From childhood to adulthood, males
and females differ in their thresholds of pain: women tend to
experience more pain that they perceive as more intense. Specialists in pain genetics,
such as Jeffrey Mogil, believe that these differences cannot be explained solely
factors (for example, a tendency for society to encourage men to endure pain).
A number of Mogil’s experiments reveal differences in neuronal “wiring”
according to sex—a disparity associated with the differential expression
of certain genes in men and women. For example, some of these genes cause the
two sexes to respond differently to analgesics.
This difference in the
way the pain circuits operate, making women’s more sensitive than men’s,
has direct repercussions on the way that pain research is done. Nearly three-quarters
of all pain studies done with mice or rats use males only, because researchers
have traditionally believed that the hormonal fluctuations in females would introduce
excessive variability into the results—a belief that Mogil refutes.
Mogil’s opinion, researchers may introduce far more error if they continue
to experiment with male rodents only, and then assume that their findings apply
to females as well.
As its name suggests, chronic
fatigue syndrome is characterized mainly by heavy fatigue that no amount
of rest ever eliminates. Sufferers may also experience other, secondary symptoms
to varying degrees, such as a slight fever, painful lymph nodes, persistent tiredness
after exercise, constant headaches, and sensitivity to light.
immune system may also play an important role in the onset of chronic fatigue
syndrome. Allergies and certain viruses also are on the list of suspects. Stress
appears to be an aggravating factor, inasmuch as it is recognized as opening the
way to a multitude of pathologies by weakening the immune system.
which affects about 3% of the population, is very similar to chronic fatigue syndrome.
The main difference is that in chronic fatigue syndrome, the predominant symptom
is generalized fatigue, while fibromyalgia is characterized by diffuse pain in
the musculoskeletal system. (Fibromyalgia can also be accompanied by fatigue,
But the most specific manifestation of fibromyalgia consists
of pain at any of 18 “tender points”. Fibromyalgia is diagnosed when
this pain persists at 11 or more of these points for more than 3 months.
differs from arthritis in that fibromyalgia pain is associated with the muscles,
tendons, and ligaments, whereas arthritis pain occurs only in the joints. Also,
while arthritis pain is accompanied by inflammation, fibromyalgia pain is not:
the tissues that hurt show no visible signs of injury or disease, which is what
makes this syndrome so strange.
In addition to experiencing this pain,
which they often liken to a burning sensation, people with fibromyalgia may be
very sensitive to cold. They may feel very stiff in the morning and may experience
sleep disorders, migraines, and digestive problems. People with fibromyalgia often
feel that they are not understood, and sometimes not even believed, by their friends
and families, who do not always respond well to someone who says that they hurt
The symptoms of fibromyalgia often first appear
when people are in their thirties. These symptoms may eventually diminish, but
without ever disappearing altogether. Few treatments are available, except for
antidepressants and for anti-inflammatories intended to ease the pain.
cause of fibromyalgia is not really known. Some authors hypothesize that it is
a biochemical disorder in which muscle pain interacts with countless biological
agents. The entire syndrome may be triggered by stress, trauma, or an infection
and may be related to certain malfunctions in the neuroendocrine and immune systems.
Irritable bowel syndrome is a disorder of the colon. The origin
of this syndrome is unknown, but it too has many things in common with fibromyalgia.
In this syndrome, however, digestive problems predominate, such as abdominal pain,
constipation, diarrhea, and abdominal swelling from accumulated gas.
Taking a page from British psychologist
Susan Blackmore’s book, instead of asking the traditional philosophical
question “Why does pain hurt?”, we might do better to ask, “Why
does pain hurt me?” Because after all, how can there be any pain if there
is no sense
of a self on whom the pain acts?
Damasio says that the “self” is necessary for the experience
of pain. In his view, the neuronal patterns caused directly by a pain stimulus
do not suffice for pain to be experienced as painful. To experience this entire
emotional dimension of pain, you must also know that it is you who are experiencing
it. For Damasio, there must therefore be something that comes after the nociceptive
signal and that is deployed in the appropriate areas of the brain to produce the
feeling of pain.
Because Damasio is not a dualist,
in his world view these two steps must correspond to states of the nervous system.
The pain system must therefore makes its neuronal patterns accessible to the self
system. Here we have the concept of accessibility that is central to the theory
of the global workspace, in which various unconscious processing systems pool
the results of their work and make them available to one another. But even then,
it is still hard to explain how this interaction among neuronal patterns is transformed
into the subjective feeling of pain.
VARIOUS TYPES OF PAIN
has given human beings a matchless system to protect
the body’s integrity: the sense of pain. (For example, any child who
touches a hot iron once remembers for the rest of his or her life not to do that
again.) But if, for various reasons, pain persists even though the original injury
has healed, then pain can become a poisoned gift indeed.
how this can happen, we can begin by distinguishing acute
pain from chronic pain, according to how long they last. We can also classify
pain into three main categories according to the mechanisms that generate it:
pain arising from excess nociception, neuropathic or neurogenic pain, and psychogenic
Pain arising from excess nociception is caused by
the normal activation of our neurophysiological pain pathways. A classic example
would be when you accidentally strike your thumb with a hammer, thus damaging
peripheral tissue and generating an excess of nerve impulses in your nociceptors.
Pain arising from excess nociception can
come from the skin, joints, or muscles, as well as from internal organs such as
the liver, heart, and kidneys. The source of the painful stimulus can be an injury,
which may be mechanical (crushing, twisting, pulling), thermal (a burn) or chemical
(an irritant substance). The source can also be an inflammation or ischemia (restricted
blood supply to muscles, resulting in insufficient oxygenation that causes pain).
Usually, pain is maintained or increased by the release
of endogenous substances that activate the nociceptors directly or indirectly.
Treating pain that arises from excess nociception
thus involves weakening or eliminating the nociceptive message at various peripheral
and/or central locations, mainly by the administration of analgesics.
pain arising from excess nociception, some kinds of pain arise spontaneously,
in the absence of any peripheral stimulation, as the result of direct injuries
to the nerves or neurons of the nociceptive pathways. Such types of pain are referred
to collectively as neuropathic pain or neurogenic pain
(though various distinctions are sometimes made between the two). These complex
neurological dysfunctions can involve structures in both the peripheral and the
central nervous systems.
pain in the peripheral nervous system may arise, for example, from nerves that
have been severed by a bad cut, or compressed when a vertebra became displaced.
Such pain is experienced in the vicinity of the affected nerves and may feel like
an electric shock, or a stabbing, burning, or prickling sensation. The extreme
example of pain due to nerve injuries is the phantom pain that amputees sometimes
experience in their missing limbs (see box below).
the mechanisms responsible for chronic pain are still poorly understood, some
processes that occur naturally following an injury appear to play a significant
role. One such process is inflammation, which, by mobilizing large numbers of
molecules to optimize healing in the injured area, also alters the properties
of the nociceptors
in this area, causing some of them to undergo peripheral
sensitization. Some of these sensitized nociceptors will then start
to generate action potentials more readily, or even spontaneously.
cases where, for various reasons, the pain persists for too long, two symptoms
of neurogenic pain may then set in: hyperalgesia, where a given
nociceptive stimulus causes more pain than it normally would, and allodynia,
in which a simple tactile stimulus, even a light caress, triggers severe pain.
The continued transmission of pain signals
to the central nervous system can also result in central
sensitization, in which the neurons in the dorsal root of the spinal
cord and in the higher brain centres associated with pain become hyperexcitable.
The pain then becomes ingrained, as it were, in the nervous system. A chronic
sensation of pain may then set in and persist well after the initial injury has
Chronic pain of central origin
can arise from other causes as well. Strokes affecting the thalamus or subthalamus
can result in chronic pain. So can damage to the medulla as the result of trauma,
inflammation, or demyelination (due to multiple sclerosis, for example). These
phenomena can also cause imbalances in the descending
pain-control pathways, making it too easy for pain messages to get through
system in the spinal cord.
caused by neurogenic pain is demoralizing for the people who have it and sometimes
for their doctors as well, because it is so hard to treat. It is estimated that
scarcely one-third of all cases of neuropathic pain can be treated with the analgesics
commonly used for other kinds of pain, such as opioid analgesics and non-steroidal
anti-inflammatories. Moreover, because these medications have major side effects,
many patients decide to stop taking them. Despite
all these obstacles, pain specialists agree that treating persistent pain as soon
as possible reduces the likelihood of its becoming chronic.
addition to pain arising from excess nociception, and neurogenic or neuropathic
pain, the third main category of pain, based on the mechanisms that generate it,
is psychogenic pain. People diagnosed with psychogenic pain show
no apparent injuries, despite the pain that they report as being quite apparent.
This pain often occurs inexplicably at various places in the body and at various
times. Science does not yet understand the physiological causes of psychogenic
pain, but it is often associated with difficulties in family relationships, stressful
conditions at work, alcoholism, and drug
Though some authors still
question whether psychogenic pain is real at all, many authors think that it might
result from synergy between a small injury that acts as a trigger and psychological
phenomena that amplify pain. Psychogenic pain could then be defined more strictly
as a lowering of the nociceptive threshold in conjunction with mood disorders.
It would then have to be shown that in people who have fibromyalgia, for example
(see sidebar) or tension headaches (see box below), there is indeed a lowering
of the nociceptive threshold. A number of studies have already made findings suggesting
that this may indeed be the case.
approach to explaining psychogenic pain for which no physical explanation can
be found involves attempting to relate this pain to traumatic events very early
in the individual’s life, going back even as far as infancy or the perinatal
period. Animal research has shown that stress during the perinatal period can
affect how individuals experience pain as adults. These findings suggest that
of the human limbic
system can also be modified by early physical or psychological traumas.
physical pain inevitably has an effect on the individual’s psyche as well,
so the relationships between the two are obviously quite complex. Who among us
hasn’t experienced muscle
pains when we were under psychological pressure as the result of stress, anger,
Headaches are unquestionably
among the most familiar types of pain. Generally not life-threatening, they can
nevertheless be very disabling.
Like adults, children can experience headaches.
Before puberty, headaches are more common in males, but after, they are more common
in females: in adulthood, women experience more headaches than men, often in relation
to the menstrual cycle. These benign headaches generally disappear on their own
after a while, or with the help of a light analgesic.
Headaches can have
various causes and are often only a secondary symptom of other pathologies. For
example, an infection in the upper respiratory tract, such as a cold, can lead
to infection of the nasal sinuses (sinusitis), which in turn can lead to a headache.
Two other examples of headaches as secondary symptoms of something else
are headaches due to high blood pressure (whether chronic or effort-induced) and
facial neuralgia, which causes acute pain in the area controlled by the trigeminal
nerve, which transmits sensations from the face.
Headaches can also be
triggered by exposure to chemicals, by hemorrhaging or ischemias, by trauma to
the skull or to neck vertebrae, or by withdrawal
from drugs, to name just a few other causes. Sometimes headaches can also
be the symptom of a more serious problem such as a stroke, a brain tumour, or
another cause of headaches is migraine, a multi-facetted neurovascular
disorder that affects 10 to 15% of the adult population and three times more women
than men. The word “migraine” comes from the Greek word hemikranion,
meaning a pain affecting one side of the head. Migraine does in fact often affect
only one side of the head, though sometimes it affects both.
headaches are usually pulsating and often accompanied by other symptoms such as
nausea, vomiting, disturbed vision, and hypersensitivity to light, noise, and
odours. A migraine attack can last for a few hours or a few days, during which
the individual may be suffering so much that he or she cannot continue any normal
daily activities. More than 50% of the people who suffer from migraines have one
or more per month, and 25% have at last one per week.
Migraines often occur
in several recognizable stages. For example, some migraine sufferers experience
a set of early symptoms (the “prodrome”) before the full-blown attack.
These symptoms may include excitation, heavy fatigue, unexpected hunger, heaviness
in the legs, yawning, and minor diarrhea. Then, about 10 to 30 minutes before
the headache begins, some sufferers experience an “aura”, which may
be manifested as flashing lights, jagged lines, or blind spots in the field of
vision. The aura stage can also involve language disturbances (difficulty in pronouncing
or finding words) and sensory disturbances (pins-and-needles sensations).
the aura, the migraine headache itself arrives. It often starts close to the temple
on one side of the head and can then eventually extend to the other side, accompanied
by all of the symptoms described above. After some hours or even days, the pain
finally dissipates, leaving the sufferer weak and exhausted.
causes of migraine are not yet well understood, but we do know
that it is a neurovascular disorder which, though it originates in the brain,
disturbs several structures inside the skull that trigger the pain more directly.
On the one hand, observations indicate that there is a migraine-generating
“centre” in the brain stem that appears to remain active until a migraine
attack is over. But observations also confirm some more well known phenomena,
such as spasms in the blood vessels of the brain—in other words, repeated
alternating contractions and dilations, which are the direct physical cause of
the characteristic headache. Many of the medications that provide relief for migraines
(triptans, for example) act by regulating the flow of blood inside the skull.
Theoretical models for migraine also increasingly incorporate the phenomenon of
cortical spreading depression (CSD)—a wave of increased
neuronal activity observed at the surface of the cortex, followed by a wave of
depressed neuronal activity. According to these models, CSD is a preliminary phase
of migraines and seems to be the physiological basis for the aura perceived by
some migraine sufferers.
Some neuroscientists also believe that the release
of certain ions or molecules from the brain or the blood into the cerebrospinal
fluid during CSD activates the neural pathways along the blood vessels of
the meninges and contributes to the painful
Many factors that would affect neuronal
excitability may trigger a migraine: hormonal changes (over the menstrual cycle),
certain foods and food additives (such as chocolate, aged cheeses, ice cream,
nitrites, and monosodium glutamate), some beverages (such as wine), skipping a
meal, strong smells and loud noises, lack
of sleep, overexertion, and stress.
Genetic predispositions, possibly
expressed as cortical hyperexcitability, probably play a role too. Genes on chromosomes
1, 19, and X are on the list of suspects.
If you are a migraine sufferer,
one of the first things to do to help alleviate your migraines
is to try to identify the factors that trigger them and then to avoid these factors
as much as possible. One way to help identify these triggering factors is to keep
a daily log of what you ate, what you did, how well you slept, and so on.
a migraine has begun, the best things for it are calm, dim light, and relaxation.
Massaging the neck, scalp, or temples can also provide relief to some migraine
sufferers. A cold cloth on the forehead may also help.
can alleviate or shorten migraine attacks include analgesics (such as aspirin
and acetaminophen), non-steroidal anti-inflammatories (such as ibuprofen and naproxen),
and migraine-specific medications(such as triptans and ergotamine). However, like
all medications, these substances vary in effectiveness from one patient to another
and have side effects that must be considered. Even more caution is advisable
for medications that are taken daily to prevent migraine attacks (such as beta
blockers, calcium blockers, tricyclic
antidepressants, and anti-epileptics).
One interesting non-medical
treatment for migraine, developed in the mid-1990s, is called myotherapy
and involves only the use of the therapist’s hands. The goal of myotherapy
is to permanently eliminate muscle
spasms (often in the neck area) from which the patient suffers continuously
as the result of a trauma that may have occurred very early in his or her life.
myotherapy, the therapist attempts to relax these muscles by means of manipulations
that overcome a natural “myotatic” reflex and return the muscles to
their original state. The muscles thereby cease to exert tension at the base of
the skull—tension which, when exacerbated by the slightest stress, can impede
intracranial blood circulation.
According to the advocates of myotherapy,
though a good night’s rest, relaxation, or appropriate medication might
decontract the muscles enough to relieve a particular migraine episode, as long
as the muscle contractions caused by early trauma have not been eliminated, the
individual will remain vulnerable to the factors that trigger migraines. For myotherapists,
the vascular phenomena involved in migraines and the neck pain frequently associated
with them therefore are not contradictory but rather complementary, because though
migraines are indeed of vascular origin, they are ultimately caused by mechanical
disturbances in the venous drainage that are themselves of muscular origin.
The term phantom limb refers
to a strange phenomenon in which someone who has had a limb amputated still feels
its presence. This feeling can last for years, or even decades. Cases have also
been reported of phantom breasts, phantom jaws, and even phantom penises that
have phantom erections!
Phantom limbs would be only an interesting curiosity
were it not that at some time or other, about 80% of all amputees (the figures
cited in the literature range from 50% to 98%) experience pain that seems to come
from their amputated limb. And in some types of amputations, more than one-third
of all amputees experience severe pain in their phantom limb.
sensation is referred to as phantom pain. It may feel like a
burning or stabbing sensation, or as if the phantom limb were bent into an uncomfortable
position, and it is very hard to treat by traditional approaches.
of pain in a missing limb is so strange that when American neurologist and author
Silas Weir Mitchell used the expression “phantom limb” for the first
time, in 1872, when thousands of Civil War veterans had had limbs amputated as
the result of wounds or gangrene, he wrote anonymously to avoid ridicule.
have proposed several mechanisms that may account for phantom
pain. For example, when damaged nerves heal and regenerate, they do not always
do so correctly. Spontaneous activity may then arise in these nerves and be perceived
as pain signals by the brain. Some surgeons have even attempted to reamputate
a limb higher up, in hopes that severing the nerves more cleanly might reduce
the phantom pain, but unfortunately without much success.
healing of nerves does not appear to be the only possible cause of phantom pain.
Another possible cause is the original pain in the limb—the pain that often
leads to the decision to amputate. This pain might continue to exist, probably
because it has become “engrammed” in the central nervous system.
fact, treatments based on this central component of the origin
of phantom pain are among the most promising. Researchers have shown that the
intensity of phantom pain is proportional to changes in the representation of
the various parts of the body in the sensory cortex. Scientists have not yet really
determined how these changes following an amputation generate phantom pain, but
have determined that anything that tends to reduce or reverse these changes also
reduces this pain.
One method of achieving such reductions is to have amputees
use, for several hours per day, an electrical prosthesis that is activated by
signals from their own muscles. Another method involves tasks where repeated touching
of the skin in the stump area (by the patient or a therapist) improves tactile
discrimination at this location and also reduces phantom pain, possibly by letting
the cortex again receive a portion of the sensory inputs that it lost as a result
of the amputation.
S. Ramachandran developed a device called a “mirror box” that
gives arm amputees with phantom pain the impression that they are seeing their
missing arm. When someone touches their intact hand, the mirror box makes it look
and feel as if their missing hand is being touched as well, and this sensation
eases their phantom pain. Seeing someone else caress their own hand induces a
similar sensation in the phantom hand, a phenomenon in which certain mirror
neurons may be involved.
Other experiments with this mirror box suggest
that phantom pain may also be related to loss of motor control of the amputated
limb. When a person with an amputated hand moves their intact hand inside the
mirror box, they get the illusion that they are moving their amputated hand, and
this too has the effect of reducing the phantom pain.
Paralyzed limbs also
can generate phantom pain, and researchers have achieved some encouraging results
in reducing this pain by having subjects imagine that they were moving their paralyzed
All of these findings point to the increasingly accepted idea that
the pain generated by a missing limb can be alleviated by methods that recreate
a complete, coherent body image. The explanation would be that the sensory inputs
from the amputated limb and the interrupted motor control signals to this same
limb conflict with the bodily representation that is prewired in the brain, and
that for some as yet unknown reason, it is this discrepancy that causes the phantom
The importance of conditioning
as a source of expectations that produce the placebo effect was demonstrated
in an original experiment by Italian physiologist Fabrizio Benedetti and his colleagues.
First, they administered morphine on two occasions to athletes who were in training
for a competition. Then, on the day of the competition, the researchers gave the
athletes an injection that was apparently the same, but actually contained only
saline solution, with no morphine. The researchers nevertheless observed an activation
of the athletes’ endorphin
systems, which enabled them to improve their performance and better endure
their pain! Imagine the headaches that an approach like this could cause for anti-doping
Besides pain, Parkinson’s
disease is another condition that is especially susceptible to the placebo
effect. This degenerative disease, which involves a loss of muscle control, is
caused by a deficit of the neurotransmitter dopamine.
In order to compensate for this deficit, Parkinson’s patients are treated
with L-DOPA, a dopamine precursor. The L-DOPA is absorbed by those neurons in
the patients’ brains that are still capable of secreting dopamine, thereby
activating them and causing them to increase the levels of dopamine in the brain.
Several studies have shown that administering a placebo to Parkinson’s
patients activates these neurons almost like administering L-DOPA. The increased
dopamine levels are especially apparent in one of the brain’s centres of
motor control, the striatum.
It is worth noting that the dopaminergic system also plays a very important
role in the reward
mechanisms of the human brain and is very likely involved in the expectations
of relief that are created by administering placebos to Parkinson’s patients.
The clinical improvements that can then be observed, along with the improved quality
of life reported by the patients themselves, also seem to last a fairly long time
(a few weeks, but sometimes for years).
Many medical sources indicate that
over 10% of all men and over 20% of all women will experience depression
at some time in their lives, so it is no surprise that antidepressants
are among the most-prescribed types of medications. But the real effectiveness
of their active ingredients, compared with the placebo effect, is the subject
of ongoing debate.
In 1998, after analyzing 38 previously published studies
on antidepressants, psychologists Irving Kirsch and Guy Sapirstein concluded that
the placebos used in these studies produced about 75% as much improvement as the
antidepressants themselves. The authors added that even the remaining 25% of the
improvement that was exclusive to the antidepressants might have been attributable
to an increased placebo response to the side effects caused by their active ingredient,
or to other non-specific effects (see box to right).
In 2000, another meta-analysis
of previously published results found a 30% reduction in suicide attempts among
subjects who had received placebos compared with a 40% reduction among subjects
who had received real antidepressants.
In 2008, in another analysis of
several studies on antidepressants, Kirsch and his team showed that 12 weeks after
trials lasting 6 to 8 weeks, 79% of the patients who had received placebos were
still doing well, compared with 93% of the patients who had been treated with
Some researchers have even hypothesized that the reappearance
of symptoms that is often observed after patients have been taking antidepressants
for some time, and that is generally attributed to a growing tolerance
for the antidepressant, might be explained largely by the fading of the placebo
The most amazing finding in all of these analyses is just how powerful
the placebo effect can be for treating depression. It should be noted, however,
that the more severe the depression, the more effective that antidepressants seem
to be, compared with placebos.
The lively debates on this subject have
been going on for years and continue to this day. Scientists now seem to agree
that, in certain circumstances, antidepressants do have a greater effect than
placebos. But this effect often seems to be smaller than the pharmaceutical companies
would have us believe. The difference between the effect of antidepressants and
that of a simple sugar pill is not always very great, and may sometimes even be
close to zero. The debate continues.
is the act by which someone introduces
an idea into someone else’s brain and they accept it. Hypnotizing someone
is one of the many things that can be done by suggestion, although that person’s
brain will be in a distinct state once he or she is actually under hypnosis.
the placebo effect, the doctor suggests to the patient the idea that a given treatment
will make the patient get better. This suggestion then causes a sort of narrowing
of the patient’s field of awareness around the thing that has been suggested,
that is, the idea that a particular medication will do him or her some good. This
conscious thought then induces real physiological changes, the mechanisms of which
are not yet well understood.
is another psychological mechanism behind the placebo effect, but an
one. Its operation was well described by Russian physiologist Ivan Pavlov in the
early 20th century: through a learning process, a permanent association can be
created between an unconditioned response and a neutral stimulus, so that subsequently,
that neutral stimulus can produce a conditioned response. In Pavlov’s studies,
dogs learned to associate an unconditioned response (salivating in the presence
of food) with a neutral stimulus (a bell ringing at mealtime), so that subsequently,
they salivated when they heard the bell ring. Another example would be when people
learn to associate taking an analgesic pill with experiencing pain relief, and
then experience pain relief when they are given an identical-looking sugar pill.
can be very deeply rooted, because in the Western world, we have learned that
when we are sick, we have to go to the doctor, who will give us a medication that
will eventually cure us. The sequence pain-doctor-pill-cure is therefore very
firmly embedded in our minds. As a result of this conditioning, simply making
an appointment to see a doctor may therefore be enough to set the placebo effect
Thus, far from working against
each other, suggestion and conditioning actually have additive effects that are
hard to differentiate and that reinforce each other to bolster the patient’s
confidence. This confidence also helps to diminish the patient’s anxiety
and the well known harmful physiological effects associated with them.
also now know about some of the physiological mechanisms involved
in the placebo effect. These mechanisms have been studied chiefly with regard
to the role of the placebo effect in treating pain. (Notable placebo effects have
also been observed in the treatment of other conditions, such as Parkinson’s
disease, and studies of these effects have also generated hypotheses about some
of the neurobiochemical mechanisms underlying them; see sidebar.)
a pioneering study published in 1978, Jon Levine tested the possible
involvement of endorphins
when the placebo effect reduces pain following the extraction of molars. For some
of the patients in this study, injecting saline solution as a placebo while telling
them that it was an antipain medication was just as effective as a dose of 6 to
8 milligrams of morphine. But if these placebo-responsive patients were then given
naloxone, a morphine antagonist that also blocks the effects of the body’s
own endogenous morphines, it significantly increased their pain. In contrast,
the same dose of naloxone caused no additional pain for those patients who had
not responded to the placebo effect.
This study had
considerable repercussions, because it was the first to reveal biological bases
for the placebo effect on pain, while also demonstrating a direct link between
psychological expectations and a biological effect.
in the study of the brain, nothing stays simple for long. In 1982, Richard Gracely
showed that the analgesic effects of a placebo can persist even after the effects
of endorphins have been blocked by naloxone. That same year, Priscilla Grevert
showed that initially, naloxone has no significant effect on ischemic pain induced
for experimental purposes by cutting off blood and hence oxygen supply. But she
also showed that if this experiment is then repeated with the same subject, naloxone
does reduce the analgesic effect of a placebo.
and Grevert’s studies suggest that the placebo effect might be governed
by both endorphin-based and non-endorphin-based mechanisms simultaneously. Some
authors believe that the placebo effect resulting from expectations might be attributable
to endorphins, while the placebo effect resulting from conditioning might depend
on other mechanisms.
In addition, dopaminergic activation
associated with the placebo effect has been reported in the ventral central grey
nuclei, including the nucleus accumbens. And conversely, responses to the nocebo
effect have been found to diminish the release of opioids and dopamines in
Thus, in strong placebo responses, an
activation of the reward
circuit is observed, with increased release of dopamine
in the nucleus accumbens. This suggests that these structures may play a role
in the motivation necessary for the the placebo effect. The involvement of the
frontal cortex has also been reported frequently. Its role might be to help recall
the administration of the placebo and strengthen positive expectations regarding
Thus the areas of the brain involved in these
phenomena are part of the circuit typically involved in motivation and the quest
for gratification. Given that these structures also activate
descending pain-inhibiting pathways in the spinal cord, the placebo response
would definitely seem to be a typical case of top-down
control. Consistently with this conclusion, patients whose pathology affects
the higher centres of the brain, such as the prefrontal cortex in Alzheimer’s
disease, do seem to be less susceptible to the placebo effect.
In the mass
media, and sometimes even in certain scientific publications, reports of patients’
getting better after receiving a placebo (such as a sugar pill or an injection
of saline solution) often make the mistake of attributing this improvement entirely
to the placebo effect, and specifically to the patients’ positive expectations.
True, such positive psychological predispositions can lead to favourable physiological
changes. But the placebo effect is only one of a number of non-specific
effects that can contribute to such improvements.
The term “non-specific
effects” refers to those effects, other than the specific effects of the
active ingredient of a medication, that also can contribute to a favourable change
in a pain or a pathology. One of the most common of these non-specific effects
is simply the natural course of the disease: quite often, the
body successfully heals itself if given the time to do so. Thus, when a positive
change is seen in a patient who has received a placebo, this self-healing process
may also have been partly responsible, especially if it has been given enough
time to do its work.
In fact, many researchers who study the placebo effect
recommend that clinical trials, in addition to following one group that receives
the medication and a second group that receives a placebo, should also follow
a third, control group that receives absolutely nothing, so that the true placebo
effect can be distinguished from the natural course of the disease.
certain degenerative diseases whose natural course is well known and involves
ongoing deterioration in the patient’s condition (for example, Parkinson’s),
improvements in this condition after administration of a placebo can thus be attributed
largely to the placebo effect.
In addition to the natural course of the
disease, there are several other non-specific factors that may account for an
improvement observed in or reported by a patient who has taken a placebo. One
of these factors is the Hawthorne
effect, in which the very fact that sick people are participating
in a scientific study modifies their behaviour. For example, patients who participate
in clinical trials receive a lot of attention from their doctors, who explain
things to them about their health. That alone suffices to give many patients a
feeling of being well cared for that improves their condition.
non-specific effect that can result in positive changes in a sick person’s
health is the biostatistical phenomenon known as regression to the mean:
biological parameters that vary randomly tend to move toward average values. For
example, patients tend to consult their doctors at the times when their symptoms
are at their worst. Hence the odds are that these symptoms will return to their
average baseline values. If someone’s blood pressure is abnormally high
on their first visit to the doctor, then by their next visit, it is statistically
more likely to have fallen back to a closer-to-normal value.
factors can give the impression that one is dealing with a “real”
placebo effect, whereas in fact it is only a “perceived” placebo effect
and these other factors are actually responsible for the improvement. Anything
that is evaluated subjectively, such as pain or fatigue, can be influenced by
various psychological phenomena. For instance, participants in
a clinical trial may be positively biased about future changes in their health,
because they want to believe that the time that they are investing in the trial
will prove worth it. They also simply may not want to disappoint their doctors
and hence will give them polite responses that tend to put the results of the
trial in the best possible light. In short, patients may simply convince
themselves that they have gotten better.
The importance of these
other non-specific factors has led some researchers to minimize the importance
of the actual placebo effect. In a study that received much attention when it
was published in 2001, Hrobjartsson and Gotzsche attempted to define the relative
importance of the placebo effect and the natural course of an illness. To do so,
they analyzed 29 double-blind
clinical trials of pain treatments. They concluded that in reality, the placebo
effect is probably far smaller than it is generally thought to be.
attacked this study, in particular by pointing out that the members of the control
groups who received no treatment were patients on waiting lists. Perhaps, these
critics speculated, the reason that Hrobjartsson and Gotzsche saw no great differences
between these groups and the groups that received placebos was simply that the
two were not really qualitatively different. As these critics saw it, sick patients
who are on waiting lists often turn to other forms of treatment, in which they
too then benefit from a sense of being cared for in a doctor-patient relationship—one
of the most determining factors in the placebo effect.
Other authors have
repeated Hrobjartsson and Gotzsche’s literature review, but distinguishing
what the subjects were told in the various studies. In those studies whose specific
purpose was to study the placebo effect, all of the subjects were told that they
were going to receive an active treatment, whereas in those studies where a placebo
was used solely as a control, the subjects were told that they might end up receiving
a sugar pill. The placebo effect was found to be greater in the former set of
studies, most likely because the subjects had higher expectations.
said, in studies that compare three groups of subjects—one that receives
an active treatment, one that receives a placebo, and one that receives nothing—the
placebo group’s condition generally improves significantly more than that
of the group that receives nothing.
Humphrey has developed a theory to explain the evolutionary
origins of the placebo effect. Humphrey begins by pointing out that many unpleasant
symptoms that we would like to get rid of are actually defences against even greater
threats to our organisms. Pain is the most obvious example: its main purpose is
to make us aware of injuries and thereby encourage us to immobilize ourselves
so as to promote healing. (The serious consequences suffered by those rare
individuals who cannot feel any pain are a vivid reminder of why pain is so
Another such symptom is fever, a response in which the body
raises its temperature to try to eliminate bacteria or viruses that are attacking
it. Other examples would include inflammation
and various other symptoms triggered by an immune response.
But these often
complex adaptive responses inevitably have a cost for the organism, a cost that
may sometimes be too high for the benefits that it is supposed to provide. For
example, the pain that you feel when you sprain your ankle may well be of some
use if you are just out for a walk, but not if it happens while you are trying
to run away from a hungry bear. In the latter case, you are better off if your
body can temporarily suppress the immobilizing pain (something that the
body’s natural anti-pain system does very well) so that you can try
to run away, even if it makes the injury worse, instead of getting eaten by the
The same question arises when you have an infection: is this the
right time for the body to trigger a costly immune response, or should it save
its energy in case something even more serious happens? If you are safe at home
and have plenty of time to convalesce, then the answer is probably yes—your
body should put everything it has into fighting the bacteria or virus. But maybe
not if you are in an uncertain environment where other dangers may arise. The
crucial question is thus always something like, if I let my adaptive response
be triggered, what will happen then?
Humphrey’s thesis is that if
you are convinced that conditions in the future will be good, then you can let
down your guard and allocate all of your body’s resources to healing. And
by extension, Humphrey believes that any condition that helps to give you this
peace of mind will lead you to allocate a lot of resources to your own healing.
The analogy here with the factors, such as positive expectations, that
are known to promote the placebo effect is quite striking. And for Humphrey, the
reason that the doctor-patient relationship has so often been found to be so important
for the placebo effect is that we humans are such a highly social species. Our
own personal experience is too limited to be our best source of knowledge when
we can use the faculty of language
to access everyone else’s experience as well. This “outside permission”,
as Humphrey calls it, is the kind most likely to convince us that the conditions
are right to let ourselves allocate all of our resources to healing. And that
is why the placebo effect is so important when people go to see their doctors
or, as they have since time immemorial, their shamans, healers, gurus, or any
other charismatic therapists.