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Pleasure and pain
Pleasure-Seeking Behaviour
Pleasure and Drugs
Avoiding Pain

HelpLink : Chronic Pain Can Impair MemoryLink : Depression And Chronic Pain Linked In Stanford Study; May Influence Diagnosis And TreatmentLink : Chronic Pain Harms The Brain
Link : Newly Identified Drug Relieves SufferingLink : Pain and prejudiceLink : Book : Feeling Pain and Being in PainLink : Feeling Pain and Being in Pain Reviewed by Murat Aydede
Link : Pain and deliberate self-harmLink : Surtout, ne pas souffrirLink : Animation: A novel mechanism of allopathic pain, by Michael S.C. CorrinLink : Nerve injury-induced tactile allodynia is mediated via ascending spinal dorsal column projections
Link : The McGill Pain QuestionnaireLink : Fetal Pain?Link : Reflex Sympathetic Dystrophy SyndromeLink : Racked with Pain: Millions of people suffer from incurable pain that has no immediate cause. The reason may lie with crossed connections in the nervous system
Link : LA DOULEURLink : International Association for the Study of PainLink : The Alan Edwards Centre for Research on Pain
Researcher : Dr. Serge MarchandResearcher : Serge Marchand , Neurophysiologiste
History : Book :  Histoire de la douleurHistory : A Brief History of PainHistory : A Short History of Pain PracticeHistory : Pain: History

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 by socio-cultural 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.

In 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.

Link : Sex, genes and social factorsLink : Sex differencesResearcher : Jeffrey Mogil

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.

A malfunctioning 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.

Fibromyalgia, 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, however.)

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.

Fibromyalgia 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 “all over”.

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.

The 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.

Link : Fibromyalgie et fatigue chronique: un lien biologique possible identifiéLink : LA FIBROMYALGIE EN 2002: Des pistes intéressantesLink : Fibromyalgia NetworkLink : Vivre avec la fibromyalgie: série de six articles
Link : Association québécoise de la fibromyalgieLink : LA FIBROMYALGIELink : Fatigue Chronique et FibromyalgieLink : Maladie intestinale inflammatoire

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?

Neuroscientist Antonio 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.

Tool Module : Theories of SelfResearcher : Susan Blackmore

Evolution 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.

To understand 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.

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.

Unlike 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.

Neuropathic 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).

Though 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.

In 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 healed.

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 the gating system in the spinal cord.

The suffering 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.

In 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 addiction.

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.

Another 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 the development of the human limbic system can also be modified by early physical or psychological traumas.

Any 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, or overwork?


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 meningitis.

Yet 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.

Migraine 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).

After 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.

The primary 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 inflammatory responses.

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.

Once 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.

Medications that 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.

In 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.

Link : Migraine: The headache that’s not really a headache Link : Headache Network Canada Link : La sérotonine, les triptans et la migraine Link : Mapping Migraine Pain Link : The Biology of Serotonin Receptors: Focus on Migraine Pathophysiology and Treatment Link : American Council for Headache Education Link : Migraine
Link : Édith Hamel Link : Myothérapie Link : Société Internationale de Myothérapie Link : CAUSES ET TRAITEMENT DE LA MIGRAINE : NOUVELLE HYPOTHESE, NOUVELLES POSSIBILITES Link : Migraine as inspiration Tool Module : Anaesthesia and Analgesia Link : Why do humans have headaches?


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.

This overwhelming 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.

The idea 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.

Scientists 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.

Thus improper 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.

In 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.

Neurologist V. 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 limbs.

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 pain.

Link : Phantom limbsLink : Book: Phantoms in the Brain: Probing the Mysteries of the Human MindLink : Phantom limb painLink : Membre fantômeLink : La réalité virtuelle contre la douleur fantômeLink : Phantoms in the BrainHistory : Silas Weir Mitchell's The Case of George DedlowLink : We can generate a novel body image internally, without external feedbackLink : Manipulating Phantom Limbs


Link : Greater Response to Placebo in Children Than in Adults: A Systematic Review and Meta-Analysis in Drug-Resistant Partial EpilepsyLink : L’effet placebo et ses paradoxesLink : PlaceboLink : Effet placebo: votre cerveau est-il doué pour libérer des antidouleurs naturels?
Link : Revealed: how the mind processes placebo effectLink : Placebo effects on human μ-opioid activity during painLink : The Benson-Henry Institute for Mind Body Medicine at Massachusetts General Hospital (BHI)Link : Link between brain anatomy, personality, and the placebo analgesic response
Link : Review - Talking Cures and Placebo EffectsLink : Placebo effect on human opiod pain systemLink : The placebo effect is hard wired into the brainLink : The placebo effect affects pain signalling in the spine
Researcher : André Leblanc
Experiment : Commercial Features of Placebo and Therapeutic EfficacyExperiment : The mechanism of placebo analgesiaExperiment : Placebo and nocebo effects are defined by opposite opioid and dopaminergic responsesExperiment : Activation of the Opioidergic Descending Pain Control System Underlies Placebo Analgesia
Original modules
Tool Module : Neurobiological Correlates of the Mystical Experience and MeditationNeurobiological Correlates of the Mystical Experience and Meditation
Tool Module : Ethical Issues Raised by the Placebo Effect Ethical Issues Raised by the Placebo Effect
 Tool Module : Anesthesics and Analgesics Anesthesics and Analgesics

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 committees!

Experiment : Opioid-Mediated Placebo Responses Boost Pain Endurance and Physical Performance: Is It Doping in Sport Competitions?

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).

Link : Parkinson's DiseaseLink : Mind-body Connection In Placebo Surgery Trial Studied By University Of Denver ResearcherExperiment : Placebo-responsive Parkinson patients show decreased activity in single neurons of subthalamic nucleus

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 antidepressants.

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 effect.

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.

Link : Antidépresseurs ou placebo ? La controverseLink : Antidépresseurs inefficaces après 6 mois? L'effet placebo pourrait être terminéLink : Against Depression, a Sugar Pill Is Hard to BeatLink : Antidepressant-Placebo Debate in the Media : Balanced Coverage or Placebo Hype?


The reason that the placebo effect is an inextricable part of any therapeutic intervention is that it works on the basis of our expectations. When one human brain interacts with others, it is predisposed to develop expectations, or what some authors have called a theory of mind. In generating these expectations, two psychological mechanisms in particular would appear to be at work: suggestion and conditioning.

Suggestion 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.

In 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.

Conditioning is another psychological mechanism behind the placebo effect, but an unconscious 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.

And this conditioning 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 in motion.

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 stress and the well known harmful physiological effects associated with them.

Scientists 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.)

With regard to pain, however, the discovery of endorphins and of the body’s natural neural pain-control pathways quickly provided avenues to explore in search of a biological foundation for the placebo effect.

In 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.

But 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.

Gracely’s 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.

The brain structures where researchers have begun to situate these neurophysiological mechanisms behind the placebo effect are consistent with this reasoning. For example, the activation of mu opioid receptors during the placebo effect has been detected in the anterior cingulate, orbitofrontal, and insular cortexes, as well as in the nucleus accumbens, the amygdala, and the periaqueductal grey matter.

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 these areas.

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 it.

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.

In 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.

Another 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.

Other non-specific 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.

Critics 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.

That 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.

Link : Is the Placebo Powerless?— An Analysis of Clinical Trials Comparing Placebo with No TreatmentLink : placebo effectLink : Ne pas prescrire un placebo mais utiliser l’effet placeboLink : Placebo effectExperiment : When a placebo is not a ‘placebo’: a placebo effect on postprandial glycaemiaExperiment : When a placebo is not a ‘placebo’: a placebo effect on postprandial glycaemiaLink : L’effet placebo n’existe pas !Link : Placebo has strength in numbers

Nicholas 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 important.)

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 bear.

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.

Link : Great Expectations: The Evolutionary Psychology of Faith-Healing and the Placebo Effect

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