Brain scans confirm hunch about methadone's effectThose 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 brain—including 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 common—they 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 these receptors.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.
|Professor Mary Jeanne Kreek is head of the Laboratory of Biology of Addictive Diseases.|
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 methadone maintenance.
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 levels—and the amount of opioid binding—would 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 patients—the 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 periods—sometimes for decades—without 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.