scans confirm hunch about methadone's effect
Those who pursue heroin's fleeting pleasures suffer long-term damage
that goes well beyond deteriorating mood and stability. As if the
excruciating addictive effects weren't bad enough, heroin also profoundly
disrupts essential physiologic systems regulated by the brainincluding
response to stress and pain, gastrointestinal and immune function
and control of reproductive hormones.
Heroin's temporary rush and its physical disruptions have something
in commonthey both can be traced to specific receptors in the
brain, the mu opioid receptors. The appealing sensation sought by
heroin users occurs when the drug, a short-acting opiate, binds to
Professor Mary Jeanne Kreek is head of the Laboratory
of Biology of Addictive Diseases.
Through animal and human studies, researchers have determined that
these same receptors normally interact with the body's own opioids
to help govern neuroendocrine function. When artificial opioids
bind to the receptors, the body's natural opioids are displaced
from the site and cannot carry out their usual role.
Because of heroin's short half-life, addicts must re-dose themselves
frequently to avoid painful withdrawal symptoms. This constant re-dosing
causes great fluctuations as the opiate bombards the receptors and
then quickly loses effect. During the short-acting, on-off cycles
of heroin addiction, the percentage of occupied mu opioid receptors
swings wildly between high and low, and the systems they regulate
move in and out of balance.
Heroin addicts had little hope of escaping these agonizing rhythms
until the advent of methadone maintenance therapy. The approach
was pioneered at Rockefeller in 1964 by Professor Emeritus Vincent
Dole, his wife and colleague Marie Nyswander, and Mary Jeanne Kreek,
then an assistant resident at New York Hospital. Since then, methadone
maintenance has proven to work remarkably well, and Kreek, now a
Rockefeller professor and head of the Laboratory of Biology of Addictive
Diseases, has remained a leading figure in addiction research.
A synthetic drug developed as a replacement for morphine, methadone,
which is a long-acting opioid in humans, relieves the craving for
heroin and negates its effects. It does this essentially by taking
heroin's place, binding to the same receptors. Unlike those of heroin,
the effects of methadone last 24 hours, so patients need only take
it once a day. And perhaps best of all, because it provides a stead-state
of opioid, methadone does not cause heroin's physiologic disturbances.
But if methadone relieves cravings by binding to the same receptors,
why doesn't it cause the same disruptions? Kreek and her colleagues
hypothesized that it was because methadone, in addition to having
slow onset of action and long-acting effects, mimics heroin's action
in the brain without occupying all the mu opioid receptors, leaving
enough of them free to perform their roles. This theory has been
difficult to prove conclusively, as researchers had no way of directly
observing the receptors being bound.
Recently, however, Kreek's laboratory got the chance to see opioid-receptor
binding occur in living brains. Through collaboration with the National
Institutes of Health (NIH) and the use of positron emission tomography
(PET), the researchers were able to map receptor binding, both in
healthy volunteers and in former heroin addicts who were in long-term
The researchers conducted PET scans on 28 subjects, mostly from
the New York City area, who were recruited through The Rockefeller
University Hospital. They included 14 healthy volunteers and 14
former heroin addicts who were long-term stabilized methadone-maintenance
patients (MTPs) at the Hospital. The scans were done at an NIH Clinical
Center in Bethesda, Md.
The scientists took images of the methadone-maintained patients
during 90-minute periods that began 22 hours after their last methadone
dose. (The delay between dosage and PET scan ensured that methadone
levelsand the amount of opioid bindingwould be stable
throughout the imaging session.) The patients were injected with
a synthetic tracing chemical called cyclofoxy, which binds to opioid
receptors and shows up on PET scans.
The PET scans focused on opioid-receptor binding in 13 different
brain regions, the first study to do so in young-to-middle-aged
patientsthe age range of most patients in addiction treatment.
(Previous multi-region studies on opioid receptors have been conducted
on elderly patients.) The cyclofoxy indicated the various binding
densities in the 13 regions.
In both groups, the study showed the highest binding in brain regions
that have been of specific interest for addiction and pain research.
The area with the most binding was the thalamus, where opioids are
known to play an enormous role in the modulation of pain. Other
densely bound regions included the amygdala, the insula and the
anterior cingulate cortex, which are involved in emotion, fear and
pleasure, and the caudate and putamen, which are involved in well-known
locomotor effects of commonly abused drugs.
"It was very fascinating to us because those included the very
areas we thought might be differentially regulated, if any would
be, since they are centrally involved in reinforcing and rewarding
properties of drugs of abuse," Kreek says.
Perhaps more important was that the PET scan results from the methadone-maintained
group confirmed what Kreek and others had hypothesized: Methadone
leaves a significant number of opioid receptors unoccupied, allowing
those regions of the brain to carry out normal physiological roles.
Although the MTPs, not surprisingly, showed less binding than the
normal volunteers did, the reduction was only 19 to 32 percent,
depending on the region. This means that methadone leaves a significant
percentage of receptors unbound.
"Through this look at the living brain, we've validated that in
methadone-maintained patients there is modest occupancy of the receptors
but still a lot of available receptors for normal cognition, normal
reproductive function and normal stress responsivity," Kreek says.
Results of the study were published in the December issue of the
Journal of Pharmacology and Experimental Therapeutics.
The modest occupancy may be the key to why methadone can have such
powerful effects against addiction without causing its own problems.
The bulk of evidence shows that methadone can be taken daily over
very long periodssometimes for decadeswithout apparent
harm to the body. For all that scientists have learned about the
brain since methadone treatment began, researchers have yet to come
up with a more effective treatment for heroin addiction.
"This study provides more evidence that methadone maintenance is
a safe, effective form of therapy over the long term," Kreek says.
"It is now our 36th anniversary of this therapy, and some of the
patients in the methadone program, initially started at The Rockefeller
University Hospital, have been in continuous treatment for the entire
period. The studies, dating all the way back to the original trio
of researchers, show that the treatment not only worked in the 1960s,
it works in 2000, and we expect it to keep working in 2001."
The research was supported in part by the National Institute
on Drug Abuse and the Center for Research Resources, both part of
the National Institutes of Health.