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zenith

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Mar 10 10 8:40 AM

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VOLUME 12, NUMBER 12 • DECEMBER 15, 2000

Brain 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 brain—including response to stress and pain, gastrointestinal and immune function and control of reproductive hormones.
Professor Mary Jeanne Kreek is head of the Laboratory of Biology of Addictive Diseases.
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.
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.

 

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easc

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#1 [url]

May 21 11 7:14 PM


Wow! What a great article! This is such key information to my overall treatment plans and goals. This is one of the biggest questions I have carried around with me since I began Methadone Maint. treatment. While it has been proven that partial agonist medications such as Subutex and Suboxone do not occupy a significant percentage of the brain's opioid receptors, it has never truly been scientifically proven thus for methadone. This really is great news and a load off my mind!

  Thank you for this article!

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cynditraber

Posts: 10 Member Since:04/29/13

#3 [url]

Jul 7 13 8:21 PM

I don't know who this is going to...I was wondering about getting off methadone? I've reduced from 70 to 23 and I'm feeling funny...if you know what I mean. Are more of my receptors open the lower I go? How fast or slow should I go? anyway..oh I see I'm writing to the other methadone people.... HI everybody!! I really want to e-mail this lady or others who know about detox.

hello..

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sapphire76

Posts: 3,678 Member Since:02/22/10

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Jul 8 13 3:42 AM

    I don't know who this is going to...I was wondering about getting off methadone? I've reduced from 70 to 23 and I'm feeling funny...if you know what I mean. Are more of my receptors open the lower I go? How fast or slow should I go? anyway..oh I see I'm writing to the other methadone people.... HI everybody!! I really want to e-mail this lady or others who know about detox. 

-cynditraber


No. the lower the dose does not leave more receptors open.

You should go as fast or slow as your body will let you. If you are going to quick, your body will let you know, so listen to it!!

Out of interest, why are you getting of methadone?

I would say that if you are already "feeling funny", as you say, things are only going to get worse the lower you go in dose.

How long have you been in treatment for. The recommended time is at least 2 years, and that's before starting to taper.
 

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janewatts63

Posts: 10 Member Since:07/08/13

#5 [url]

Jul 8 13 2:19 PM

Very informative!  Now, if those against MMT would a.) Read this article and b.) Believe what it says!  Tall order since the naysayers usually don't try to educate themselves.  I have often wondered why methadone works without causing more problems.  Also, sounds like the long-term effects are virtually nonexistent.

Jane

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sapphire76

Posts: 3,678 Member Since:02/22/10

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#6 [url]

Jul 9 13 5:14 AM

LOL Jane, you can say anything about positive about methadone, but those determined naysayers have it ingrained so far into them that methadone is "bad", that I think they are too proud to even admit that they might have been wrong, and that methadone is actually a very effective treatment that saves peoples' lives.

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zac talbott

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Aug 26 13 4:40 PM

Very informative!  Now, if those against MMT would a.) Read this article and b.) Believe what it says!  Tall order since the naysayers usually don't try to educate themselves.  I have often wondered why methadone works without causing more problems.  Also, sounds like the long-term effects are virtually nonexistent.

-janewatts63


You're so right @janewatts63... I have often been "dumbfounded" myself that there is sooo much evidence & science (almost 50 years worth of research and data!!) about the efficacy of methadone in treating addiction yet so many myths and misconceptions persist! It's crazy. But I think you hit the nail on the head when you said, "naysayers usually don't try to educate themselves!"



zt

Zac Talbott | Director & Patient Advocate

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Visit NAMA Recovery's We Speak Methadone (and buprenorphine) Forums
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zac talbott

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#9 [url]

Oct 17 13 9:44 PM

Just noticed this thread while browsing and it made me think of an opportunity at AATOD for any patients that are going... One that you'll NOT want to miss! Dr. Kreek - the only one of the 3 "originals" of Dole/Nyswander/Kreek that is still alive - is giving a session at AATOD at 4pm on Mon. 11/11 "50 Year Follow-up of Methadone Treatment for Opioid Addiction" that provides a historical overview of the evolution of methadone treatment from the work of Dole, Nyswander & Kreek (herself) through the expansion of MMT nationally and internationally... treatment in jails & prisons, the development and disappearance of LAAM, and the growing use of buprenorphine and Vivitrol.... This is one where there is a rare opportunity to hear it all from the "horse's mouth," so to speak. If I am able to video any of the sessions - even just sneaking with my mobile (lol) - THIS is one I am going to try to get so I can share it with folks that weren't able to attend. This could very well be a once in a lifetime opportunity, ya know? Probably the one thing I'm more excited about than anything else at the Conference this year - I bet it will be PACKED.

Zac Talbott | Director & Patient Advocate

Together we can make a difference!

Visit NAMA Recovery's We Speak Methadone (and buprenorphine) Forums
and/or the Methadone & Buprenorphine Discussion group on Facebook

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HenryHenry

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Posts: 34 Member Since:11/13/14

#12 [url]

Nov 17 14 3:00 AM

very informative! it's a great thing i read it :)

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