Just anticipating that a medication will bring pain relief can trigger the
brain's endorphin system, dispatching endogenous opioids to specific pain
centers in the brain. The intensity of pain reduction, both sensory and
affective, is measurable and gradual, and is not an on-off phenomenon.
These findings were reported by a research team headed by Jon-Kar Zubieta,
M.D., Ph.D., an associate professor of psychiatry and radiology at the
University of Michigan Medical School and an associate research scientist at
the school's Molecular and Behavioral Sciences Institute. The group has spent
several years developing brain-imaging techniques that keep tabs on the
brain's natural painkillers in action. Currently their work is focused on the
function of the μ-opioid system, one of the principal systems involved in
the modulation of pain, stress responses, and stress-induced
The brain at left shows areas of a subject's brain that were activated
while experiencing pain. The brain at right shows areas activated after the
subject was given a placebo while experiencing pain.
University of Michigan
In the μ-opioid system endogenous opioids, or endorphins, dock at
pain-receptor sites on the surface of brain cells to block impulse
transmission between cells.
The latest report of the team's work, which appeared in the August 24
Journal of Neuroscience, is believed to present the first direct
evidence that endorphins are closely associated with the placebo effect.
"This deals another serious blow to the idea that the placebo is a
purely psychological, not a physical, phenomenon," Zubieta said."
We were able to see that the endorphin system was activated in
pain-related areas of the brain, and that activity increased when [subjects
were] told they were receiving a medicine to ease their pain. They then
reported feeling less pain. The mind-body connection is quite
The Michigan group used positron emission tomography (PET) to follow the
response of the μ-opioid system and relate its function to subjective
reports from 14 young male volunteers during a sustained pain challenge.
Before being scanned, subjects were injected with radioactively tagged
carfentanil, a molecule that binds only to μ-opioid receptors and releases
positrons. Since carfentanil competes with the brain's natural endogenous
opioid painkillers for space on nerve-cell receptors, PET scans reveal the
activity level of the opioid system and μ-opioid receptors. Magnetic
resonance imaging (MRI) scans of the subjects' brains were cross-registered
with PET scans to give accurate information on exactly which brain regions
were active during the experiment.
In a blind, randomized, and counter-balanced-designed trial, all subjects
received two injections: one with salt solution, the other a placebo. During
one scan they were told they would receive a medicine, which was actually a
small amount of hydrating solution, that might relieve pain. The pain
challenge consisted of 1.5 ml of 5 percent hypertonic saline injected into the
relaxed masseter muscle for 40 minutes, long enough to establish the brain
conditions and emotions closely related to those seen with chronic pain
conditions like temperomandibular joint disorder.
While being scanned, every 15 seconds subjects rated the intensity of their
pain sensations on a scale of 0 to 100 on a computer system. The same computer
system controlled the intensity of the pain stimulus so that each subject's
rating would be about the same throughout the experiment. This allowed the
researchers to compare the response of the brain's antipain system across
individual subjects and correlate the subjects' ratings with their PET
As the researchers alerted the subjects that the placebo was coming and
injected it, the additional volume of concentrated saline needed to maintain
their pain over time increased, indicating a reduction in pain sensitivity of
which the subjects were not aware. Merely imagining they were getting an
analgesic helped the young men tolerate even more pain-inducing saline than
There were significant differences between the subjects' ratings after the
scan during which they received the placebo and after the scan during which
they received the saline injection alone. Nine subjects 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 saline infused. The other five were classified as "low placebo
"These subjective ratings are consistent with previous
findings," Zubieta said, "but the simultaneous imaging of the
subjects' endogenous pain-reducing opioid systems sheds new light on why the
placebo effect occurs."
The results showed that opioids migrated to specific pain centers in the
brain. All of the subjects had an increase in the activation of theirμ
-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
When the researchers correlated the μ-opioid activity changes with the
subjects' 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 subjects. 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 study involved only healthy men between the ages of 20 and 30,
further research is needed to determine whether the effect occurs in women and
in people with various illnesses. In addition, the study only addressed the
functions of the μ-opioid system, leaving open the question whether other
opioid receptor neurotransmitter mechanisms may also be involved in the
Psychiatric News asked Zubieta whether some people respond better
to placebos simply because they believe in promised pain relief more than
"Not really," he said. "Subsequent analyses have shown
that expectations were not as important as the experience of pain
itself—creating a `need' for a placebo effect." A paper on this
aspect of the study has been accepted for publication.
The study was supported by the National Institutes of Health.
An abstract of "Placebo Effects Mediated by Endogenous Opioid
Activity on μ-Opioid Receptors" is posted at<www.jneurosci.org/cgi/content/abstract/25/34/7754?>.
More information about pain and the μ-opioid system is posted at<www.med.umich.edu/opm/newspage/2003/paingene.htm>.▪