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Placebo Effect
Pain Really Does Go Away When We Think It Will
At least it did in test of young men; no senior
citizens were tested
Aug. 26, 2005 – Mind over matter – it has long been
a subject of wonder and debate. The “placebo effect” – where persons
given a placebo, particularly for pain relief, but think it is real and
their pain goes away - has been a part of this debate. Now scientists
say it works. Just thinking that a medicine will relieve pain is enough
to make it happen. It is, however, no answer to the mind-over-matter
debate, because in this case it is actually “matter” that is making the
difference.
University of Michigan researchers have proven that
just thinking a medicine will cure pain prompts the brain to release its
own natural painkillers, and soothe painful sensations.
This, they say, is first direct evidence that the
brain’s own pain-fighting chemicals, called endorphins, play a role in
the phenomenon known as the placebo effect — and that this response
really does correspond with a reduction in feelings of pain.
Previous studies at U-M and elsewhere have shown
that the brain reacts physically when a person is given a sham pain
treatment, which they believe will help them.
But the new study is the first to pinpoint a
specific brain chemistry mechanism for a pain-related placebo effect. It
may help explain why so many people say they get relief from therapies
and remedies with no actual physical benefit. And, it may lead to better
use of cognitive, or psychological, therapy for people with chronic
pain.
The results will be published in the August 24
issue of the Journal of Neuroscience by a team from the U-M Molecular
and Behavioral Neurosciences Institute (MBNI). The research was funded
by the National Institutes of Health.
“This deals another serious blow to the idea that
the placebo effect is a purely psychological, not physical, phenomenon,”
says lead author Jon-Kar Zubieta, M.D., Ph.D., associate professor of
psychiatry and radiology at the U-M Medical School and associate
research scientist at MBNI. “We were able to see that the endorphin
system was activated in pain-related areas of the brain, and that
activity increased when someone was told they were receiving a medicine
to ease their pain. They then reported feeling less pain. The mind-body
connection is quite clear.”
The findings are based on sophisticated brain scans
from 14 young healthy men who agreed to allow researchers to inject
their jaw muscles with a concentrated salt water solution to cause pain.
The injection was made while they were having their brains scanned by a
positron emission tomography (PET) scanner. During one scan, they were
told they would receive a medicine (in fact, a placebo) that might
relieve pain.
Every 15 seconds during the scans, they were asked
to rate the intensity of their pain sensations on a scale of 0 to 100,
and they gave more detailed first-person ratings after the experiment.
The researchers correlated the participants’ ratings with their PET scan
images, which were made using a technique that reveals the activity of
the brain’s natural painkilling endorphin chemicals, also called
endogenous opioids.
Endogenous opioids bind to brain cell receptors
called mu-opioid receptors, and stop the transmission of pain signals
from one nerve cell to the next. Besides the brain’s own chemicals,
drugs such as heroin, morphine, methadone and anesthetics also act on
the mu opioid receptor system to reduce pain.
Because the endorphin system naturally tries to
quell pain whenever it occurs, the researchers slowly increased the
amount of concentrated salt water being injected in the muscle as the
scans continued, in order to keep the participants’ rating of their pain
within the same point range throughout the experiment. The placebo, a
small amount of hydrating solution, was then given intravenously every
four minutes.
As the researchers alerted participants that the
placebo was coming, and injected the placebo dose, the amount of
additional concentrated salt water needed to maintain participants’ pain
over time increased — indicating a reduction in pain sensitivity that
the subjects were not aware of. In other words, thinking they were
getting a pain drug actually allowed the participants to tolerate even
more pain-inducing concentrated salt water than before.
After each scan, the researchers asked the
participants more questions about their mood, emotions and other aspects
of how they felt during the scans. There were significant differences
between post-scan ratings given by participants after the scan in which
they received the placebo, and after the scan during which they received
the jaw injection alone.
Nine of the participants were classified as “high
placebo responders” because they had more than a 20 percent difference
between pain and placebo scans in their average pain ratings per volume
of salt water infused — in other words, the placebo effect was strong.
The other five were classified as “low placebo responders.”
These subjective ratings are consistent with
previous findings, Zubieta notes. But the simultaneous imaging of the
participants’ endogenous pain-reducing opioid systems sheds new light on
why the placebo effect occurs.
The imaging method used in the study involves tiny
doses of a medicine called carfentanil that is attached to a short-lived
radioactive form of carbon, which releases subatomic particles known as
positrons. These positrons are detected with the PET scanner, which acts
like a photographic camera to capture those particles. It then
determines exactly which part of the brain they originated from, and how
many of them are coming from each brain region. The researchers also
made MRI scans of the participants’ brains, which they cross-registered
with the PET scans to give accurate information on exactly which brain
regions were active.
Because carfentanil competes with the brain’s
natural endogenous opioid painkillers for space on nerve cell receptors,
the PET scans can be used to see how active the opioid system and
mu-opioid receptors are. The stronger the positron signal from a
particular brain region, the less active the mu opioid system, and vice
versa.
All of the participants showed an increase in the
activation of their mu opioid endorphin system after they were told that
the “medicine” was coming and the placebo was given. The most pronounced
differences were seen in four areas of the brain known to be involved in
complex responses to, and processing of, pain: the left dorsolateral
prefrontal cortex, the pregenual rostral right anterior cingulate, the
right anterior insular cortex and the left nucleus accumbens.
When the researchers correlated the mu opioid
activity changes with the participants’ own ratings of their pain and
emotions, they also observed that the placebo-induced activation of the
opioid system was correlated with various elements of the experience of
pain.
For example, activity in the dorsolateral
prefrontal cortex was associated with the expectation of pain relief
reported by the volunteers. In other areas, that activation was
associated with relief of the intensity of pain, how unpleasant it was,
or even how the individuals felt emotionally during the pain experience.
Because the new study was done only in healthy men
between the ages of 20 and 30, further research will be needed to
determine whether the effect occurs in women, senior citizens and in
people with various illnesses. The power of placebos to ease pain
symptoms has been well-documented in many groups of subjects and
illnesses, but the researchers started with healthy young males to rule
out the impact of chronic pain, mood disorders and hormone variations,
which can also affect the endorphin system.
In addition to Zubieta, the research team included
MBNI members Joshua Bueller, Lisa Jackson, David Scott and Janyun Xu;
radiology professor Robert Koeppe, Ph.D.; Thomas Nichols, Ph.D., an
assistant professor of biostatistics in the U-M School of Public Health;
and Christian Stohler, formerly of the U-M School of Dentistry and now
at the University of Maryland School of Dentistry.
Reference: The Journal of Neuroscience, August 24,
2005, Vol. 25, No. 34
For more on the story with photos and charts –
Click Here
To learn more about other U-M research -
Click Here
For more on pain and the mu opioid system, read
these press releases:
http://www.med.umich.edu/opm/newspage/2003/paingene.htm
http://www.med.umich.edu/opm/newspage/2003/painbrain.htm
http://www.med.umich.edu/opm/newspage/2001/brainpain.htm
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