Functional MRI shows that placebo analgesia changes the actual pain experience

[Guest guest]

Rheumawire

Feb 26, 2004

Functional MRI shows that placebo analgesia changes the actual pain

experience

New York, NY - The controversy over whether placebo treatments produce

analgesia by changing sensory pain transmission, pain effect, or just by

the power of suggestion has been tilted in favor of functional changes

by work reported in the February 20, 2004 issue of Science [1].

Dr Tor D Wager(then at the University of Michigan, Ann Arbor;

now at Columbia University, New York, NY) and colleagues used functional

MRI (fMRI) to show that placebo responders have decreased brain activity

in pain-sensitive regions, including the thalamus, insula, and anterior

cingulate cortex (see figure). Placebo analgesia response was also

associated with increased activity in the prefrontal cortex during

anticipation of pain, an indication that placebos actually change the

experience of pain.

" There's been a great deal of controversy over whether placebos affect

the actual experience of pain or simply the tendency to report what you

expect to experience or what other people expect you to report. We found

that placebos decrease the brain's response to pain in areas that seem

to code for the magnitude of pain experience. This suggests that the

experience of pain really is altered, " Wager tells rheumawire.

The researchers used fMRI to test 2 hypotheses. The first was that if

placebo reduced the experience of pain, there should also be reduced

activity in pain-sensitive brain regions. This " pain matrix " includes

the thalamus, somatosensory cortex, insula, and anterior cingulate

cortex.

The second hypothesis was that placebo might work by creating

expectations for pain relief that then inhibit activity in

pain-processing regions. Chief among these are the prefrontal cortex

(PFC) and the dorsolateral aspect (DLPFC), which maintain internal

representations of goals and expectations and which modulate processing

in other brain areas.

Wager explained, " Stronger PFC activation during the anticipation of

pain should correlate with greater placebo-induced pain relief as

reported by participants and greater placebo-induced reductions in

neural activity within pain regions. "

The first hypothesis was tested in 24 participants who were scanned by

fMRI as they received painful or nonpainful electric shocks to the right

wrist. Subjects were told that they were participating in a study of

brain responses to a new analgesic cream (the " placebo " ). The method

allowed the investigators to distinguish the brain's response to pain

from its anticipation of pain.

Each subject went through 5 trials lasting 15 to 30 seconds, each of

which began with a 3-second warning cue that indicated whether the shock

would be intense or mild. After the shock, subjects rated its intensity

on a 10-point scale. Before the second trial, an investigator applied a

skin cream to the participant's right wrist. Half the participants were

told that this was an analgesic cream (the " placebo " ), the other half

that it was an ineffective cream needed as a control. After trials 2 and

3, the cream was removed and the same cream was reapplied, but

participants who had first had the placebo cream were told that this 1

was a control, and vice versa. The main outcome measures were

differences in reported pain ratings and in regional brain activity.

Wager found that the magnitude of reduction in reported pain correlated

with the magnitude of reduction in neural activity in pain-responsive

brain regions.

In the " anticipation " period before the pain stimulus, the patients who

expected to receive pain relief had increased activity in the DLPFC and

orbitofrontal cortex. The increased activity in the DLPFC correlated

with reduced activity in several pain-sensitive brain regions.

The second hypothesis was tested in 50 subjects using a design similar

to the first series of tests, except that there was a " manipulation

phase " to enhance participants' expectations of pain relief. In this

phase the pain in the stimulus to the " analgesic " -treated patch of skin

was surreptitiously reduced. Subjects were screened before fMRI

scanning, and 72% of participants had an average 22% decrease in

reported pain. These " placebo responders " were then studied with fMRI.

Again pain produced significant activation in the pain-sensitive brain

regions. When patients thought they were receiving an active analgesic,

both early changes and later changes in brain activity were observed,

but in different brain regions. Patients who expected pain relief also

had increased prefrontal-cortex and midbrain activity during the

" anticipation " phase.

The investigators concluded that these studies support the hypothesis

that placebo manipulations decrease neural responses in brain regions

that are pain sensitive and that the size of decrease in neural activity

parallels the reduction in reported pain. They comment, " These findings

provide strong refutation of the conjecture that placebo responses

reflect nothing more than report bias. "

Wager says that the anterior cingulate showed decreases early in pain,

perhaps related to how uncomfortable or aversive pain feels. " Changes in

the thalamus and insula happened later during pain and may reflect your

evaluation of how bad this experience is for you, " Wager says. In each

of these areas, the subjects with greater placebo decreases reported

greater pain relief.

" Another important aspect of the study is understanding the mechanisms

whereby belief is translated into relief, " Wager says. " We found that

anticipating pain with placebo produced increases in activity in the

dorsolateral prefrontal and orbitofrontal cortices, areas of the brain

related to the control of attention and linking stimuli with reward

value. These brain areas store signals related to expected value and

relevance and rules about how tasks should be performed. "

The investigators think expectations of pain relief are maintained and

pain signals are influenced in at least 2 ways. One is by increasing

activity in the periaqueductal gray, a region in the brainstem that

produces morphinelike chemicals that can block pain signals coming into

the brain. A second, which appears to produce larger effects, is by

directly modifying the activity in higher pain-processing regions of the

brain (the medial thalamus and anterior insula), which may be related to

tracking the emotional significance of pain.

" The study underscores the importance of conveying a sense of confidence

to patients. If they believe a treatment will work, it's more likely to

be effective. This isn't expected to be true for all diseases, but may

be particularly true in processes in which brain-body interactions may

play a role, as in rheumatoid arthritis, although the study doesn't

speak to this directly, " Wager says.

Janis

Source

1. Wager TD, Rilling JK, EE, et al. Placebo-induced changes in

FMRI in the anticipation and experience of pain. Science 2004 Feb 20;

303(5661):1162-7.

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