placebo

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A placebo (from the Latin placebo “I'll like”) or dummy drug is a drug that usually does not contain any medicinal substance and therefore has no pharmacological effect that could be caused by it. In a broader sense, other remedies are also referred to as placebos, for example "sham operations".

Placebos serve as a control substance in clinical research. Placebo drugs are used in placebo-controlled clinical studies in order to be able to record as precisely as possible the medical / pharmacological effectiveness of various processes, each known as verum , ideally in double-blind studies .

The use of placebos to treat symptoms of illness is ethically controversial, especially if it is not based on informed consent .

Placebo effects are positive changes in the state of health that are brought about by treatment with placebo. In a generalized sense, this also refers to the effects of treatments that are not sham treatments, but can ultimately only produce the respective effect in the same way as a placebo. The counterpart to the placebo effect is the nocebo effect . These are undesirable effects that occur with apparent pollutants that do not contain any pollutants (e.g. electro- sensitive reaction even when the cell phone tower is switched off).

The effect of placebos is explained by psychosocial mechanisms. The partially reported effectiveness of some alternative medical procedures is also attributed to the placebo effect. Even with “conventional” treatments, some of the effects can be explained by the placebo effect and in some cases doctors even use them specifically as placebos. Whether and to which application areas there really is a placebo effect but remains controversial .

etymology

Placebo domino in regione vivorum, page from the Très Riches Heures

The term placebo comes from the Christian liturgy. The verse Placebo domino in regione vivorum ( Ps 114,9  Vul ) of the Vulgate translation of the church father Jerome, which follows the Hebrew text, reads in Luther's translation “I will walk before the Lord in the land of the living” ( Ps 116,9  Lut84 ) - so it agrees with the Vulgate translation. In the Septuagint, the ancient Greek translation of the Old Testament, the Hebrew verb for “to go” or “to walk” is not translated literally, but in a figurative sense. This corresponds to the Latin translation of Hieronymus after the Greek with the verb form “placebo”; the German translation of this verse is accordingly: "I will please the Lord in the land of the living".

The derogatory phrase “sing someone a placebo” is derived from the funeral rite of the Catholic Church. The reason for this change in meaning in the late Middle Ages is believed to be, among other things, in the changes in the design of the funeral devotion, which made it possible for the alternate chants with this Vulgate verse to be sung by paid singers and no longer only by the mourners themselves. “Placebo” was therefore seen as something hypocritical, a flattering and spurious substitute.

In the 18th century, “placebo” became part of the medical vocabulary in its current meaning.

Definitions

placebo

According to the classic definition, a placebo is a preparation that is produced in a dosage form that is customary for drugs , but does not contain any medicinally effective ingredients.

In medicine, a distinction is made between different types:

Real or pure placebos
This is used to describe dummy drugs that only contain sugar or starch . It can also contain auxiliaries such as flavor corrections or colorings. This category also includes special placebo acupuncture needles that do not pierce the skin, but slide into the needle holder. The needle holder will then stick to the skin.
Active placebos
Active placebos are used as controls for special clinical trials. They do not have the effect of the drug , just mimic its side effects. They are used to reinforce the impression of test directors and test persons that the test preparation is the verum or to prevent the test condition from being guessed by knowing the side effects ("unblinding"). One example is the study of gabapentin and morphine for the treatment of neuropathic pain, where low-dose lorazepam was administered as an active placebo : although it does not have an analgesic effect, it has the same side effects as drowsiness and dizziness.
Pseudoplacebos
These are drugs that, according to current scientific knowledge, cannot work in a specific application because either the dose administered is too low or the spectrum of activity has no specific influence on the existing disease. Wiesing refers to all "scientifically cloaked" procedures that pretend to be effective without a scientific review as pseudoplacebos.

Placebo effect, placebo response and placebo effect

Placebo effects are all positive psychological and physical reactions that are not attributable to the specific effectiveness of a treatment, but rather to the psychosocial context of the treatment.

The terms "placebo effect" and "placebo response" ( placebo response ) are often used interchangeably. Enck differentiates between the terms by defining the “placebo effect” in the sense of the placebo effect in clinical studies, where the term encompasses all factors that, in addition to the specific efficacy of a drug under study, have an influence on the test result, such as regression to the mean value , natural disease course , Spontaneous remission, and finally the true placebo response. The placebo response describes the individual reaction to a treatment that is triggered on the basis of psychosocial factors such as suggestion / expectations and conditioning . A well-documented example of such placebo responses is recovery from behavioral problems or disorders caused by a sudden (un) expected event - a dream, vision, lightning strike, etc. Ä. - which is interpreted in traditional societies as a "calling by the spirits" to become a shaman .

Several meta-analyzes by various authors, which examined the existing literature on the placebo effect, came to the conclusion that the observed effects with regard to the placebo effect did not meet the strict scientific criteria. It has been found that the response seen in the placebo group in a clinical trial is often mistakenly equated with the placebo effect. The observed effects can usually be explained by factors that are not related to the placebo administration. These include: the natural course of the disease, spontaneous improvements, regression to the mean, additional treatments and other non-specific effects.

Some authors use the term “placebo effect” and define it as the effect of the context of the placebo administration. You want to emphasize that placebos themselves have no effect, but are the cause of context factors in the administration.

Nocebo effect

In contrast to placebo effects, nocebo effects are all negative physical reactions that are not due to the effects or side effects of a treatment, but rather to the psychosocial context of the treatment. A distinction must be made between nocebo effects and intolerance reactions such as allergies that are caused by certain components ( pharmaceutical excipients ) of the placebo.

Further use of the term

At the beginning of 2015, after research on the positive reaction of brain structures to products whose properties were inappropriately linked with praising advertising messages or high-priced quality, there was also talk of a marketing placebo .

The history of the placebo

The sick were treated early on through discussion . Corresponding texts were canonized and partially recorded by priest-doctors in the ancient Orient. The placebo effect was first mentioned in the West not by a doctor, but by the Greek philosopher Plato (427–347 BC). He was of the opinion that words have the power to heal the sick. He also legitimized the medical lie. As a result, he considered using words to make a critically ill patient feel that he had a good chance of recovery, or that his illness was far less bad than he thought.

That this contradicted the idea of ​​good medical treatment at the time can be seen in the example of Hippocrates (460–377 BC), an outstanding physician of his time. He founded the humoral pathology , according to which the human body contains juices that determine its state of health. Blood, phlegm, black and yellow bile, and water were considered to be body fluids. Another Greek doctor named Galenus von Pergamon (129–200) also assigned temperaments to the body fluids and thus added a psychological component. Since ancient times, doctors have repeatedly described the effect of the imagination in healing, but without using the term placebo. In the 14th century, the term placebo appeared in poems, but it referred to a flatterer or joke.

The Scottish doctor and pharmacologist William Cullen (1710–1790) may be considered the creator of the term . It is documented that he used this term for the first time in 1772 in his Clinical Lectures of 1772, in connection with a patient to whom he administered an external medicine (mustard powder), of whose specific effect Cullen was not convinced: Cullen understood by "placebo" not yet an inert substance, but mostly used low-dose medicines or drugs that he considered ineffective given the severity of the disease. The decisive factor for him was not what he prescribed for the patient, but that he actually complied with the patient's will for medication, even if he himself was not convinced of the pharmacological effectiveness of the medication. Only a few years later, the founder of homeopathy, Samuel Hahnemann (1755–1843), used milk sugar powder to observe the long-term effects of homeopathic medicines.

The term first appears in a medical lexicon in 1785, and evidence can be found for 1811 that it was also in a similar context as it is today. The first documented experiment that was controlled with a type of placebo dates back to 1784, carried out by the eminent scientist Benjamin Franklin . At that time, Franz Anton Mesmer claimed that there was a kind of "fluid" in the body that he could influence from a distance. The King of France called together a committee which was supposed to check his work. This committee, to which young Benjamin Franklin also belonged, now carried out a series of tests. Women in one room let themselves be mesmerized in the belief that the performer was sitting behind a curtain in the next room, and the information could be right or wrong. Franklin succeeded in demonstrating that the success of the treatment only depends on whether the women believe the mesmerist is there, and thus refuted the mode of action attributed to the new fashion.

The first controlled clinical trials with "inert" substances were developed by doctors who either wanted to provide evidence of the effectiveness of homeopathy or who intended to expose this new healing method as "humbug". For the first time, as we know it today, placebos were used systematically in 1830 by a Doctor Herrmann under the supervision of a Doctor Gigler in a military hospital in the Russian city of Saint Petersburg . It should be examined whether a homeopathic treatment is effective. This study not only compared the then new homeopathic treatment with the medical treatment commonly used at the time, but also systematically introduced a non-treatment group for the first time, which was treated with placebos in the form of pseudopills without active ingredients. It was found that the placebo group had the best results. In 1834 a witness to this investigation and an opponent of homeopathy, Carl von Seidlitz, carried out a simple blind comparison of homeopathic drugs with placebo in a marine hospital in the same city .

In 1835 the theologian and editor George Löhner published a test of the effects of a homeopathic saline solution carried out in a Nuremberg inn on a group of 55 healthy volunteers; the initiative for this went back to homeopathic critics. This is probably the first randomized, double-blind, placebo-controlled study ever. 42 people had noticed "nothing unusual" (19 table salt potency, 23 water as a placebo), nine people had noticed "something unusual" (six table salt potency, including one who knew he had taken the potency and three water). The supervising commission concluded that the potentiation had no effect. Further placebo-controlled studies on homeopathy followed in the course of the 19th century.

Many doctors in the 19th and 20th centuries still made the drugs themselves, so the placebos were not given out. Since the “lie of medicine legitimized by Plato” was still considered an ethical principle, they had no problem with it. In addition, the doctors were aware that there were no effective drugs available for many diseases. This led some doctors to believe that placebos would disappear from the scene once enough effective remedies were available. This was one of the reasons why placebo use declined over the course of the 20th century. Another was the change in ethical principles; deceiving a patient no longer seemed adequate. In addition, many doctors believed that placebos only work if the patient only imagines the pain.

The first double-blind placebo-controlled study based on modern criteria was carried out in 1907 by WHR Rivers. Despite such individual pioneering work, it was not until the mid-20th century that placebo-controlled trials became the standard in clinical research. This was also due to a lack of methodology. It was not presented until 1932 by the Bonn clinician Paul Martini (1889–1964). Almost at the same time, there was also a growing understanding in England and the USA to neutralize the suggestion factor in clinical studies by means of blinding, if possible. It was not until the 1970s, however, that double-blind, randomized, placebo-controlled studies became the standard in scientific studies on the effectiveness of drugs , as recommended by the Food and Drug Administration .

In 1955, the Journal of the American Medical Association published an article by anesthetist Henry Knowles Beecher (1904–1976) entitled "The Powerful Placebo". Beecher evaluated 15 different placebo studies for the treatment of headaches, nausea or pain after operations and came to the conclusion that of the total of 1082 patients who took part in these studies, an average of 35% responded to placebos - a percentage that which was quoted frequently afterwards. For the first time, the placebo effect was quantified and scientifically documented on a relatively broad basis. In German-language publications, the term “placebo” appears for the first time in connection with controlled clinical studies at the end of the 1950s.

In the late 1970s, another topic was added to placebo research after the discovery of endorphins. An American research group has shown that it was possible to achieve endorphin release with placebos and thereby switch off pain receptors. This convinced them that they had tracked down a mechanism of action of the placebo effect. At almost the same time, Robert Ader and Nicholas Cohen were experimenting with a strain of mice that spontaneously became ill due to an overreaction of the immune system that is usually treated with an immunosuppressive drug. The two researchers were able to show that conditioning could replace the verum with sugar water. This made it clear that the placebo effect obviously cannot be reduced to a special, interpersonal interaction relationship.

At the beginning of the 1980s, there was a further development: in 1983, the American anthropologist Daniel E. Moerman of Michigan University suggested replacing the term “placebo effect” with meaning response (“reaction to meaning”).

The fact that placebos still have a bad reputation is partly due to their mode of action, which for a long time could only be explained with the help of psychological factors. Nevertheless, anonymous surveys of doctors and nurses have shown that a large number of them have already consciously used placebo effects. There are estimates that 20% to 80% of the effects of drugs are caused by placebo effects.

commitment

research

Placebos are used in research. Placebo-controlled, double-blind , randomized studies are used to closely examine the therapeutic effectiveness of drugs. Some of the test persons receive the drug to be tested (verum) , while the control group receives a placebo that is identical (in terms of appearance, taste and, if necessary, with the side effects of the verum). A difference between the measured effects in both groups in favor of the verum can thus be regarded as its effectiveness. This effect of the verum can be larger or smaller than the placebo effect. The statistical significance of the effect found in scientific studies and speaking for the verum (which in this context must be distinguished from the relevance of the effect of the verum) is one of the most important prerequisites for the approval of a drug by the responsible health authorities .

  • The studies in which neither the doctor nor the patient know whether the placebo or verum was administered are double-blind. This rules out any influence on the result. The double-blind approach can present major challenges in conducting studies in which the verum is not available in a form that can easily be converted into a placebo. Their execution can then possibly only be implemented imperfectly.
  • Randomized means that the control group is determined by chance, for example by drawing lots. This prevents factors such as the stage of the disease from being unconsciously included.

Placebo therapy

The placebo effect plays a more or less important role in any treatment success. Pure or supplementary placebo therapies are also often used in clinical practice. The use of placebos to treat symptoms is ethically controversial. Especially in pain therapy, placebo effects can provide a strong positive support for the treatment.

A study of patients with irritable bowel syndrome who received three differently intense placebo treatments shows how effective placebo effects can be for certain symptoms . The first group was only examined, the second received a sham acupuncture and the last sham acupuncture in connection with empathic , attentive, trusting conversations. In the group with sham acupuncture, the symptoms improved significantly compared to the untreated group, and in the group with sham acupuncture and additional discussions, the improvement in symptoms was again significantly greater than in the group that was only treated with sham acupuncture.

The placebo researcher Bertrand Graz considers the correlation between the positive expectations of the doctor and the healing success of a treatment to be so important that he has a new name for this effect factor curabo effect (curabo: lat. "I will heal") instead of placebo (lat. " I'll please ”) suggests.

According to a number of scientists, the placebo effect is not to be equated with spontaneous healing , even if it is assumed that similar biochemical processes can be observed in both . With spontaneous healing, the body eliminates the disease without any knowing outside help. With the placebo effect, on the other hand, the body is stimulated by external influences that are supposed to have an intensifying effect on healing . This thesis contradicts the opposite opinion, according to which the placebo effect is exclusively due to spontaneous remission, natural fluctuation of symptoms and subjective influence on the results on the part of doctors and patients (see below).

Further areas of application

Another area of ​​application in clinical practice is maintaining the intake habits of an active ingredient that is administered intermittently (a typical example is the birth control pill , in which the active ingredient is suspended for one week per cycle).

Triggers for placebo effects

The placebo effect does not work for every patient. According to one study, 35% of people respond to the effects of placebo treatment. It is not so much the personality that plays a role, but rather psychological factors that cause somatic changes. Placebo effects can be triggered by evoking expectations or by a conditioned stimulus . The neuronal activations triggered in the brain can influence the metabolism and thereby cause physical reactions.

Expectation

Many placebo researchers consider positive expectations of treatment to be the most important prerequisite for the occurrence of a placebo effect. Expectations regarding the effectiveness of a treatment depend on many factors. This includes individual basic attitudes to certain treatment methods or practitioners, general opinions about the effectiveness and ineffectiveness of treatment methods or about the curability of a disease. The factors that influence expectations also include behavior, professional status or the good reputation of the practitioner. A practitioner who takes time for the patient, reacts empathically to the patient and is convinced of his treatment, strengthens the patient's expectations.

Furthermore, treatment modalities have an influence on expectations. Invasive measures such as injections or surgical interventions arouse greater expectations than the oral administration of drugs or placebos. In 2008 it was experimentally demonstrated that the price quoted for a dummy drug alone influenced the placebo effect. A specified high price had a stronger placebo effect than a lower price. It has also been proven that the color, size and shape of oral preparations can have an impact.

A representative New York study from 1970 on asthma patients shows, for example, how extreme the effects of expectations on the body are. They were given two different drugs: isoproterenol, which dilates the bronchi and carbachol , which narrows the bronchi. In the latter, an aggravation of the asthma is to be expected. After the administration, the lung volume and air flow of each patient were measured. One time the patient was told what drug it was, the other time they were told that they were getting the exact opposite drug.

As a result, it was primarily found that the drugs work better if the patient knows which drug he is receiving. Of far greater interest in this case is the fact that the measured lung volume and airflow actually changed positively in the patients who received carbachol but believed they were receiving isoproterenol - and vice versa. These were not side effects known to occur for the drug in question under normal circumstances. This astonishing result shows that under certain circumstances the expectation can support the placebo effect so strongly that it not only cancels the chemical effect, but can even reverse it.

However, unblinded blind studies are of dubious value and unblinded test subjects tend to massively falsify the results through prejudice-laden behavior.

A subsequent study, which also examined the extent to which expectations influence lung function, could not confirm these results.

Other more recent studies that examined the placebo effect in asthma patients also come to the conclusion that neither the placebo nor the expectations affect lung function. According to the much higher scientific standard, these studies have an additional control group of untreated patients. The results were the same in all studies: the administration of placebo could only positively influence the subjective parameters expressed by the patients themselves, but not the objective parameters. An improvement in lung function could only be achieved through the drugs used.

Conditioning

The classical conditioning is decisively influenced a mostly unconsciously learned response to a stimulus, so this factor the effect of placebos without the knowledge of the subject.

In a complex series of experiments, Amanzio and Benedetti were able to demonstrate in detail that a pain-reducing placebo effect can be triggered both by cognitively induced expectations and by classical conditioning.

Classical conditioning says that a new, conditioned reflex can be added to the natural, mostly innate reflex . Given is an unconditioned stimulus (US), which triggers an unconditioned reaction (UR) as a reflex. If a previously neutral stimulus (NS) is presented several times before the US, the latter becomes a conditioned stimulus (CS). It now also triggers a reflex reaction (the conditioned reaction CR), which is usually very similar to the unconditioned reaction UR.

Placebo conditioning was demonstrated in an animal experiment by Manfred Schedlowski on rats. For this purpose, heart transplant rats received a sweetener solution ( saccharin ) in connection with the drug cyclosporin A , which has an immunosuppressive effect. A control group received the drug in conjunction with normal water, which has no conditioning effect on the rats. The drug was discontinued three days after the operation. The effect persisted in the conditioned rats.

According to a more recent study, these results can also be transferred to humans. In this study, the rats' saccharin was replaced with a green drink with a lavender odor and strawberry flavor. In a double-blind, placebo-controlled study design, the test subjects received the immunosuppressant cyclosporin A together with this drink in the first week of the experiment. In the second week of the experiment, the drink was administered together with placebo capsules. Similar to the specific cyclosporin A effect, a clearly suppressed synthesis of the relevant cytokines , interleukin-2 and interferon , could be determined.

Placebo effect of invasive measures

Not only drugs, but also operations have a placebo effect. In an experiment in Houston, Texas, 120 patients with knee osteoarthritis were operated on; 60 received superficial incisions on the skin. After two years, 90 percent of patients in both groups were satisfied with the operation. The only difference was that those who had not operated on felt less pain than their control group. Whether this indicates the active effect of a placebo operation, or rather negative effects from the actual operation, is controversial.

A similar experiment was carried out in a Dutch clinic. A laparoscopy was performed in 200 patients, and a random decision was made as to whether the operation would be performed or not. Thereafter, the patients were observed for a year; the two groups hardly differed. Once again, however, the objection must be raised that the operation could simply be an ineffective treatment.

Prospective, controlled, blinded clinical studies are considered to be the gold standard for evidence-based medicine and are the basis of the guidelines developed by scientific societies, which are intended to improve patient care or ensure optimal therapy. In surgery too, clinical studies should prove whether a new procedure is safe and effective. There are only about twenty clinical studies in surgery worldwide in which patients from control groups received a sham treatment. There has been evidence in the past that placebo-controlled studies can be meaningful in surgery. A classic example is a study from 1959: In patients with angina pectoris, doctors either ligated the thoracic artery on the left side or only pretended to stop the blood flow. The symptoms improved in 80 percent of the patients, both in the verum and in the placebo group. The effects of transmyocardial laser revascularization in patients with refractory coronary ischemia are also apparently due to a placebo effect, as a study from 2000 showed. When using stents in stable angina, a randomized, double-blind, placebo-controlled study found a placebo effect in terms of alleviating symptoms.

A good example of the placebo effect is the use of botulinum toxin for chronic tension headaches . Here the response rate was 70%, but it was just as high for the injection of botulinum toxin into the neck and head muscles as for the injection of isotonic saline solution . Again, this is an example of how invasive procedures have a significantly higher placebo effect than drug therapies. A study carried out by Relja et al. On 495 migraine patients also produced similar results .

In a current meta-analysis (December 2016), researchers from Oxford University investigated the extent of the placebo effect in surgical interventions. A database search identified 88 controlled studies, 47 of which were suitable for further statistical analysis. It was investigated to what extent the sham treatment has a positive effect on the patient. When subjective parameters are used for the analysis, a strong placebo effect was observed. However, if objective criteria were used to control the success of the treatment, the picture was different: In the studies that recorded objective criteria, no statistical evidence of the effectiveness of a sham intervention could be found.

Effect of open placebo treatment

There are indications that open-label placebo therapy or nonblind placebo therapy , which takes place with the patient fully informed and with the patient's conscious consent, could also be effective. In the study published in 2010, the 80 participants who suffered from irritable bowel syndrome were informed in detail beforehand about the placebo effect, and possible positive effects of placebos were mentioned. As a hypothesis for a possible mechanism of action, one of the authors of the study, the psychologist Irving Kirsch, named an activation of the patient's self-healing powers as a form of self-regulation .

Placebo effects in animals

Placebo effects are also known in animals and are the subject of research. In addition to the aforementioned rat experiment on immunosuppression, conditioning with regard to morphine (already by Pawlow) and insulin was shown. Whether an expectation model can be transferred to animals has not yet been empirically investigated. Conditioning, like expectations, is based on experience and learning. Thus, these two plausible explanatory approaches are limited to repeated treatments with clear improvement. However, this is  rarely the case in practice - for example with alternative therapies such as acupuncture , herbal remedies or homeopathy . Repetition can be controlled in randomized clinical trials. It is thus possible to exclude the factors conditioning and expectation, and animal studies can be more meaningful than studies with human subjects in order to differentiate any specific effects of alternative therapies from placebo effects. In addition, the placebo group generally comes close to a situation without treatment, a natural cure.

While the role of opioids (see below) in placebo phenomena in animals is unknown, there are many studies of the effects of human contact on the physiological state and health of animals. To the extent that they can develop sympathy and empathy, the attitude towards the therapist (or owner) - as has been demonstrated in humans - can possibly influence the result of the treatment. According to placebo researcher Paul Enck, such a placebo-by-proxy effect can be observed particularly in horse keeping.

Influential effects

Some previous studies looked at the physical aspects of tablets and capsules. They showed that the perception of the tablets is influenced by their color. However, no statistically significant effect could be shown in the clinical study. Studies have also shown that capsules are perceived as more effective than tablets. The number of tablets also influences the perception of the tablet strength. The brand name and symbolism can also play a role. Placebo effects are evidently more pronounced in analgesia , the more the analgesic effect of a substance becomes known. Injections produce a stronger placebo effect than drugs taken orally. Even stronger placebo effects can be achieved with operations. In an arthroscopic study of the knee, no differences in pain improvement were found between patients who actually had surgery and those who only got cuts and sutures. However, there was a significant reduction in pain in both groups.

The expectation of a drug can also be influenced by personal history with doctors or their style of interaction. For example, one study randomly divided patients with the same symptoms into different groups. One group was given a solid diagnosis and promised speedy recovery; patients in the other group were told they did not know what condition they had. Indeed, the patients in the group who received a specific diagnosis and were promised improvement did more often than the patients in the group without a diagnosis.

If too many negative details about a drug are revealed by the doctor, this can lead to a nocebo effect.

Mechanisms of action of placebo effects

The exact mechanisms of action of the placebo effects have not yet been adequately researched. Especially neurobiological research since the 1990s has contributed a lot to the understanding of the placebo phenomenon . Most often, placebo effects in the area of pain and analgesics have been investigated neurobiologically. Their mechanisms of action in the areas of the immune system , depression and movement disorders ( Parkinson's disease ) have also been successfully researched.

pain

Opioids have been one of the most widely used pain relievers for centuries . Opioids bind to opioid receptors found on cells in different areas of the nervous system. The attachment increases the perception of pain in the brain, e.g. T. also reduces the transmission of pain to the brain.

Opioids work as pain relievers because they have a similar structure to the body's own opioids, the endorphins , and therefore bind to the corresponding receptors. When researching endorphins more closely, a problem arose: molecules in the brain find it more difficult to get into the body's bloodstream ( blood-brain barrier ). In the normal way -  blood sampling and subsequent analysis  - it was not possible to make correct statements about the endorphin content of the body. A study with naloxone , a substance that temporarily blocks the receptors for endorphins, appeared to show that positive placebo effects can be reversed by administration of naloxone. It was now thought that the placebo effect had been found. Since placebos are not only effective against pain, this is only an insufficient explanation. It was later discovered that naloxone can cause pain without affecting endorphins. It has now been found that there are at least five different types of endorphins and three different types of endorphin receptors.

So this theory cannot fully explain the effect of placebos. However, it is likely that the endorphins are involved in the pain relief from placebo. In the more recent literature there is increasing evidence that the reduction of negative emotions plays a role in the pain-relieving effect of placebos.

In a more recent study, it was possible to use magnetic resonance imaging to demonstrate that a sham analgesic can inhibit the activity of neurons in the spinal cord that specialize in processing pain stimuli ( nociceptors ). According to this, it is proven that psychological factors can not only reduce the subjective pain sensation, but can also have measurable effects on pain-related neuron activities at the first stage of pain processing in the central nervous system .

Stress and immune system

The human body is very sensitive to stress . Often people who are exposed to high work stress suffer from headaches or high blood pressure .

Different areas of the brain such as the amygdala (almond kernel, responsible for the emotional coloring of experiences) or the hippocampus (responsible for the transfer of information from short to long-term memory) react to emotional changes. They are connected to the cerebral cortex , the thinking and switching center of the brain. This in turn is connected to the hypothalamus . The hypothalamus lies outside the blood-brain barrier (see above). Thus it can be influenced by chemical substances in the bloodstream . When the body is under stress, more corticotropin-releasing hormone (CRH) is produced here. The CRH moves to the nearby pituitary gland , the pituitary gland. The pituitary gland, stimulated by the CRH, produces the adrenocorticotropic hormone ( ACTH ). The ACTH reaches the adrenal gland through the bloodstream . The steroid cortisol is then formed in the outer area . Among other things, cortisol increases blood sugar levels and reduces immune reactions . In another area, more catecholamines are formed, which have a strong effect on the heart and blood vessels.

The human body is now briefly prepared for a dangerous situation. Attention is increased, as is pulse and blood pressure , while at the moment unnecessary functions such as digestion are put on hold. The high cortisol level ensures that more sugar is available in the blood for quick burning. In the long term, however, this condition is the cause of lower back pain and tension headaches. Now, studies can measure cortisol and catecholamine levels by simply drawing blood to see if taking placebo reduces them.

A number of older studies show that placebos work best in people who come to the doctor with a little fear. If the cortisol and catecholamine levels were very low in the beginning as a stress indicator , no decrease could be achieved, and if they were very high the decrease might not be enough to get clear results. This theory believes that the placebo effect is particularly effective in reducing stress.

Ethical aspects when giving placebos

In treating diseases

For legal and ethical reasons, placebos may only be used in the treatment of complaints with the patient's consent. On the other hand, once the patient has been fully informed, placebos show little or no effect. In the past, these contradicting facts have repeatedly led to discussions about the extent to which circumventing the legal provisions and ethical principles is justifiable for the benefit of the patient, for example if it is feared that prolonged administration of painkillers could lead to overdosing. In surveys, up to 50% of the doctors surveyed state that they have used ineffective or ineffective drugs at least sometimes.

In clinical trials

The General Assembly of the World Medical Association (World Medical Association, WMA) in Seoul in 2008 calls in a revised version of the Declaration of Helsinki a more limited use of placebos in clinical trials for ethical reasons. The use of placebos is then only justifiable if there is no other effective treatment. Exceptions are permitted if there are compelling and scientifically conclusive methodological reasons and if serious or irreversible harm to the patient is excluded. In a second amendment to the declaration, the World Medical Association demands that patients not only have to be informed about the study results, but also have to receive the examined treatment if it has advantages over another treatment.

Clinical relevance

To examine the effectiveness of drugs, placebo-controlled, double-blind, randomized studies are carried out. It is often observed that the condition of the patients in the placebo group also improves. This led to the widespread belief that placebos themselves are potent.

Several meta-analyzes by various authors that checked the existing literature on the placebo effect, however, came to the conclusion that the observed effects with regard to the placebo effect did not meet the strict scientific criteria. It has been found that the response seen in the placebo group in a clinical trial is often mistakenly equated with the placebo effect. The observed effects can usually be explained by factors that are not related to the placebo administration. These include: the natural course of the disease, spontaneous improvements, regression to the mean, additional treatments and other non-specific effects.

In order to check whether placebos themselves are highly effective, these factors must be taken into account. Therefore, several authors came to the conclusion that the "true" placebo effect can best be determined by comparing the effect that is shown in the placebo group of a study with that of an untreated control group.

This approach was implemented by two scientists from the University of Copenhagen. In a meta-analysis published in the New England Journal of Medicine in 2001 , they investigated the question of whether there is statistical evidence that placebo treatment is superior to non-treatment / treatment abstinence. In a review of a total of 114 randomized studies, they found no evidence that placebos had a greater effect than therapeutic nihilism . A study by the same authors published three years later, which included a further 52 randomized studies, confirmed this view.

The authors' views have been criticized for various reasons. Very different studies were included in the meta-analyzes. If the studies are differentiated into those in which peripheral physical parameters were examined (such as high blood pressure, asthma, hyperplasia, anal fissure, bronchitis) and those in which bio-chemical parameters were examined, it becomes apparent that significant improvements are achieved in the physical parameters Placebo effects could be measured. This applies to half of the studies examined. In contrast, the administration of placebo led to a statistically significant deterioration in the bio-chemical parameters. In clinical trials, placebos are not as effective because the people being treated do not know whether they are receiving real treatment or fake treatment. In studies where patients are convinced they are getting the real treatment (and not just maybe), the placebo effect is stronger.

In a third meta-study in 2010, Hróbjartsson and Gøtzsche found - albeit very variable or small - soothing effects of the use of placebo on pain and nausea, with greater uncertainty also associated with phobia and asthma . No statistically significant effect was found for the following more easily observable symptoms or diseases: smoking, dementia , depression, obesity , high blood pressure, insomnia and anxiety. Overall, larger effects were also reported in small studies, those that specifically examined placebo effects, and when patients were not aware of a possible placebo administration.

British rheumatologists analyzed 198 placebo-controlled studies with osteoarthritis patients . 14 of these studies had an untreated control group . This allowed a meta-analytical comparison between placebo and untreated patients, which in turn enabled statements to be made about the size of the effect of placebo. The analyzes show that placebo not only reduces pain, but also improves function and reduces the measured joint stiffness . The effects are both statistically significant and clinically relevant. The placebo effect is particularly noticeable if the placebo therapy was not administered orally, but instead involves injections or acupuncture needles .

Drug market

Placebos are sold in the form of coated tablets, tablets and suppositories. Trade names: P-coated tablets, P-tablets, P-suppos. Placebos are only available from pharmacies.

literature

Web links

Wiktionary: Placebo  - explanations of meanings, word origins, synonyms, translations

Individual evidence

  1. ↑ Placebo effects and their use in medical practice. Online edition of the Medical Tribune. Placebo effects and their use in medical practice ( Memento from August 5, 2012 in the web archive archive.today ).
  2. ↑ Even with placebo: observe four basic ethical principles. (No longer available online.) In: springermedizin.at. April 16, 2009, archived from the original on February 3, 2015 ; Retrieved February 9, 2015 .
  3. ↑ a b Thure von Uexküll , Wolf Langewitz: The placebo phenomenon. In: Psychosomatic Medicine: Models of medical thought and action. Urban & Fischer bei Elsevier, 2008, p. 311 ff. ( Limited preview in the Google book search).
  4. ↑ Hróbjartsson A, Norup M: The use of placebo interventions in medical practice - a national questionnaire survey of Danish clinicians . In: Eval Health Prof . 26, No. 2, June 2003, pp. 153-65. doi : 10.1177 / 0163278703026002002 . PMID 12789709 .
  5. ↑ a b c German Medical Association on the recommendation of its Scientific Advisory Board (ed.): Placebo in medicine . Deutscher Ärzte-Verlag, Cologne 2011, ISBN 978-3-7691-3491-9 , p. 3 ff . ( online: German Medical Association [PDF]).
  6. ↑ Sabine Bobert-Stützel : Jesus prayer and new mysticism: Foundations of a Christian mystagogy . 1st edition. Buchwerft-Verlag, Kiel 2010, ISBN 978-3-940900-22-7 , p. 267 ( Online: Mystik-und-Coaching.de [PDF]).
  7. ^ Robert Jütte : The early history of the placebo . In: Complementary Therapies in Medicine . tape 21 , no. 2 , April 2013, p. 94-97 ( online: Science direct ).
  8. ^ I. Boutron, C. Estellat et al .: Methods of blinding in reports of randomized controlled trials assessing pharmacologic treatments: a systematic review. In: PLoS medicine. Volume 3, number 10, October 2006, p. E425, doi: 10.1371 / journal.pmed.0030425 . PMID 17076559 , PMC 1626553 (free full text) (review).
  9. ↑ FM Quitkin: placebos, drug effects, and study design: a clinician's guide. In: The American journal of psychiatry. Volume 156, Number 6, June 1999, pp. 829-836. PMID 10360119 (Review).
  10. ^ Placebo in medicine . Published by the German Medical Association on the recommendation of its Scientific Advisory Board, 2011 ( ISBN 978-3-7691-3491-9 ), p. 7.
  11. ↑ Ian Gilron et al .: Morphine, Gabapentin, or Their Combination for Neuropathic Pain . 2005, doi : 10.1056 / NEJMoa042580 .
  12. ↑ U. Wiesing: Who Heals Is Right ?: about pragmatics and plurality in medicine. Schattauer Verlag, 2004, ISBN 3-7945-2304-0 , p. 92 ( limited preview in the Google book search).
  13. ^ F. Benedetti, HS Mayberg et al.: Neurobiological mechanisms of the placebo effect. In: The Journal of neuroscience. Volume 25, number 45, November 2005, pp. 10390-10402, doi: 10.1523 / JNEUROSCI.3458-05.2005 . PMID 16280578 (Review).
  14. ↑ a b P. Enck, S. Zipfel, S. Klosterhalfen: The placebo effect in medicine. In: Federal Health Gazette. June 2009, Volume 52, Number 6, pp. 635-642 doi: 10.1007 / s00103-009-0849-x
  15. ↑ Dorothea Kupferschmidt-Neugeborn: "Heal into time and other people." Shamanism and analytical psychology in the poetic aesthetic of effect by Ted Hughes. Edition, Gunter Narr Verlag, Tübingen 1995, ISBN 3-8233-5027-7 , pp. 62-67.
  16. ↑ GS Kienle, H. Kiene: The powerful placebo effect: fact or fiction? In: Clin Epidemiol. 50, 1997, pp. 1311-1318. doi: 10.1016 / S0895-4356 (97) 00203-5 .
  17. ^ E. Ernst : Concept of true and perceived placebo effects. In: BMJ. 311, 1995, pp. 551-553.
  18. ^ Matthias Breidert, Karl Hofbauer: Placebo: misunderstandings and prejudices . In: Deutsches Ärzteblatt . tape 106 , no. 46 . Deutscher Ärzte-Verlag , November 13, 2009, p. 751–5 , doi : 10.3238 / arztebl.2009.0751 .
  19. ↑ More expensive equals better? Certain brain structures make us more susceptible to “marketing placebos” . scinexx.de ( Rheinische Friedrich-Wilhelms-Universität Bonn , January 22, 2015). Based on: Hilke Plassmann, Bernd Weber: Individual Differences in Marketing Placebo Effects: Evidence from Brain Imaging and Behavioral Experiments. In: Journal of Marketing Research. No. 4, 2015, pp. 493-510, doi: 10.1509 / jmr.13.0613 .
  20. ↑ Plato Charmides 155e.
  21. ↑ Plato Politeia 389b.
  22. ^ Robert Jütte : The History of Placebo . In: World Medical Journal . No. 56 , 2010, p. 109-114 .
  23. ^ Robert Jütte: Hahnemann and placebo . In: Homeopathy . No. 103 , 2014, p. 208-212 .
  24. ↑ Michael Stolberg : Homeopathy on the test. The first double-blind experiment in medical history in 1835 . In: Münchner Medizinische Wochenschrift . No. 138 , 1996, pp. 364-366 .
  25. ^ ME Dean: An innocent deception: placebo controls in the St Petersburg homeopathy trial, 1829-1830. In: Journal of the Royal Society of Medicine. Volume 99, Number 7, July 2006, pp. 375-376, doi: 10.1258 / jrsm.99.7.375 . PMID 16816271 , PMC 1484568 (free full text).
  26. ^ ME Dean: The Trials of Homeopathy. Origins, Structure and Development . KVC, Essen 2004.
  27. ↑ George Löhner: The homeopathic salt experiments in Nuremberg: As an appendix: An example of a homeopathic healing method. 1835. ( limited preview in Google Book search)
  28. ↑ a b c H. K. Beecher: The powerful placebo. In: Journal of the American Medical Association. Volume 159, Number 17, December 1955, pp. 1602-1606. PMID 13271123 .
  29. ^ Ray M. Merrill: Introduction to Epidemiology. Jones and Bartlett, 2009, ISBN 978-0-7637-6622-1 . ( limited preview in Google Book search)
  30. ^ JD Levine et al .: The mechanisms of placebo analgesia . In: Lancet . tape 2 , 1978, p. 654-657 , PMID 80579 .
  31. ^ Daniel E. Moerman: Physiology and Symbols: The Anthropological Implications of the Placebo Effect . In: Daniel E. Moerman et al. (Ed.): The Anthropology of Medicine . JF Bergin Publishers, New York 1983, pp. 156-167 .
  32. ↑ Carsten Binsack, Hilmar Liebsch, Kristin Raabe , Corinna Sachs: The Placebo Effect - Faith as Medicine? ( Memento from January 19, 2012 in the Internet Archive ) (PDF; 759 kB) Quarks & Co , p. 14; Retrieved April 25, 2009.
  33. ↑ M. Bernateck, M. Karst, S. Eberhard, W. Vivell, MJ Fischer, DO Stichtenoth: Placebotherapie. Analysis of scope and expectation in a maximum care clinic. In: The pain. February 2009, Volume 23, Number 1, pp. 47-53 doi: 10.1007 / s00482-008-0733-x
  34. ↑ How well pain therapy works also depends on expectations. Family doctor highlights from the German Pain Congress. In: MMW-progress of medicine , No. 51–52 / 2007 (149th year), p. 6.
  35. ↑ TJ Kaptchuk, JM Kelley et al .: Components of placebo effect: randomized controlled trial in patients with irritable bowel syndrome. In: BMJ. Volume 336, number 7651, May 2008, pp. 999-1003, doi: 10.1136 / bmj.39524.439618.25 . PMID 18390493 , PMC 2364862 (free full text).
  36. ^ Bertrand Graz: Let us call it “Curabo effect”. In: BMJ. April 15, 2008.
  37. ↑ RL Waber, B. Shiv et al .: Commercial features of placebo and therapeutic efficacy. In: JAMA. Volume 299, Number 9, March 2008, pp. 1016-1017, doi: 10.1001 / jama.299.9.1016 . PMID 18319411 .
  38. ↑ Placebo, misunderstandings and prejudices. aerzteblatt.de, 2009, accessed on April 4, 2017 .
  39. ↑ TJ Luparello, N. Leist u. a .: The interaction of psychologic stimuli and pharmacologic agents on airway reactivity in asthmatic subjects. In: Psychosomatic medicine. Volume 32, Number 5, 1970 Sep-Oct, pp. 509-513. PMID 4097491 .
  40. ^ H. Bang, L. Ni, CE Davis: Assessment of blinding in clinical trials. In: Controlled Clinical Trials . Volume 25, number 2, April 2004, pp. 143–156, doi: 10.1016 / j.cct.2003.10.016 . PMID 15020033 . Quote: “Success of blinding is a fundamental issue in many clinical trials. The validity of a trial may be questioned if this important assumption is violated. "
  41. ↑ PJ Devereaux, M. Bhandari, VM Montori, BJ Manns, WA Ghall, GH Guyatt: Double blind, you have been voted off the island! McMaster University, Hamilton, Ontario, Canada. In: Evidence-Based Mental Health. 5 (2), pp. 36–37, May 2002. Quotation: “When unblinded, participants may introduce bias through use of other effective interventions, differential reporting of symptoms, psychological or biological effects of receiving a placebo (although recent studies show conflicting evidence), or dropping out ... "
  42. ↑ SA Isenberg, PM Lehrer, S. Hochron: The effects of suggestion on airways of asthmatic subjects breathing room air as a suggested bronchoconstrictor and bronchodilator. In: J Psychosom Res. 36 (8), 1992, pp. 769-76. PMID 1432867
  43. ^ RA Wise, SJ Bartlett, ED Brown, M. Castro, R. Cohen, JT Holbrook et al .: Randomized trial of the effect of drug presentation on asthma outcomes: the American Lung Association Asthma Clinical Research Centers. In: J Allergy Clin Immunol. 124 (3), 2009, pp. 436-44. 44e1-8. doi: 10.1016 / j.jaci.2009.05.041 . PMID 19632710
  44. ^ O. May, NC Hansen: Comparison of terbutaline, isotonic saline, ambient air and non-treatment in patients with reversible chronic airway obstruction. In: Eur Respir J. 1 (6), 1988, pp. 527-30. PMID 3169222
  45. ↑ ME Wechsler, JM Kelley, IO Boyd, S. Dutile, G. Marigowda, I. Kirsch et al: Active albuterol or placebo, sham acupuncture, or no intervention in asthma. In: N Engl J Med. 365 (2), 2011, pp. 119-26. doi: 10.1056 / NEJMoa1103319 . PMID 21751905 .
  46. ↑ M. Amanzio, F. Benedetti: Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated specific subsystems. In: The Journal of neuroscience: the official journal of the Society for Neuroscience. Volume 19, Number 1, January 1999, pp. 484-494. PMID 9870976 .
  47. ↑ Manfred Schedlowski: Conditioned immunosuppression prolongs the rejection reaction after heart transplantation in rats. In: Conditioning and Allergy. 1992.
  48. ↑ Almuth Elisabeth Trebst: Classically conditioned effects on lymphocyte circulation and cytokine synthesis in humans. Dissertation, University of Duisburg-Essen, 2003.
  49. ↑ a b J. B. Moseley, K. O'Malley et al. a .: A controlled trial of arthroscopic surgery for osteoarthritis of the knee. In: The New England Journal of Medicine . Volume 347, Number 2, July 2002, pp. 81-88, doi: 10.1056 / NEJMoa013259 . PMID 12110735 .
  50. ↑ Sham op: the placebo effect also deceives surgeons. In: Doctors newspaper . October 27, 2008.
  51. ↑ Rasha Al-Lamee et al: Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomized controlled trial . In: The Lancet . doi : 10.1016 / s0140-6736 (17) 32714-9 ( elsevier.com [accessed November 3, 2017]).
  52. ↑ Quoted in slightly modified form from: Hans-Christoph Diener: Editorial. In: Akt Neurol. 33, 2006, pp. 531/532, doi: 10.1055 / s-2006-951881 , Georg Thieme Verlag, Stuttgart / New York, reference: SD Silberstein, H. Göbel u. a .: Botulinum toxin type A in the prophylactic treatment of chronic tension-type headache: a multicentre, double-blind, randomized, placebo-controlled, parallel-group study. In: Cephalalgia: an international journal of headache. Volume 26, Number 7, July 2006, pp. 790-800, doi: 10.1111 / j.1468-2982.2006.01114.x . PMID 16776693 .
  53. ↑ Hans-Christoph Diener: Healing of migraines by cosmetic surgeons. In: Akt. Neurol. Volume 33 (2006), pp. 531-532. doi: 10.1055 / s-2006-951881
  54. ↑ SD Silberstein, H. Göbel et al .: Botulinum toxin type A in the prophylactic treatment of chronic tension-type headache: a multicentre, double-blind, randomized, placebo-controlled, parallel-group study. In: Cephalalgia: an international journal of headache. Volume 26, Number 7, July 2006, pp. 790-800, doi: 10.1111 / j.1468-2982.2006.01114.x . PMID 16776693 .
  55. ↑ M. Relja, AC Poole et al .: A multicentre, double-blind, randomized, placebo-controlled, parallel group study of multiple treatments of botulinum toxin type A (BoNTA) for the prophylaxis of episodic migraine headaches. In: Cephalalgia: an international journal of headache. Volume 27, Number 6, June 2007, pp. 492-503, doi: 10.1111 / j.1468-2982.2007.01315.x . PMID 17428299 .
  56. ↑ KA Wartolowska, BG Feakins, GS Collins et al .: The magnitude and temporal changes of response in the placebo arm of surgical randomized controlled trials: a systematic review and meta-analysis. In: Trials. 17, 2016, p. 589. doi: 10.1186 / s13063-016-1720-7 . PMID 27955685 .
  57. ↑ LC Park, L. Covi: Nonblind Placebo Trial: An Exploration of Neurotic Patients' Responses to Placebo When Its Inert Content Is Disclosed. In: Archives of general psychiatry. Volume 12, April 1965, pp. 36-45. PMID 14258363 .
  58. ↑ TJ Kaptchuk, E. Friedlander et al.: Placebos without deception: a randomized controlled trial in irritable bowel syndrome. In: PloS one. Volume 5, number 12, 2010, p. E15591, doi: 10.1371 / journal.pone.0015591 . PMID 21203519 , PMC 3008733 (free full text).
  59. ↑ Kirsch: “We have the capacity for healing physical conditions through psychological means. First, we have to accept that. Studies of placebo effects are great demonstrations of it. You might think of this healing capacity as a self-regulatory mechanism. " Meet the Ethical Placebo: A Story that Heals. Irving Kirsch in an interview with Steven Silberman, Plos Blogs.
  60. ^ David Ramey: Is There a Placebo Effect for Animals? In: Science-Based Medicine . October 25, 2008.
  61. ^ L. Hectoen: Review of the current involvement of homeopathy in veterinary practice and research. In: The Veterinary Record. 157 (8), Aug. 20, 2005, pp. 224-229. PMID 16113167 .
  62. ↑ Jens Lubbadeh: Homeopathy: This is how placebos work in animals. In: Spiegel Online . June 11, 2014, accessed February 9, 2015 .
  63. ↑ K. Schapira, HA McClelland et al: Study on the effects of tablet color in the treatment of anxiety states. In: British medical journal. Volume 1, Number 5707, May 1970, pp. 446-449. PMID 5420207 , PMC 1700499 (free full text).
  64. ↑ a b L. W. Buckalew, KE Coffield: An investigation of drug expectancy as a function of capsule color and size and preparation form. In: Journal of clinical psychopharmacology. Volume 2, Number 4, August 1982, pp. 245-248. PMID 7119132 .
  65. ↑ AJ de Craen, DE Moerman et al: Placebo effect in the treatment of duodenal ulcer. In: British journal of clinical pharmacology. Volume 48, Number 6, December 1999, pp. 853-860. PMID 10594490 , PMC 2014313 (free full text).
  66. ↑ A. Branthwaite, P. Cooper: Analgesic effects of branding in treatment of headaches. In: British medical journal. Volume 282, Number 6276, May 1981, pp. 1576-1578. PMID 6786566 , PMC 1505530 (free full text).
  67. ↑ Nicola Siegmund-Schultze: Pain Research: Just watching works: Positive expectation alleviates pain . In: Deutsches Ärzteblatt . tape 105 , no. 37 . Deutscher Ärzte-Verlag , September 12, 2008, p. A-1889 / B-1628 / C-1592 .
  68. ↑ AJ de Craen, JG Tijssen et al .: Placebo effect in the acute treatment of migraine: subcutaneous placebos are better than oral placebos. In: Journal of neurology. Volume 247, Number 3, March 2000, pp. 183-188. PMID 10787112 .
  69. ↑ TJ Kaptchuk, P. Goldman et al .: Do medical devices have enhanced placebo effects? In: Journal of clinical epidemiology. Volume 53, Number 8, August 2000, pp. 786-792. PMID 10942860 (Review).
  70. ^ H. Brody: The placebo response. Recent research and implications for family medicine. In: The Journal of family practice. Volume 49, Number 7, July 2000, pp. 649-654. PMID 10923577 (Review).
  71. ^ Z. Di Blasi, E. Harkness et al .: Influence of context effects on health outcomes: a systematic review. In: Lancet. Volume 357, Number 9258, March 2001, pp. 757-762. PMID 11253970 .
  72. ↑ KB Thomas: General practice consultations: is there any point in being positive? In: British medical journal. Volume 294, Number 6581, May 1987, pp. 1200-1202. PMID 3109581 , PMC 1246362 (free full text).
  73. ↑ AM Daniels, R. Sallie: Headache, lumbar puncture, and expectation. In: Lancet. Volume 1, Number 8227, May 1981, p. 1003. PMID 6112373 .
  74. ↑ a b Karin Meissner, Ulrike Bingel, Luana Colloca, Tor D. Wager, Alison Watson, Magne Arve Flaten: The Placebo Effect: Advances from Different Methodological Approaches . Mini symposium. In: The Journal of Neuroscience . tape 31 , no. 45 . Society for Neuroscience, Washington, DC November 2011, pp. 16117–16124 , doi : 10.1523 / JNEUROSCI.4099-11.2011 , PMID 22072664 , PMC 3242469 (free full text).
  75. ^ Gerben ter Riet, Anton JM de Craen, Anthonius de Boer, Alphons GH Kessels: Is placebo analgesia mediated by endogenous opioids? A systematic review . In: Pain . tape 76 , no. 3 . Elsevier, June 1998, pp. 273-275 , PMID 9718245 .
  76. ^ F. Eippert, J. Finsterbusch et al.: Direct evidence for spinal cord involvement in placebo analgesia. In: Science. Volume 326, number 5951, October 2009, p. 404, doi: 10.1126 / science.1180142 . PMID 19833962 .
  77. ^ Barry S. Oken: Placebo effects: clinical aspects and neurobiology . In: Brain . tape 131 . Oxford University Press, Oxford November 2008, pp. 2812-2823 , doi : 10.1093 / brain / awn116 , PMID 18567924 , PMC 2725026 (free full text).
  78. ↑ Scientific Advisory Board of the German Medical Association: Statement of the Scientific Advisory Board of the German Medical Association "Placebo in Medicine". July 19, 2010, accessed June 26, 2019 . , Dtsch Arztebl 2010; 107 (28-29): A-1417 / B-1253 / C-1233.
  79. ^ P. Lichtenberg: The role of the placebo in clinical practice. In: McGill journal of medicine. Volume 11, Number 2, July 2008, pp. 215-216. PMID 19148325 , PMC 2582669 (free full text).
  80. ↑ German Medical Association on the recommendation of their Scientific Advisory Board (ed.): Placebo in Medicine . Deutscher Ärzte-Verlag, Cologne 2011, ISBN 978-3-7691-3491-9 , p. 93 f . ( online: German Medical Association [PDF]).
  81. ^ Rüdiger Meyer: Declaration of Helsinki: Better protection of patients in clinical studies . In: Deutsches Ärzteblatt . tape 105 , no. 45 . Deutscher Ärzte-Verlag , November 7, 2008, p. A-2362 / B-2016 / C-1964 .
  82. ↑ TJ Kaptchuk: Powerful Placebo: the dark side of the randomized controlled trial. In: Lancet. 351, 1998, pp. 1722-1725. doi: 10.1016 / S0140-6736 (97) 10111-8 . PMID 9734904
  83. ↑ GS Kienle, H. Kiene: The powerful placebo effect: fact or fiction? In: Clin Epidemiol. 50, 1997, pp. 1311-1318. doi: 10.1016 / S0895-4356 (97) 00203-5 . PMID 9449934
  84. ^ E. Ernst: Concept of true and perceived placebo effects. In: BMJ. 311, 1995, pp. 551-553. PMID 7663213 .
  85. ^ A b K. Meissner, H. Distel, U. Mitzdorf: Evidence for placebo effects on physical but not on biochemical outcome parameters: a review of clinical trials. In: BMC Medicine. Volume 5, 2007, p. 3, doi: 10.1186 / 1741-7015-5-3 . PMID 17371590 , PMC 1847831 (free full text) (review).
  86. ^ A. Hróbjartsson, PC Gøtzsche: Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. In: N Engl J Med. 2001 May 24; 344 (21), pp. 1594-1602. Review. Erratum in: N Engl J Med. 2001 Jul 26; 345 (4), p. 304. PMID 11372012 .
  87. ^ A. Hróbjartsson, PC Gøtzsche: Is the placebo powerless? Update of a systematic review with 52 new randomized trials comparing placebo with no treatment. In: J Intern Med. 2004 Aug; 256 (2), pp. 91-100. PMID 15257721 .
  88. ^ L. Vase, JL Riley, DD Price: A comparison of placebo effects in clinical analgesic trials versus studies of placebo analgesia. In: Pain. Volume 99, Number 3, October 2002, pp. 443-452. PMID 12406519 .
  89. ^ A. Hróbjartsson, PC Gøtzsche: Placebo interventions for all clinical conditions. In: Cochrane Database Syst Rev. 2010 Jan 20; (1). PMID 20091554 .
  90. ^ W. Zhang, J. Robertson et al .: The placebo effect and its determinants in osteoarthritis: meta-analysis of randomized controlled trials. In: Annals of the rheumatic diseases. Volume 67, number 12, December 2008, pp. 1716–1723, doi: 10.1136 / ard.2008.092015 . PMID 18541604 (Review).
  91. ^ W. Zhang, J. Robertson et al .: The placebo effect and its determinants in osteoarthritis: meta-analysis of randomized controlled trials. In: Annals of the rheumatic diseases. Volume 67, number 12, December 2008, pp. 1716–1723, doi: 10.1136 / ard.2008.092015 . PMID 18541604 (review) quoted from: Edzard Ernst : Is placebo an effective anti-inflammatory drug? In: MMW advances in medicine . No. 32–35 / 2008 (150th year), p. 24.