NEW WAYS TO LOOSEN ADDICTION'S GRIP

When Aaron, a 33-year-old writer from New York, decided to get help
for his five-year addiction to painkillers, there was really only one
option.

Every morning, he visited a local clinic for a small cup of methadone,
the standard treatment for addiction to heroin and other opiates since
the 1960's. But his life soon revolved around the clinic's hours, he
said, and the daily routine was humiliating.

"I had to stand in line with a bunch of people who were talking about
getting high," and take a urine test for illicit drugs each week, said
Aaron, who spoke on the condition that his last name be withheld.

Then, a year and a half ago, a quiet scientific advance gave Aaron -
and 60,000 other Americans - a chance to break their dependence on
drugs without shame.

Buprenorphine, made by Reckitt Benckiser and sold under the brand name
Suboxone, became the first prescription medication for people addicted
to heroin or painkillers.

The small orange tablet is available by prescription at any
neighborhood pharmacy. It relieves symptoms of opiate withdrawal like
agitation, nausea and insomnia.

But unlike methadone, buprenorphine (pronounced byoo-pre-NOR-feen) is
only weakly addictive, and is thus less tightly regulated. Above a
certain dosage, more will not produce a high, so it has a far lower
risk of overdose than methadone. And once a patient has taken a pill,
the effects last for about three days, greatly decreasing the chance
of a relapse.

Serious drug addiction is a problem that afflicts more than 10 million
Americans. The grip of hard-core drugs like heroin and cocaine is
notoriously stubborn, and relapse rates are staggering. Rehabilitation
programs have only limited success. Dropout rates are high, and even
many addicts who do stay in rehab slide back into using drugs
periodically.

But buprenorphine is the first of a new generation of prescription
drugs that is changing the landscape of addiction treatment, providing
new hope and moving addiction from clinics and rehab centers, long
seen as magnets for junkies, pushers and gloom, into the comfort of
the doctor's office.

In laboratories around the country, researchers are creating
prescription medications to alleviate craving or blunt euphoria, and
working on vaccines that can prevent people from getting high by
mopping up a drug in the bloodstream. In some cases, the research is
already bearing fruit: Campral, a new prescription drug to block
cravings for alcohol, was approved by the Food and Drug Administration
last week. Other medications are likely to enter the market within a
few years.

At some point, experts say, the new treatments will allow addiction to
be viewed - and treated - like any other chronic, relapsing disease.

"There has been a revolution in the way we view addiction," said Dr.
Charles A. Dackis, chief of psychiatry at the University of
Pennsylvania Medical Center-Presbyterian. "It's being seen now as a
disease of the reward centers of the brain, much like pneumonia is
seen as a disease of the lungs."

The new treatments arrive as scientists are beginning to unravel the
underlying neurobiology of drug dependence.

Researchers have known for some time that all substances of abuse,
including nicotine, alcohol, cocaine, marijuana and heroin, activate
the same pleasure pathway in the brain. But they are now finding that
many drugs cause subtle changes in brain activity that remain for
weeks, months or years. Such alterations, studies have found, help
unleash the cravings that can plunge recovered users back into the
throes of addiction long after their last puff or snort.

"We now know the changes these drugs cause in the brain at the
molecular level that lead to addiction," said Dr. Eric J. Nestler,
chairman of the department of psychiatry at the University of Texas
Southwestern medical center. "Because of imaging studies we know where
to focus, and that's a brand new advance."

Although experts acknowledge that drug abuse begins as a voluntary
behavior, many argue that at some point a perilous line is crossed.
Brain cells that are repeatedly assaulted by addictive drugs change
shape. The brain's reward pathway - the same, primitive system that by
evolutionary design makes basic drives like sex and eating pleasurable
- - is hijacked. The urge to get high is insatiable. In experiments, lab
animals will press a lever for cocaine until it kills them.

Each drug manipulates the reward circuitry in a different way, but in
brain scans every drug lights up a link in the neural pathway called
the nucleus accumbens, the universal site of addiction. After repeated
bombardment by drugs, the system loses sensitivity to more natural
rewards.

"These drugs stimulate the reward circuitry so acutely that over time
they disrupt it," said Dr. Dackis, adding that addiction is so lethal
because it tricks the brain into acting as if the drugs were necessary
for survival.

Over the years, chemical substitutes that mimic addictive drugs,
activating the reward circuitry and reducing cravings, have had the
most success in treating addiction. Methadone, a reddish liquid first
used as a maintenance treatment for heroin addicts in 1964, has long
been considered the gold standard. Chemically, it is not so different
from heroin. It binds to the same receptors, gradually stimulating
them. Patients say they experience a warm glow, though not the
euphoric daze of heroin, the feeling of being wrapped in God's warmest
blanket.

In its time, methadone was considered a breakthrough: It got people
off heroin, reduced fatal overdoses and slowed the spread of
infectious diseases through dirty needles. But it became clear that
methadone had its own problems. Like heroin, it was strongly
addictive. It was classified by the Drug Enforcement Administration as
a Schedule 2 drug, in the same category as cocaine and PCP. And by
law, it had to be distributed by special clinics that were so bathed
in stigma that several states banned them. Former Mayor Rudolph W.
Giuliani of New York declared five years ago, when he was in office,
that methadone programs encouraged people to trade one addiction for
another, and should be shut down.

Between 180,000 and 200,000 Americans are on methadone, said Dr. David
M. McDowell, director of a program at Columbia University that helps
people make the transition from methadone to buprenorphine, then
refers them to other doctors for private care. In New York, 36,000
people are on methadone.

"The most stigmatized thing in this world is methadone," said Dr.
Edwin A. Salsitz, director of Beth Israel Medical Center's methadone
program in New York. "There is nothing people try to hide more than
being on methadone. They don't want to be seen going into a clinic.
They won't tell anyone they're taking it."

Methadone's limitations prompted experts to look for medications that
were less likely to place recovering addicts in a stranglehold. What
they found was buprenorphine. Like methadone, it is a chemical
substitute for heroin. But it activates receptors so weakly that it
has a better safety profile and many users can be slowly weaned from
it, leaving them drug-free.

"Buprenorphine is the most important advance certainly in heroin and
opiate treatment if not all addiction treatments in the last 30
years," said Dr. Alan I. Leshner, a former director of the National
Institutes of Drug Abuse.

In the brain, buprenorphine pries heroin from opiate receptors, binds
tightly for two or three days, then produces just enough stimulation
to relieve withdrawal symptoms. It is not perfect by any means. One
drawback is that for some longtime heroin users, its effects are too
weak, and methadone ends up as their only alternative. But for those
who can take it, buprenorphine's effects last longer than methadone's,
experts say, which drives the likelihood of relapse down sharply.

"If you get stressed out and decide you want to get high, you can go
see your dealer but you're wasting your money because there's that
three-day safety cushion where buprenorphine is blocking the
receptors," Dr. McDowell said.

Last year, only 5 out of 43 patients at Dr. McDowell's center had
relapsed after their first six months on buprenorphine, an 88 percent
success rate; on methadone, treatment programs for most forms of drug
addiction have less than a 50 percent success rate after six months,
he said. In France, where buprenorphine has been on the market less
than 10 years, fatal overdoses from heroin and other opiates have
fallen almost 80 percent. "In the field of addiction treatment, those
figures are just unbelievable," he said.

Doctors in the United States wrote 80,000 prescriptions for
buprenorphine in 2003, a number that is expected to soar in the coming
years. Lured by the prospect of privacy, many heroin and opiate
abusers are seeking help for the first time. Others are switching from
methadone.

Dr. Chadd A. Herrmann, a psychiatrist in Manhattan, said he has
received about 20 telephone calls in the last three weeks from people
looking for buprenorphine. He had to turn them away, he said, because
he was still awaiting authorization to prescribe it. In New York,
doctors who want to prescribe buprenorphine are required to take an
eight-hour training course and then receive approval from the state.

Dr. Herrmann, whose practice is on Fifth Avenue, said many of the
people who called did so "because of my address." He added, "They make
it really clear that they don't want to be in a program or clinic in
some other part of the city."

Perhaps buprenorphine's biggest draw, said Roberta P. Sales, a nurse
coordinator at the Columbia program, is that it frees addicts from the
methadone clinic. With a prescription, they can get a month's supply
of the medication at the pharmacy. The cost is about $5 to $10 a day.

"How can you possibly work or go to school when the primary focus of
your day is going to a methadone program?" she said. "With
buprenorphine, I've had patients literally break down and cry because
they can travel to another state and see their family for the first
time in years."

For all its promise, buprenorphine, whose use is confined to opiates,
will help only a fraction of the Americans who abuse drugs.
Researchers say their focus now is on finding new treatments for a
wide variety of drugs. They hope to find medications that are not
simply chemical substitutes but eliminate dependence altogether. In
some laboratories, researchers are working on developing medications
that do away with the cravings that make abstinence from any drug a
struggle.

"It's never as simple as just washing the drug out of your body," said
Dr. Anna Rose Childress, a research associate professor of psychology
at the University of Pennsylvania medical school.

The shift toward treating cravings came largely from imaging studies.
Researchers found that when a recovering addict was shown slight cues
or reminders of an old drug habit - an antidrug advertisement, for
example, a cigarette or a syringe - it set off intense activity in the
brain's reward circuitry, and produced an urge to relapse.

"Often, this is what pulls people back in," Dr. Dackis
said.

Campral, the anticraving medication, made by Merck and approved for
alcoholism by the F.D.A. last week, appears to dampen that response by
elevating levels of GABA, the brain's major inhibitory
neurotransmitter. Dr. Childress believes that GABA helps rein in the
reward circuitry that drives people to seek drugs and other
pleasurable experiences. Campral has been used in Europe for several
years.

At least two other drugs that increase GABA, topiramate and baclofen,
seem to curb cravings for cocaine, heroin, cigarettes and alcohol. Dr.
Childress, who is involved in clinical trials of baclofen for cocaine,
said the medications may even help conquer compulsive behaviors like
pathological gambling and sexual compulsion. Scientists have also
found that the prescription medication modafinil, used for sleep
disorders, can blunt the euphoria of cocaine.

Still other scientists are trying to solve two problems common among
substance abusers: They often forget to take their medications, and
even those who stay in recovery end up "slipping" periodically.

Vaccines, some researchers believe, may provide answers to these
problems.

At Yale and Columbia, for example, researchers are testing a vaccine
that uses molecules of cocaine bound to harmless pathogens. When the
vaccine is injected into the body, the immune system responds by
producing antibodies to the cocaine and to the pathogen it is paired
with. After a handful of immunizations over the course of three
months, the user has enough antibodies to prevent at least three times
the typical dose of cocaine from reaching the brain.

"The people that make significant amounts of antibodies say that
cocaine isn't what it used to be, and the people who make the highest
levels of antibodies stop using it altogether," said Dr. Thomas
Kosten, a professor of psychiatry and medicine at the Yale medical
school.

In Australia, scientists are experimenting with a similar vaccine that
blocks nicotine.

It may be years, experts concede, before the promise of vaccines,
anticraving drugs and other new treatments can be fully realized. And
if the prospect of a world without drug addiction seems too good to be
true, it just might be. None of the drugs is a magic bullet.
Psychotherapy will still be needed to help addicts repair frayed
relationships and overcome psychological dependence. Moreover, an
addict who is determined to get high, experts say, can counteract even
the most effective medication - by not taking it.

"In the drug abuse field you have to be humble," said Dr. Margaret
Haney, a researcher at the New York State Psychiatric Institute who is
involved in clinical trials of the cocaine vaccine. "There is nothing
that is going to work for everyone, but we're just hoping to increase
the odds that someone will be able to stay clean and have just enough
time to get their lives back in order."