes was founded in 1987, during one of the early boom periods of the U.S. biotech industry. The company specializes in developing long-acting versions of existing medications, and the handful it has produced so far have not been particularly profitable.

Vivitrol—an injectable form of a drug called naltrexone—is Alkermes's most ambitious project yet, and there is hope that the drug, which went on the market last month at $695 a shot, will help turn things around.

"In some ways, this is a grand experiment," says Richard Pops, the company's CEO. "We've been making Vivitrol and testing its utility for the last five, six years. We built a factory to make it in. We've invested hundreds of millions of dollars."

Pops took over at Alkermes when he was 29. Fifteen years later, he still comes across as being awfully young to be spearheading a healthcare revolution. He is a ringer for Jon Stewart, and apt to use words like "whatnot" while describing cortical functions.

But get Pops started on his company's newest drug and he is all business. "Years ago, we sketched out a future," he says. "We said that if we could be successful with Vivitrol, a decade on people would look back at that time as when this field began to gel."

Certainly, the drug has a giant potential market. There are about 18 million Americans who either abuse alcohol or are dependent on it. Alcoholism affects one in three families, costing the United States an estimated $185 billion annually.

Up to 100,000 Americans die from the disease every year—putting it just behind cancer and heart disease in the league of fatal afflictions. "We were never really worried about 'Is there a need? Is there a demand?'" Pops says. "It's more, 'Can you deliver the outcome? Can you give physicians a tool that can help people?' The rest will take care of itself."

There are, to date, a total of four brand-name drugs with FDA approval to treat alcoholism, including Vivitrol.

Campral, which eases withdrawal symptoms, was approved in 2004. ReVia, a pill form of naltrexone, was approved to treat alcoholism in 1994. Before this, the only game in town was Antabuse, which received FDA approval in 1983.

The dearth of medical treatments for alcoholism stems largely from the way we perceive its symptoms. As with many psychological disorders, we diagnose this one through sets of behaviors rather than involuntary physical responses.

Alcoholics—rather than doing things like turning bright orange or bleeding from the ears—lie about their drinking, drink to avoid their problems, and so on.

And while no one would suggest that a person cure himself of a cold by not sneezing, a person can, in theory, refrain from hiding bottles of vodka behind his car seat—a fact that has led to the widely held belief that the alcoholic, as AA co-founder Bill Wilson put it, "is an extreme example of self-will run riot."

This diagnosis may defy medical principles, but as New York–based addiction specialist Alexander DeLuca notes, medical principles have traditionally played little part in our understanding of alcoholism. "The disease model was promulgated by AA, a non-medical body," he says. "It was an allegory in a way, and not an un-useful one. It was a way of decreasing shame: 'Let's call this a disease, let's pretend it's a disease.'"

Calling something a disease, however, is not the same as treating it as one. "It's a lot of gobbledygook, man," DeLuca adds. "The terminology is just gibberish. The word 'disease' attached to alcoholism is a mishy-mashy concept."

IN RECENT YEARS, the science of alcoholism has grown less cloudy. The alcoholic brain, we now know, is different from the non-alcoholic brain. Those with a propensity to alcoholism have what is sometimes called a depression gene, a congenital deficiency in endorphins, the feel-good hormones that allow us to smile through life's slings and arrows.

Alcoholics also respond to drinking in ways that are "super-physiological," or excessive: In short, they get a much bigger buzz than the rest of us, a euphoria that supersedes all other drives, that obliterates all other considerations.

The mangled car, the estranged spouse, the career-ending holiday party—the fallout from the most abject of benders pales into insignificance beside the exquisite blast of pleasure that booze brings.

The medical explanation for this dynamic is predictably impenetrable, filled with references to "dopaminergic" systems and "euphorigenic" properties.

A recovering alcoholic in Boston, whom we'll call David M., outlines alcohol's allure in simpler terms: "The sun shone brighter, music sounded better. There was this mellow everything's-right-with-the-world, instead of fear, doubt, and anxiety. You'd feel the warmth of it going down. None was as good as that first one. That was just fabulous. It was just great. Wow."

What Vivitrol does, essentially, is remove the wow.

Again, the scientific details bear simplification: Picture the pleasure center of the brain as being fraught with little golf tees, the receptors that capture and disperse the feel-good chemicals generated by alcohol intake.

Vivitrol blocks these receptors, reducing the rush, more or less, to the levels felt by non-alcoholics. The great innovation here is that the drug tackles the physical symptoms of the disease rather than the behaviors; where Antabuse targets the patient's liver, Vivitrol goes to the heart (or mind) of the matter.

And rather than making drinking a fearful prospect, Vivitrol seeks to make it a matter of relative indifference.

Jerri Kult, 49, used to go through a fifth of whiskey a day. "Plus three or four drinks at a bar, sometimes more," she says. Two years ago, Kult volunteered to partake in a safety study for Vivitrol. Before long, she lapsed. "I had a drink, just to see."

Previously, booze had made Kult brim with manic energy, "like I could do anything." This time: "Nothing. No euphoria, no nothing. I was like, 'Why am I doing this?' It was going nowhere."

Kult was not the only trial subject who drank on the drug: Of the 401 people who completed a subsequent six-month FDA clinical trial for Vivitrol, 38 stayed sober. The rest "substantially reduced" their alcohol intake.

This point marks the drug's most controversial aspect. Though its makers insist Vivitrol is meant to promote abstinence, the very idea of a medication to dull the euphoria of drinking would seem to presuppose that there will be some drinking involved—or why take it?

It doesn't require a huge leap of logic to conclude that a drug inducing "normal" responses to alcohol might also promote "normal" drinking patterns.

"I'm curious to see what the results will be," says DeLuca, who was recently hired as a Vivitrol representative. "Will there be increased abstinence or will there be reduced harmful drinking? I think the latter."

Harvard professor of psychiatry George Vaillant is appalled by that possibility. A reduction in heavy drinking, he says, does not necessarily mean an end to booze-fueled screwups. "You only need to break your wife's jaw once, or have one Patrick Kennedy auto accident, to spoil your whole day."

The science behind Vivitrol, he adds, represents little more than a futile attempt to exercise control over the uncontrollable. "We know how Russian roulette works, too—but it still doesn't stop the bullet from killing you," he says.

"What we know about the neurobiology of alcoholism has no effect on the fact that it kills 100,000 Americans a year. Our improved neurological understanding is displacement. We're comforting ourselves."

THE DISPUTE OVER whether Vivitrol's active ingredient, naltrexone, should be used to promote controlled drinking has simmered for more than a decade. That it hasn't exploded into an all-out cultural war may be due to the fact that the drug has failed to really take root.

From the outset, ReVia—the first brand name under which naltrexone was sold—was never really marketed properly, meaning that nobody bothered to educate the doctors who might prescribe it, meaning that the drug was misunderstood, misapplied, and, eventually, ignored altogether.

Twelve years later, the situation hasn't changed much. "Naltrexone antagonizes opiates, which probably means that people get the same buzz from lower amounts of alcohol," says a Cambridge-based psychiatrist.

"So instead of needing to have 12 drinks, they might stop after a lower number." Actually, this is close to being the opposite of what naltrexone does. Even today, it seems, many in the medical profession remain in the dark about the drug. 

To ensure that Vivitrol doesn't suffer the same fate as ReVia, Alkermes has partnered with Cephalon, a pharmaceutical company with extensive marketing experience. Over the next year or so, Cephalon reps will travel around the country, spreading the word to thousands of healthcare professionals.

Alkermes has also stressed the importance of generating major clinical trials, to reassure the skeptics. Recently, two much publicized studies have taken place, both of which demonstrated the drug's effectiveness.

The biggest question hovering over Vivitrol, though, is whether it will avoid the noncompliance issues that have dogged ReVia. A daily pill, ReVia all too often leaves alcoholics standing before the bathroom mirror, a little beige tablet in hand, trying to decide whether or not they want to kill that night's buzz.

As a former ReVia patient puts it, "You can't imagine the energy it takes, every day, to take that pill."

Vivitrol's most vital and tangible selling point is that it's delivered in a monthly injection. One benefit of the long-term dose is that it prevents alcoholics from employing their flair for deception.

As Pops says, "You come in [to your doctor's office] once a month, and your spouse knows you should be there, your brother, your friends, your coworkers. You go in and get your shot."

More significant is the fact that Vivitrol reframes the alcoholic's central dilemma. With the daily pill, the question was always situational: "Do I want to get obliterated tonight?" With the time-release injection, it becomes existential: "Do I really want to get obliterated night after night?" If the answer is no, then for a month at least, the alcoholic gets to feel what life is like without the wow.

It is this shift, say the Alkermes people, that will take naltrexone from the margins to the mainstream. If Vivitrol does become widely used, though, it will likely meet with furious resistance—particularly if it's seen as providing an alternative to abstinence.

"Coming out publicly on alternatives can be very dangerous," says Andrew Tatarsky, a New York clinical psychologist who heads a group called Moderation Management. "Vocal advocates for controlled drinking have received death threats."

THE LAST TIME the moderation debate really flared up was in 2000, when DeLuca, then medical director of the Smithers Alcoholism Treatment and Training Center in New York, talked publicly about the possible benefits of helping alcoholics curtail their drinking, a position that contravened the clinic's "long and proud tradition of treating alcoholism by advocating total abstinence."

After a week or so of hysterical press coverage, DeLuca lost his job. "You know," he says, "every 20 years someone like me comes along and says, 'Surely now the sun has risen, surely now it's safe to come out, surely now a hundred flowers will bloom.' And then vergh!"

DeLuca is quick to point out that he doesn't believe alcoholics should be encouraged to enjoy a few hits of their favorite poison every now and then. Nobody in the treatment community, not even the most devout proponent of moderation, will argue against the idea that abstinence is the best possible outcome for the alcoholic.

Instead, moderation is equated with "harm reduction," a step on the path to sobriety. "The debate is whether to let people hit rock bottom before offering treatment," says Tatarsky, "or get to them earlier to begin a process of positive change."

According to moderation advocates, controlled drinking is actually more likely to help a patient achieve sobriety than the conventional all-or-nothing approach—which, says Tatarsky, often leads an alcoholic to opt for all.

Indeed, according to some counts, up to 80 percent of alcoholics either can't or won't stop drinking.

These people, the argument goes, should at least be given the option to drink moderately. That argument, though, fails to sway those in the opposite camp, whose belief in complete abstinence is so entrenched it's become, as DeLuca says, "a holy principle."

"These positions are going to be difficult to bridge," says Ames Sweet, a spokesman for the National Council on Alcoholism and Drug Dependence, a group closely aligned with AA. "It's almost biblical."

In this climate, to suggest moderation might be an alternative to abstinence rather than a way to achieve it would be so extreme as to be unthinkable, a violation of both practical and moral standards, like denying the Holocaust and the laws of physics at the same time.

Little surprise, then, that Pops wants no part of the idea that Vivitrol might help alcoholics drink moderately. "You will not see us making claims anywhere near there," he says. "Our label, approved by the FDA, says that this drug is going to be used by professionals in conjunction with counseling to produce a certain outcome."

Actually, there appears to be some confusion over what this outcome will be. The FDA label for Vivitrol states clearly that it's intended for patients who "are able to abstain from alcohol in an outpatient setting."

The summary of the FDA trial for the drug, meanwhile, states clearly that "The primary endpoint of the study was the reduction in the event rate of heavy drinking days."

It's unclear whether this inconsistency is the result of political considerations, but it's left many people puzzled. "How did the FDA come to that conclusion?" says Helen Pettinati, one of the FDA trial's principal investigators. "Everybody thought they would be labeling around this heavy drinking idea, because there was a major reduction in heavy drinking. People were surprised."

Pressed on the matter, Pops concedes that "in the real world," Vivitrol "will be used how it will be used." In other words, Alkermes will sell the drug to doctors, who will sell it to patients, who will decide for themselves what to do while taking it.

So far, the only significant real-world experience anyone's had with Vivitrol was its FDA trial, in which more than 90 percent of the patients continued to drink while taking it (albeit at lower rates).

"There are many people who drink in a moderate fashion and don't have a problem," says Sweet. "But when you've had a problem, to consider yourself a candidate for moderation is shortsighted and dangerous." Vivitrol, he adds, "ain't gonna do a damn thing for you when you crash your car in a storefront."

AT TIMES, Richard Pops seems taken aback at Vivitrol's ability to provoke such wildly opposing opinions and emotions. Above all, he says, the work he is doing at Alkermes arises from a desire to have a positive impact on the world.

"I think that feeling is a tremendous motivational force in the biotech industry in general," he says. "Because starting these companies is an unnatural act. Most of them fail."

It's probably a source of disappointment, too—with the factory built, the testing done, the invested millions finally coming to fruition—that people might start calling Vivitrol "dangerous." In any case, Pops loses a little of his composure discussing the objections to his drug. "It's interesting that many people who are not alcohol dependent are participants in this debate," he says, knitting his hands on a conference table.

"But for the people seeking treatment, there's this calm in the eye of the hurricane. The people who fight every day to maintain sobriety or drink less alcohol are excited to have these new tools in their struggle."

David M. is one of these people. Thirty years ago, he came very close to losing the battle. "I was picked up for drunk driving, public intoxication," he says. "I had an understanding that this was terminal. That much I knew."

Desperate, he tried Antabuse, the drug that makes you ill when you drink. "It put the fear of God into me," he says. But it didn't stop him from hitting the bottle. "I didn't even have a name. I was Bone-Dry Vodka with a Twist."

Today, David M. is a member of AA, sober for 26 years. Though he remains suspicious of anti-alcohol drugs, Vivitrol has got him thinking. "If someone said to me, 'Here, here's something to take this destructive behavior and turn it into something nice again?'" he says. "Well, hell's bells, write me a prescription!"

Originally published in Boston Magazine, July 2006.