CHAPTER 4
Pain and the Placebo Effect
It’s tempting to think that our senses provide us with an accurate representation
of the external and internal environment. We believe that our eyes pro -
ject into our brains a perfect three-dimensional video recording of the objects
and events around us. It’s easy to surmise that our ears detect and transmit all incoming
sound waves with sound-studio clarity, and that our mouths, noses, and
fingertips provide us with all the evidence we need to draw indisputable conclusions
about tastes, odors, and textures.
We are kidding ourselves. Our senses respond to only a fraction of what’s out
there, and they respond in ways so malleable and idiosyncratic as to call into
question the whole concept of truth. Consider the legendary unreliability of eyewitness
accounts. In a recent study, Canadian researchers showed a video clip of
a movie action sequence to eighty-eight undergraduates who then discussed what
they had seen either with one or with several of their peers. In the debriefing sessions,
a researcher, posing as a peer, deliberately introduced misinformation into
the discussion. Later, on true-false tests of facts about the movie scene, participants
in the one-on-one condition accepted the impostor’s false suggestions 68
percent of the time; participants in the larger groups were taken in 49 percent of
the time.Perhaps our eyes, ears, and memories can be fooled, you may think, but internal
pain is different. We know where we hurt, how much we hurt, and how
we feel when the pain increases, diminishes, or disappears. Pain is a very personal
and intimate sense, and there is no sidestepping it, denying it, or talking your
way out of it. You know when you hurt!
Or do you?
THE PLACEBO EFFECT
Let’s do a thought experiment. Round up three hundred harried commuters
with headaches—not hard to do on the New York subway any workday rush hour.
Of course, they are shouting and whining strident protests, which only worsen
their headaches, which is precisely what you want. You reassure them that you’ll
get their names mentioned in the New York Times in recognition of their public
service (you can’t afford to pay them), and that settles them down long enough
for you to herd them into three soundproof rooms, one hundred headaches per
room.
Now the fun begins. You do nothing with the first one hundred. They get to
glare at one another Big-Apple-style and ruminate on their throbbing temples.
You make an eloquent speech to the second group, informing them that they are
the lucky recipients of a newly developed and powerful painkilling miracle drug.
(It’s actually aspirin with codeine, a proven pain reliever.) Then you leave them,
too, alone with each other and their pain, contemplating their lawsuits against
you. You make the same speech to the third one hundred, but you are lying to
them. They think you are giving them a pain-relieving drug. In truth, they get a
sugar pill.
After a half hour, you ask your three hundred captives to report on their head -
aches. In the “do nothing” group, twenty say their headaches are gone. Eighty
are still suffering. In the second group, ninety report the complete disappearance
of pain; that drug is certainly a miracle potion, the people say, and they wonder
where they can purchase it. In the third group, the ones you deceived, forty-five
still have headaches, but fifty-five do not. That pill did the trick, they say, happily
reboarding the subway pain-free. Your experiment was a success and you are off
the hook, unless one of your subjects is a liability lawyer.
But forget the legal ramifications for now. Look at what the experiment revealed.
A sugar pill has no physiological action that will cure a headache, but
thirty-five of your headache-free subjects in the third group provide evidence to
the contrary. (Why thirty-five and not fifty-five? Because the results from the first
group, the “do nothing” group, show headache pain will cease in 20 percent of
your subjects after a half-hour regardless.) Thus, for 35 percent of the subjects
in our thought experiment, the sugar pill was just as much a miracle drug as
the painkiller the members of the “real drug” group received. This “cure” in the
absence of any truly therapeutic agent is the placebo effect, and it’s more than a
curiosity. It’s a direct result of brain action. But how?
Before we answer that question, we need to define precisely what the placebo
effect is. It is not spontaneous remission. That’s what the twenty people in the
first group (and presumably twenty more in each of the other two groups as well)
experienced. Some of us, no matter what the disease, get better for unknown reasons.
The disease process simply reverses itself without any intervention. Whether
remission is mere chance or the result of some self-healing process remains anybody’s
guess.
Neither is the placebo effect deception or self-delusion. The people whose
headaches disappear after ingestion of the sugar pill are not lying, cheating, simple-
minded, or insane. Their pain disappears—and not because they consciously
wish it to. In study after study, where both subjects and experimenters are “blind”
to the experimental conditions—that is, no one, including the researchers, knows
who is getting the placebo—measurable, clinically replicable improvements in
disease conditions occur in a sizable fraction of all cases.
Furthermore, the placebo effect is no small or insignificant statistical aberration.
Researchers at Brigham and Women’s Hospital in Boston performed some
mathematical magic to combine the results of nineteen separate studies (conducted
between 1970 and 2006) on patients with irritable bowel syndrome. Across
all studies, the placebo response averaged nearly 43 percent, ranging from a low
of 15 percent to a high of 72 percent. The longer the period of treatment and the
larger the number of physician visits, the greater the placebo effect.
Finally, the placebo effect is not restricted to subjective self-reports of pain,
mood, or attitude. Physical changes are real. Working under a grant from the
National Institutes of Health, a multistate team of researchers tested fifty-five
asthma patients who had recurrent mild to moderate symptoms. Patients were
randomly assigned either to treatment (salmeterol) or to placebo groups, and all
participants were blind to the test; neither the patients nor their doctors knew
who was getting the placebo and who was getting the drug. The researchers assessed
not the patients’ self-reports of symptoms, but the degree of constriction
in their bronchial tubes. A one-dose trial showed the placebo effect in more than
half the patients. A stringent two-dose trial narrowed the field to 18 percent of
subjects who were unequivocal placebo responders. Five of the subjects (9 percent)
were completed “cured” by the placebo treatment.
THE PLACEBO EFFECT IN THE BRAIN
The placebo effect is not deception, fluke, experimenter bias, or statistical
anomaly. It is, instead, a product of expectation. The human brain anticipates
outcomes, and anticipation produces those outcomes. The placebo effect is selffulfilling
prophecy, and it follows the patterns you’d predict if the brain were, indeed,
producing its own desired outcomes. For example, researchers have found
the following:
• Placebos follow the same dose-response curve as real medicines. Two pills
give more relief than one, and a larger capsule is better than a smaller one.
• Placebo injections do more than placebo pills.
• Substances that actually treat one condition but are used as a placebo for
another have a greater placebo effect that sugar pills.
• The greater the pain, the greater the placebo effect. It’s as if the more relief
we desire, the more we attain.
• You don’t have to be sick for a placebo to work. Placebo stimulants, placebo
tranquilizers, and even placebo alcohol produce predictable effects in
healthy subjects.
• Placebo effects can be localized. In one experiment, Italian researchers
injected capsaicin into the hands and feet of brave volunteers. Capsaicin
is a derivative of hot peppers; it produces a burning sensation. The wily
scientists then applied a cream to only one hand or foot and told their subjects
that the cream was a powerful local anesthetic. In truth, the cream
was an inactive placebo. Nevertheless, the subjects reported less or no
burning on the treated hand or foot, but the burning sensation was strong
elsewhere.As in all brain actions, the placebo effect is the product of chemical changes.
The first clues to the chemical basis of the placebo effect came in 1978, when
research on pain in the dentist’s office showed that the drug naloxone can block
placebo-induced pain relief.9 Naloxone is an opioid antagonist; it locks onto the
brain’s natural painkillers, the endorphins, and stops them from doing their job.
Numerous studies have supported the conclusion that endorphins in the brain
produce the placebo effect. In patients with chronic pain, for example, placebo
responders were found to have higher concentrations of endorphins in their
spinal fluid than placebo nonresponders.10 One clue that expectation triggers
the release of endorphins came from other studies of naloxone conducted the
1990s. Italian researchers reported that naloxone blocked the placebo effect produced
by strong expectation cues; but in the absence of expectation, the drug
had no effect.Some researchers and theorists debate whether expectation or conditioned
learning accounts for the placebo effect, but it’s not hard to construe conditioning
as a special case of expectation. Conditioned learning is the classic Pavlovian
response. When dogs were fed at the same time that a bell was rung, it wasn’t
long before the dogs started to salivate at the sound of the bell, although no food
was present. The neutral stimulus (the bell) became associated with the effectproducing
stimulus (the food). The same mechanism might explain some forms
of the placebo effect. If a pill or injection (neutral stimulus) has been associated
with a physiologically active drug (effect-producing stimulus) in the past, then
later the pill alone may produce the action without the drug. For example, your
body won’t make any more growth hormone just because your doctor tells you
it will. But if you take the drug sumatriptan, which actually does increase growth
hormone secretion, and later you take a placebo that you think is sumatriptan,
guess what? Your body will make more growth hormone when you take the
placebo drug, even if your doctor tells you it won’t.That is an example of the placebo
effect that involves neither pain nor the brain’s production of endorphins, but, if conditioning is considered a form of expectation, it makes the same point. Your brain will direct your body to act
as it’s expected to act—whether the expectation is consciously perceived or unconsciously
learned.
MAKING THE MOST OF THE PLACEBO EFFECT
At one time, researchers viewed the placebo effect as an impediment—a
statistical annoyance that got in the way of objectively evaluating the efficacy of
potentially legitimate therapies. That view has changed. The placebo effect
is today seen as an important part of the healing process. It’s been studied as a
treatment for Parkinson’s disease, depression, chronic pain, and more. For large
numbers of patients—the placebo responders—belief in the therapy will create
or enhance its effectiveness.
Placebo treatments for Parkinson’s disease offer a good example. Parkinson’s
is a decline in the brain’s ability to control movement. The disease causes a slow,
shuffling walk, stiff shoulders, and trembling. Parkinson’s symptoms result from
the death of neurons in several regions of the brain. The affected neurons normally
control motion by releasing the neurotransmitter dopamine. Cell death
means that people who have Parkinson’s have too little dopamine in their brains.
One recent study of placebo treatments used positron emission tomography
(PET) to measure the brain’s manufacture and release of dopamine. Predictably,
the brain produced more dopamine when patients were given a placebo and told
to expect an improvement in their motor performance.
In some respects, the placebo effect offers the best of all possible alternatives:
therapeutic effects without the risk of negative side effects. It does, however, have
its downside. Just as expectation can produce positive outcomes, it can also produce
negative ones. That’s the “nocebo” effect, named from the Latin for “I shall
harm.” A harmless—but dreaded or feared—treatment induces a new illness or
exacerbates an existing one. Practitioners of black magic and voodoo curses have
known that for centuries, but the nocebo effect is difficult to research for obvious
reasons. It’s unethical to threaten people with illness, but a few brave investigators
tried it before institutional review committees began to place stringent
constraints on research involving human and animal subjects. For example, in
1968, scientists asked forty nonasthmatic persons and forty asthmatics to inhale
water vapor purported to contain potent irritants and allergens. The nonasthmatics
had no reaction to the vapor, but nearly half of the asthmatics did. They
experienced a measurable narrowing of their airways. Twelve of them responded
with asthma attacks that were successfully treated with the same saline solution,
which they were led to believe contained an effective antiasthma drug.17
Doctors could do more with the placebo effect if they could understand why
it works for some people but not others. Part of the answer is—once again—
expectation. Jon-Kar Zubieta of the University of Michigan at Ann Arbor used
PET to study the brains of men who had jaw pain. Zubieta gave them a saline
solution that he told them might relieve their pain. Brain scans showed that their
brains produced more endorphins after they received the placebo. They also
produced endorphins in more regions of the brain. Those men who said ahead
of time that they expected the most relief had more endorphins than their more
skeptical peers. The endorphin difference was pronounced in the brain’s dorsolateral
prefrontal cortex, a brain region involved in paying attention and making
decisions.18 It’s as if the men made up their minds to get well and their brains
cooperated by forming and releasing the proper medication.
Brain researchers such as Zubieta are working to sort through the complexity
of the numerous brain regions and neurotransmitters that produce placebo
or nocebo results. Theirs is no easy task. The placebo effect is not a single phenomenon,
but the result of the complex interplay of anatomical, biochemical,
and psychological factors. The same can be said for all the senses, I suspect. We
see, hear, taste, touch, and smell pretty much what we expect to.
What Is Pain?
An estimated 50 million Americans experience persistent pain, often from
backache, headache, arthritis, or cancer. Like everything else in the brain,
pain is a matter of physics and chemistry. The response starts with stimulation
of nerve fibers called nociceptors. They lie in the skin, muscle, and
other body tissues. Their impulses carry messages to the thalamus and cerebral
cortex of the brain where pain signals are processed. Pain signals also
pass to other brain regions such as the rostral ventromedial medulla (RVM),
where the “volume” of the pain message can be turned up or turned down
through signals sent from the RVM to the spinal cord.Unlike the nerve endings that respond to light touch or pressure, nociceptors
ordinarily need a strong stimulus to begin firing. Inflamed or
injured tissues, however, release chemicals that make nociceptors more
sensitive so that a weaker stimulus causes them to fire. Unlike many other
kinds of receptors, which quit triggering a signal when stimulated for too
long, nociceptors become increasingly sensitive with continuing or repeated
stimulation.
All this action is under genetic control, and so is the experience of pain.
Researchers at the University of Michigan and the National Institutes of
Health have found that a variation in a single gene helps to explain why
some people can tolerate more pain than others can. The gene has two
forms called met and val. Both code for the enzyme COMT, which breaks
down the neurotransmitters dopamine and noradrenaline. (Neurotransmitters
are the chemicals that ferry an impulse from one neuron to the
next.) COMT removes neurotransmitter molecules from the space between
neurons when an impulse is finished.
However, because the genes met and val are different, they make the
enzyme in slightly different forms. People who have two copies of the met
form have a much greater response to pain than those who have two copies
of the val form. Those who have one copy of each form have pain tolerance
somewhere in between. The val form, it seems, makes an enzyme that
does its job efficiently and rapidly, reducing the experience of pain for its
lucky owner.
Placebos for Emotional Pain
Expectation is strong medicine for a variety of physical and emotional ills,
even our perceptions of horrific images and events. A research team led by
Predrag Petrovic of the Karolinska Institutet in Stockholm showed emotionally
loaded pictures, such as images of mutilated bodies, to fifteen
healthy, adult volunteers. On the first day of the two-day experiment, the
researchers gave the volunteers an antianxiety drug to dampen their subjects’
emotional response to the pictures. Then the scientists gave an antidote
to the drug and told the volunteers that the antidote would restore the
full intensity of their emotional reactions.
The next day, the subjects were told they would take the same drugs,
but they were deceived. They got nothing more than a placebo salt solution
when they viewed the pictures. The placebo reduced the subjects’ negative
reactions to the unpleasant pictures by an average of 29 percent.
Functional MRI scans of the volunteers’ brains showed that the placebo
reduced activity in the brain’s emotion-processing centers. The effect was
mathematically predictable; as brain activity diminished, so did the perception
of negative emotions in response to the pictures. The scans also
showed increased activity in the same brain regions known to respond with
the placebo effect in reducing the perception of pain. The effect was greatest
in those subjects who reported the largest effect from the real antianxiety
drug administered on the first day.
What’s the point of administering a real drug the first day and a placebo
the second? This experimental design treats the placebo effect as a case of
conditioned learning. If you’ve experienced a positive benefit from a treatment
in the past, your expectation of its benefit in the future is stronger, and
so is the placebo effect.
Life in Chronic Pain
People who suffer constant pain carry with them a load of other miseries:
depression, anxiety, sleep disturbances—even difficulty making decisions.
Dante Chialvo, a researcher at Northwestern University, has found a reason
why.
Chialvo’s research team used functional magnetic resonance imaging
(fMRI) to scan the brains of thirty adult volunteers. Half the volunteers had
chronic low-back pain. Half were pain-free. The subjects used a fingerspanning
device to rate continuously the height of a bar moving across a
computer screen.
In the pain-free group, activation of some parts of the cortex while performing
the task corresponded with deactivation of other parts—a state
Chialvo calls a “resting state network.” The chronic-pain subjects performed
as well on the task as their pain-free counterparts, but their brains operated
differently. One part of the network did not quiet down as it did in the painfree
subjects.14
A healthy, pain-free brain, Chialvo asserts, maintains a state of “cooperative
equilibrium.” When some regions are active, others quiet down. But
in people who experience chronic pain, many brain regions fail to deactivate.
A region of the frontal cortex associated with emotion “never shuts up,”
Chialvo says.
This constant firing of neurons could cause permanent damage. “This
continuous dysfunction in the equilibrium of the brain can change the
wiring forever,” Chialvo says. “It could be that pain produces depression
and the other reported abnormalities because it disturbs the balance of the
brain as a whole.”
Pain and the Placebo Effect
It’s tempting to think that our senses provide us with an accurate representation
of the external and internal environment. We believe that our eyes pro -
ject into our brains a perfect three-dimensional video recording of the objects
and events around us. It’s easy to surmise that our ears detect and transmit all incoming
sound waves with sound-studio clarity, and that our mouths, noses, and
fingertips provide us with all the evidence we need to draw indisputable conclusions
about tastes, odors, and textures.
We are kidding ourselves. Our senses respond to only a fraction of what’s out
there, and they respond in ways so malleable and idiosyncratic as to call into
question the whole concept of truth. Consider the legendary unreliability of eyewitness
accounts. In a recent study, Canadian researchers showed a video clip of
a movie action sequence to eighty-eight undergraduates who then discussed what
they had seen either with one or with several of their peers. In the debriefing sessions,
a researcher, posing as a peer, deliberately introduced misinformation into
the discussion. Later, on true-false tests of facts about the movie scene, participants
in the one-on-one condition accepted the impostor’s false suggestions 68
percent of the time; participants in the larger groups were taken in 49 percent of
the time.Perhaps our eyes, ears, and memories can be fooled, you may think, but internal
pain is different. We know where we hurt, how much we hurt, and how
we feel when the pain increases, diminishes, or disappears. Pain is a very personal
and intimate sense, and there is no sidestepping it, denying it, or talking your
way out of it. You know when you hurt!
Or do you?
THE PLACEBO EFFECT
Let’s do a thought experiment. Round up three hundred harried commuters
with headaches—not hard to do on the New York subway any workday rush hour.
Of course, they are shouting and whining strident protests, which only worsen
their headaches, which is precisely what you want. You reassure them that you’ll
get their names mentioned in the New York Times in recognition of their public
service (you can’t afford to pay them), and that settles them down long enough
for you to herd them into three soundproof rooms, one hundred headaches per
room.
Now the fun begins. You do nothing with the first one hundred. They get to
glare at one another Big-Apple-style and ruminate on their throbbing temples.
You make an eloquent speech to the second group, informing them that they are
the lucky recipients of a newly developed and powerful painkilling miracle drug.
(It’s actually aspirin with codeine, a proven pain reliever.) Then you leave them,
too, alone with each other and their pain, contemplating their lawsuits against
you. You make the same speech to the third one hundred, but you are lying to
them. They think you are giving them a pain-relieving drug. In truth, they get a
sugar pill.
After a half hour, you ask your three hundred captives to report on their head -
aches. In the “do nothing” group, twenty say their headaches are gone. Eighty
are still suffering. In the second group, ninety report the complete disappearance
of pain; that drug is certainly a miracle potion, the people say, and they wonder
where they can purchase it. In the third group, the ones you deceived, forty-five
still have headaches, but fifty-five do not. That pill did the trick, they say, happily
reboarding the subway pain-free. Your experiment was a success and you are off
the hook, unless one of your subjects is a liability lawyer.
But forget the legal ramifications for now. Look at what the experiment revealed.
A sugar pill has no physiological action that will cure a headache, but
thirty-five of your headache-free subjects in the third group provide evidence to
the contrary. (Why thirty-five and not fifty-five? Because the results from the first
group, the “do nothing” group, show headache pain will cease in 20 percent of
your subjects after a half-hour regardless.) Thus, for 35 percent of the subjects
in our thought experiment, the sugar pill was just as much a miracle drug as
the painkiller the members of the “real drug” group received. This “cure” in the
absence of any truly therapeutic agent is the placebo effect, and it’s more than a
curiosity. It’s a direct result of brain action. But how?
Before we answer that question, we need to define precisely what the placebo
effect is. It is not spontaneous remission. That’s what the twenty people in the
first group (and presumably twenty more in each of the other two groups as well)
experienced. Some of us, no matter what the disease, get better for unknown reasons.
The disease process simply reverses itself without any intervention. Whether
remission is mere chance or the result of some self-healing process remains anybody’s
guess.
Neither is the placebo effect deception or self-delusion. The people whose
headaches disappear after ingestion of the sugar pill are not lying, cheating, simple-
minded, or insane. Their pain disappears—and not because they consciously
wish it to. In study after study, where both subjects and experimenters are “blind”
to the experimental conditions—that is, no one, including the researchers, knows
who is getting the placebo—measurable, clinically replicable improvements in
disease conditions occur in a sizable fraction of all cases.
Furthermore, the placebo effect is no small or insignificant statistical aberration.
Researchers at Brigham and Women’s Hospital in Boston performed some
mathematical magic to combine the results of nineteen separate studies (conducted
between 1970 and 2006) on patients with irritable bowel syndrome. Across
all studies, the placebo response averaged nearly 43 percent, ranging from a low
of 15 percent to a high of 72 percent. The longer the period of treatment and the
larger the number of physician visits, the greater the placebo effect.
Finally, the placebo effect is not restricted to subjective self-reports of pain,
mood, or attitude. Physical changes are real. Working under a grant from the
National Institutes of Health, a multistate team of researchers tested fifty-five
asthma patients who had recurrent mild to moderate symptoms. Patients were
randomly assigned either to treatment (salmeterol) or to placebo groups, and all
participants were blind to the test; neither the patients nor their doctors knew
who was getting the placebo and who was getting the drug. The researchers assessed
not the patients’ self-reports of symptoms, but the degree of constriction
in their bronchial tubes. A one-dose trial showed the placebo effect in more than
half the patients. A stringent two-dose trial narrowed the field to 18 percent of
subjects who were unequivocal placebo responders. Five of the subjects (9 percent)
were completed “cured” by the placebo treatment.
THE PLACEBO EFFECT IN THE BRAIN
The placebo effect is not deception, fluke, experimenter bias, or statistical
anomaly. It is, instead, a product of expectation. The human brain anticipates
outcomes, and anticipation produces those outcomes. The placebo effect is selffulfilling
prophecy, and it follows the patterns you’d predict if the brain were, indeed,
producing its own desired outcomes. For example, researchers have found
the following:
• Placebos follow the same dose-response curve as real medicines. Two pills
give more relief than one, and a larger capsule is better than a smaller one.
• Placebo injections do more than placebo pills.
• Substances that actually treat one condition but are used as a placebo for
another have a greater placebo effect that sugar pills.
• The greater the pain, the greater the placebo effect. It’s as if the more relief
we desire, the more we attain.
• You don’t have to be sick for a placebo to work. Placebo stimulants, placebo
tranquilizers, and even placebo alcohol produce predictable effects in
healthy subjects.
• Placebo effects can be localized. In one experiment, Italian researchers
injected capsaicin into the hands and feet of brave volunteers. Capsaicin
is a derivative of hot peppers; it produces a burning sensation. The wily
scientists then applied a cream to only one hand or foot and told their subjects
that the cream was a powerful local anesthetic. In truth, the cream
was an inactive placebo. Nevertheless, the subjects reported less or no
burning on the treated hand or foot, but the burning sensation was strong
elsewhere.As in all brain actions, the placebo effect is the product of chemical changes.
The first clues to the chemical basis of the placebo effect came in 1978, when
research on pain in the dentist’s office showed that the drug naloxone can block
placebo-induced pain relief.9 Naloxone is an opioid antagonist; it locks onto the
brain’s natural painkillers, the endorphins, and stops them from doing their job.
Numerous studies have supported the conclusion that endorphins in the brain
produce the placebo effect. In patients with chronic pain, for example, placebo
responders were found to have higher concentrations of endorphins in their
spinal fluid than placebo nonresponders.10 One clue that expectation triggers
the release of endorphins came from other studies of naloxone conducted the
1990s. Italian researchers reported that naloxone blocked the placebo effect produced
by strong expectation cues; but in the absence of expectation, the drug
had no effect.Some researchers and theorists debate whether expectation or conditioned
learning accounts for the placebo effect, but it’s not hard to construe conditioning
as a special case of expectation. Conditioned learning is the classic Pavlovian
response. When dogs were fed at the same time that a bell was rung, it wasn’t
long before the dogs started to salivate at the sound of the bell, although no food
was present. The neutral stimulus (the bell) became associated with the effectproducing
stimulus (the food). The same mechanism might explain some forms
of the placebo effect. If a pill or injection (neutral stimulus) has been associated
with a physiologically active drug (effect-producing stimulus) in the past, then
later the pill alone may produce the action without the drug. For example, your
body won’t make any more growth hormone just because your doctor tells you
it will. But if you take the drug sumatriptan, which actually does increase growth
hormone secretion, and later you take a placebo that you think is sumatriptan,
guess what? Your body will make more growth hormone when you take the
placebo drug, even if your doctor tells you it won’t.That is an example of the placebo
effect that involves neither pain nor the brain’s production of endorphins, but, if conditioning is considered a form of expectation, it makes the same point. Your brain will direct your body to act
as it’s expected to act—whether the expectation is consciously perceived or unconsciously
learned.
MAKING THE MOST OF THE PLACEBO EFFECT
At one time, researchers viewed the placebo effect as an impediment—a
statistical annoyance that got in the way of objectively evaluating the efficacy of
potentially legitimate therapies. That view has changed. The placebo effect
is today seen as an important part of the healing process. It’s been studied as a
treatment for Parkinson’s disease, depression, chronic pain, and more. For large
numbers of patients—the placebo responders—belief in the therapy will create
or enhance its effectiveness.
Placebo treatments for Parkinson’s disease offer a good example. Parkinson’s
is a decline in the brain’s ability to control movement. The disease causes a slow,
shuffling walk, stiff shoulders, and trembling. Parkinson’s symptoms result from
the death of neurons in several regions of the brain. The affected neurons normally
control motion by releasing the neurotransmitter dopamine. Cell death
means that people who have Parkinson’s have too little dopamine in their brains.
One recent study of placebo treatments used positron emission tomography
(PET) to measure the brain’s manufacture and release of dopamine. Predictably,
the brain produced more dopamine when patients were given a placebo and told
to expect an improvement in their motor performance.
In some respects, the placebo effect offers the best of all possible alternatives:
therapeutic effects without the risk of negative side effects. It does, however, have
its downside. Just as expectation can produce positive outcomes, it can also produce
negative ones. That’s the “nocebo” effect, named from the Latin for “I shall
harm.” A harmless—but dreaded or feared—treatment induces a new illness or
exacerbates an existing one. Practitioners of black magic and voodoo curses have
known that for centuries, but the nocebo effect is difficult to research for obvious
reasons. It’s unethical to threaten people with illness, but a few brave investigators
tried it before institutional review committees began to place stringent
constraints on research involving human and animal subjects. For example, in
1968, scientists asked forty nonasthmatic persons and forty asthmatics to inhale
water vapor purported to contain potent irritants and allergens. The nonasthmatics
had no reaction to the vapor, but nearly half of the asthmatics did. They
experienced a measurable narrowing of their airways. Twelve of them responded
with asthma attacks that were successfully treated with the same saline solution,
which they were led to believe contained an effective antiasthma drug.17
Doctors could do more with the placebo effect if they could understand why
it works for some people but not others. Part of the answer is—once again—
expectation. Jon-Kar Zubieta of the University of Michigan at Ann Arbor used
PET to study the brains of men who had jaw pain. Zubieta gave them a saline
solution that he told them might relieve their pain. Brain scans showed that their
brains produced more endorphins after they received the placebo. They also
produced endorphins in more regions of the brain. Those men who said ahead
of time that they expected the most relief had more endorphins than their more
skeptical peers. The endorphin difference was pronounced in the brain’s dorsolateral
prefrontal cortex, a brain region involved in paying attention and making
decisions.18 It’s as if the men made up their minds to get well and their brains
cooperated by forming and releasing the proper medication.
Brain researchers such as Zubieta are working to sort through the complexity
of the numerous brain regions and neurotransmitters that produce placebo
or nocebo results. Theirs is no easy task. The placebo effect is not a single phenomenon,
but the result of the complex interplay of anatomical, biochemical,
and psychological factors. The same can be said for all the senses, I suspect. We
see, hear, taste, touch, and smell pretty much what we expect to.
What Is Pain?
An estimated 50 million Americans experience persistent pain, often from
backache, headache, arthritis, or cancer. Like everything else in the brain,
pain is a matter of physics and chemistry. The response starts with stimulation
of nerve fibers called nociceptors. They lie in the skin, muscle, and
other body tissues. Their impulses carry messages to the thalamus and cerebral
cortex of the brain where pain signals are processed. Pain signals also
pass to other brain regions such as the rostral ventromedial medulla (RVM),
where the “volume” of the pain message can be turned up or turned down
through signals sent from the RVM to the spinal cord.Unlike the nerve endings that respond to light touch or pressure, nociceptors
ordinarily need a strong stimulus to begin firing. Inflamed or
injured tissues, however, release chemicals that make nociceptors more
sensitive so that a weaker stimulus causes them to fire. Unlike many other
kinds of receptors, which quit triggering a signal when stimulated for too
long, nociceptors become increasingly sensitive with continuing or repeated
stimulation.
All this action is under genetic control, and so is the experience of pain.
Researchers at the University of Michigan and the National Institutes of
Health have found that a variation in a single gene helps to explain why
some people can tolerate more pain than others can. The gene has two
forms called met and val. Both code for the enzyme COMT, which breaks
down the neurotransmitters dopamine and noradrenaline. (Neurotransmitters
are the chemicals that ferry an impulse from one neuron to the
next.) COMT removes neurotransmitter molecules from the space between
neurons when an impulse is finished.
However, because the genes met and val are different, they make the
enzyme in slightly different forms. People who have two copies of the met
form have a much greater response to pain than those who have two copies
of the val form. Those who have one copy of each form have pain tolerance
somewhere in between. The val form, it seems, makes an enzyme that
does its job efficiently and rapidly, reducing the experience of pain for its
lucky owner.
Placebos for Emotional Pain
Expectation is strong medicine for a variety of physical and emotional ills,
even our perceptions of horrific images and events. A research team led by
Predrag Petrovic of the Karolinska Institutet in Stockholm showed emotionally
loaded pictures, such as images of mutilated bodies, to fifteen
healthy, adult volunteers. On the first day of the two-day experiment, the
researchers gave the volunteers an antianxiety drug to dampen their subjects’
emotional response to the pictures. Then the scientists gave an antidote
to the drug and told the volunteers that the antidote would restore the
full intensity of their emotional reactions.
The next day, the subjects were told they would take the same drugs,
but they were deceived. They got nothing more than a placebo salt solution
when they viewed the pictures. The placebo reduced the subjects’ negative
reactions to the unpleasant pictures by an average of 29 percent.
Functional MRI scans of the volunteers’ brains showed that the placebo
reduced activity in the brain’s emotion-processing centers. The effect was
mathematically predictable; as brain activity diminished, so did the perception
of negative emotions in response to the pictures. The scans also
showed increased activity in the same brain regions known to respond with
the placebo effect in reducing the perception of pain. The effect was greatest
in those subjects who reported the largest effect from the real antianxiety
drug administered on the first day.
What’s the point of administering a real drug the first day and a placebo
the second? This experimental design treats the placebo effect as a case of
conditioned learning. If you’ve experienced a positive benefit from a treatment
in the past, your expectation of its benefit in the future is stronger, and
so is the placebo effect.
Life in Chronic Pain
People who suffer constant pain carry with them a load of other miseries:
depression, anxiety, sleep disturbances—even difficulty making decisions.
Dante Chialvo, a researcher at Northwestern University, has found a reason
why.
Chialvo’s research team used functional magnetic resonance imaging
(fMRI) to scan the brains of thirty adult volunteers. Half the volunteers had
chronic low-back pain. Half were pain-free. The subjects used a fingerspanning
device to rate continuously the height of a bar moving across a
computer screen.
In the pain-free group, activation of some parts of the cortex while performing
the task corresponded with deactivation of other parts—a state
Chialvo calls a “resting state network.” The chronic-pain subjects performed
as well on the task as their pain-free counterparts, but their brains operated
differently. One part of the network did not quiet down as it did in the painfree
subjects.14
A healthy, pain-free brain, Chialvo asserts, maintains a state of “cooperative
equilibrium.” When some regions are active, others quiet down. But
in people who experience chronic pain, many brain regions fail to deactivate.
A region of the frontal cortex associated with emotion “never shuts up,”
Chialvo says.
This constant firing of neurons could cause permanent damage. “This
continuous dysfunction in the equilibrium of the brain can change the
wiring forever,” Chialvo says. “It could be that pain produces depression
and the other reported abnormalities because it disturbs the balance of the
brain as a whole.”
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