Placebo - And it still works

The real effect of a placebo has been known since Hippocrates. Over the centuries, doctors have resorted to this remedy when they were unable to give a patient a "real" treatment. In the meantime, we know what mechanisms lie behind the effect of placebos and, to some extent, how they can be used in a targeted manner.

In recent years, the placebo effect has become the subject of a separate branch of research at the interface between medicine and psychology. Pharmacists have certainly already experienced it in practice. For example, it can be behind a customer's reluctance to take an auto-idem drug because it allegedly does not work as well as the brand-name drug he is used to. For some, this may indeed be true; in most cases, however, it is likely to be because the customer trusts a no-name product less than the familiar logo on the package. This is also a facet of the placebo effect.

The best-known form of placebo is tablets and dragées without a pharmacological active ingredient. However, the effect can basically occur in any form of therapeutic intervention, including sham injections, surgery or acupuncture, and even in psychotherapy. The placebo effect always accounts for part of the effect of real drugs or medical interventions. The renowned placebo researcher Professor Dr. Manfred Schedlowski from the Institute for Medical Psychology and Behavioral Immunology at the University Hospital in Essen estimates that up to 70 percent of the effect of a "real" therapy can be based on a placebo effect.

Sham surgery

A well-known study on sham operations is that of the American surgeon Bruce Moseley. As a specialist in joint disease, he had numerous elderly people with knee osteoarthritis among his patients, and arthroscopies were part of his routine. At some point, he wanted to know if part of the treatment success was not due to a placebo effect.

He staged completely normal operations with the usual preliminaries such as admission to the hospital, sedative injection, anesthesia and the typical sounds of an operating room, but actually operated on only half of the patients. For the others, he only scored the skin during anesthesia to make the knee bleed a little and gave them a thick suture. To perfect the illusion, the fake surgeons were able to watch a real operation on a monitor just like everyone else, except that it wasn't their own operation.

The result was that the people operated on for appearances were just as satisfied with the treatment after the healing phase as those actually operated on. Moseley regarded this as proof of a placebo effect. At the same time, however, it also showed that knee joint surgery is useless or superfluous in many cases because the complaints also disappear on their own or with less invasive therapy. In fact, this intervention is now no longer considered the treatment of choice for knee joint wear and tear, but is only recommended for certain narrowly defined conditions (1).

A series of analyses also demonstrated the placebo effect in acupuncture. Scientists of the Technical University of Munich around private lecturer Dr. Klaus Linde compared the data of 33 studies, which dealt with the effectiveness of acupuncture for tension headaches and migraine. Overall, the results showed that acupuncture helps very well with both types of pain - but so does sham acupuncture. For tension headache, the real needling was slightly superior to the sham treatment; for migraine, it was the other way around. Here, even better results were achieved with the sham needles than with the real ones (2).

In psychotherapy, a placebo effect can also occur if the therapist has a high reputation or is recommended to the person seeking help by a trusted person. This trust can cause or increase the placebo effect.

How the effect comes about

Two mechanisms underlie the placebo effect: expectation and conditioning. Experts now agree on this. In the case of the branded product, both play a role. On the one hand, the logo of a well-known and established company increases trust in its products and thus the expectation that the medication will help. If the customer has been taking his antihypertensive or rheumatism medication for a long time, conditioning, i.e. a learning and habituation process, also comes into play.

Probably the best known example of how conditioning occurs is Pavlov's dog. His salivation was already stimulated when he only heard the food bell. The connection between the bell and the food had become so solidified over the course of training that the bell already triggered a reaction that normally belongs to the food.

In 1975, Robert Ader and Nicolas Cohen demonstrated that conditioning can go much further. For a time, they gave rats that were previously thirsty sugared water, which the animals pounced on. At the same time, they gave them cyclophosphamide. With this, they induced nausea in the rats, but also suppressed their immune activity. In this way, they conditioned the animals' immune system: sweetened water and immune deficiency went hand in hand. Nausea was particularly formative as a noticeable consequence of drinking. When the researchers could assume that conditioning had occurred, they omitted the cyclophosphamide and instead inoculated the experimental animals against sheep erythrocytes when they gave them the water. Subsequent measurements showed that the rats developed very few antibodies. The water alone was therefore sufficient to suppress the immune system.

This experiment shows on the one hand that the placebo effect does not only take place in the head, but actually causes physiological changes, and on the other hand, what a great influence conditioning has (3).

A more recent German study by Dr. Regine Klinger of the Psychotherapeutic University Outpatient Clinic at the University of Hamburg and Professor Dr. Margitta Worm and Dr. Stephanie Klinger of the Charité Hospital in Berlin shows how conditioning and expectation interact in humans. The researchers told their subjects that they wanted to test a new ointment for pain. They attached electrodes to the arms of the study participants and used them to trigger painful electric shocks. They then applied a drug-free cream to the arms of all the subjects. They told half of them that it was the ointment with a new active ingredient. The other half were told that they were receiving a neutral cream. Subsequently, the subjects were again exposed to a series of current stimuli. In the second phase, the two groups of subjects were again divided. For half of each of the two groups, the researchers reduced the stimulus intensity by 50 percent. These test subjects thus experienced the following: The ointment works, because the pain has decreased. It did not matter whether they knew that it was not a real ointment or not. They were conditioned. The other half of both groups received stimuli of the same intensity as before, so no relief occurred and thus no conditioning. Finally, in the third phase, the researchers exposed all subjects to equally strong stimuli, once before and once after applying the cream.

The result was impressive. The test subjects who believed they had received an active substance and who had been conditioned in the second phase showed the clearest placebo effect. For them, the expectation of receiving an analgesic and the conditioning had reinforced each other by the pain relief that actually occurred. The subjects who had gone through the conditioning phase but knew that the ointment contained no active ingredient also felt pain relief, but not as much. This experiment confirmed the assumption that expectation and conditioning are responsible for the placebo effect (4).

Conditioning seems to work better the longer it has been practiced and the more frequently the conditioning stimulus has occurred. For example, if a sick person has taken a drug for three weeks, the conditioning is less fixed than after six months of therapy. Moreover, it seems to depend on how well the tablet or injection had worked. If, for example, headaches disappear completely after taking a tablet, there may also be significant pain relief with placebo. If, however, a basic - albeit bearable - pain always remains, even a placebo does not work as well.

The lack of conditioning complicates medication in young children. Since they have not yet experienced that a drug alleviates their symptoms, there is little or no placebo effect. This also contributes to the fact that they require a comparatively high dosage of some drugs.

What influences expectation

The second triggering component of the placebo effect, expectancy, can be based on individual ideas and images. Although it is also shaped by experience, symbols and archetypes play a much stronger role, such as the protective mother or the projection of power into the white coat, by virtue of which its wearer can certainly do something against the disease. This symbolic power can be seen, for example, in the fact that the toothache often disappears as soon as the patient stands in front of the dentist's door. The mere expectation that he will be helped right now brings relief.

The expectation runs "via cognitive factors, that is, mental processes localized in the brain in the prefrontal cortex," Schedlowski explains. "It's known because the placebo effect doesn't work in people whose cognitive abilities are impaired, for example, Alzheimer's patients or even severely depressed people."

Using high-resolution magnetic resonance imaging, physicians at the University Medical Center Hamburg-Eppendorf were able to demonstrate that the body releases endogenous opioids in response to an expected pain relief. The same real pain stimulus showed reduced nerve cell activity in the spinal cord (5). The fact that the brain secretes endorphins refutes the frequently drawn conclusion that the pain was only imagined when it could disappear by "nothing".

The expectation is influenced by various factors. The reputation of a clinic or a doctor or the recommendation of trusted people play a role, as do the brand and price of a drug and the size and color of the tablets. Large capsules that are difficult to swallow, for example, arouse higher expectations than drops or small pills. Patients are more likely to trust tranquilizers if they are blue, antidepressants should be yellow, and medicines for rheumatism, arthritis and pain should be red. This also applies to placebos and corresponds to the color associations that are widespread in this country. In our latitudes, yellow stands for sun, light and cheerfulness, blue for water, relaxation and calm, red for warmth, but also alarm and danger. The red color could thus give the impression that it is a particularly penetrating remedy.

The behavior of the doctor plays an important role. If he praises the prescribed preparation, it has a better effect than if he hands over the prescription or medication to the patient without comment. The same applies if he reports that he has had good experience with the drug, that it has always helped the patient so far, or that it is a completely new, promising active ingredient.

The therapist's empathy toward his patient also accounts for much of the success of treatment. "The interaction between doctor and patient, the way the doctor talks to the patient, the way he accepts and educates him, can have a huge impact on the success of a treatment or medication," Schedlowski reports. "If we teach doctors, especially younger doctors, how this works, how to communicate in a medical consultation, how to increase patient compliance, how to approach the patient, how not to process the patient in a minute and a half of conversation and then shove a pack of blood pressure medication across the table, then this part of the placebo effect can be achieved relatively easily."

As far as medicines are concerned, positive interaction between the pharmacist and the customer certainly stimulates the placebo effect, especially in self-medication. If the pharmacist explains why he is recommending this particular medication and describes its mode of action, it will help the majority of patients better than if he simply pushes it across the hand-selling table.

Placebo and pseudo in practice

Physicians can use the stimulus "attention" without coming into conflict with ethics. It becomes more difficult when they want to prescribe starch pills. Because they have to tell their patients - at the risk of nullifying the placebo effect. That's why they usually resort to so-called pseudo-placebos. These are "real" drugs, but in an ineffective dosage, or a vitamin preparation or the like.

There are no figures for Germany on how often this happens in practice. In an anonymous survey conducted in the USA in 2008 among rheumatologists and internists, a good half stated that they regularly used placebo drugs. Five percent prescribed true placebos, while the others used pseudo-placebos, mostly light, over-the-counter pain relievers and vitamins, with a smaller proportion also using light sedatives (6). Surveys in Israel (7) and Denmark showed a similar picture, so that a comparable prescription behavior can be assumed for Germany.

Appearance or reality?

Between placebo and pseudo-placebo lie remedies whose efficacy has not been proven with certainty, such as globules and Bach flowers. While there are studies that attest to the pharmacological efficacy of both, there are even more that come to the opposite conclusion. Against the background that placebos trigger a real effect, however, the significance of this discussion pales.

Patients who want homeopathic remedies take them with a high positive expectation because they correspond to their worldview and preferences. In addition, there is a certain conditioning, since normally every adult has already had the experience in his life that medicines have helped him. This positive experience is transferred to placebos as well as to globules or other substances. Thus, with high probability, the desired effect occurs. Whether this is based on a pharmacologically detectable substance or a placebo is immaterial.

Certainly, common sense and duty dictate that clearly false expectations be dampened and patients be informed accordingly. But in cases where such remedies have been shown by experience to help, there is nothing to prevent their use - if the patient is not threatened by delay of a proven effective therapy.

No effect without side effect

The other side of the "placebo" coin is the nocebo. The Pavlovian dog also provides an example of this. Ivan Pavlov gave one of his dogs morphine injections for a while. From these the animal became sick and had to throw up. After the dog had learned, so to speak, that the injections caused him nausea, Pavlov exchanged the morphine for saline solution. The dog still vomited. The dog showed the side effects of morphine, not the effect.

Again, expectation and conditioning play a role. In the Pavlovian dog, it was a matter of conditioning. In humans, expectation is added. If someone is fundamentally opposed to "chemical hammers," the probability increases that synthetic drugs will have a bad effect on him, but that the side effects will be all the more pronounced. Nocebo effects often manifest themselves in diffuse mild complaints such as malaise, sleep disturbances, fatigue or digestive problems.

Italian neuroscientists led by Fabrizio Benedetti were able to prove that the body converts fear into pain in freshly operated patients. In the case of fear, the intestinal mucosa produces the messenger substance cholecystokinin (CKK), which triggers a pain reaction in the brain. It does not matter what the person is afraid of. It can be the side effects of a drug, radiation, injections or, as in this case, pain after surgery. The Italian physicians discovered that the nocebo effect was less pronounced in their patients after surgery if they administered proglumide. This drug slows down the activity of CKK, so that the brain's pain response is also reduced, although the underlying anxiety remains the same.

To get to the bottom of the nocebo effect and the connection between anxiety and pain in more detail, the scientists did a test. They tied off the forearm of 49 subjects, cutting off their blood supply. Then they gave the test subjects a spring and asked them to squeeze it with their hand as many times as they could stand. The researchers could be sure that this exercise would become quite painful. They told some of the volunteers this beforehand; so they expected it to hurt and built up anxiety accordingly. To the others, they said nothing. When asked about their level of pain, the informed volunteers gave much higher scores after the test than the unaware ones. However, if the informed participants were given proglumide before the test, they felt no more pain than the others. The physicians had thus proven that the nocebo effect plays a major role in the development of pain (8).

Psyche and body interact

In principle, placebo can work for anyone. A typical "placebo personality" does not exist. At least, no characteristics have yet been identified that are common to all placebo responders. "We are all placebo personalities," notes Professor Dr. Paul Enck, head of research in psychosomatic medicine and psychotherapy at the University Hospital of Tübingen. Recent studies suggest that genetic disposition determines, at least in part, who responds to placebo for which symptoms (9, 10).

However, the strength of the effect is also determined by other factors. In addition to the interaction with the physician, it also depends on the situation of the individual. When suffering is high and there is little prospect of a cure, people tend to clutch at any straw. If the doctor gives them hope that the prescribed remedy will help, they are more willing to accept it and "let it work".

For some years now, medical psychologists have been trying to use the connection between the psychological and neurological components, which also underlie the placebo effect, specifically to strengthen the immune system or to restore a wrongly conditioned immune system to normal. This relatively new research branch of psychoneuroimmunology (PNI), according to its own statements, "deals with the interactions between psychological factors and factors of the nervous, hormonal and immune systems in health and disease and thus conducts basic psychosomatic research" (11).

Professor Dr. Dr. Christian Schubert, head of the Laboratory of Psychoneuroimmunology at the University Department of Medical Psychology and Psychotherapy Innsbruck, explains in an interview, "We know today that not only do psychological factors have an influence on the immune system, but conversely immune activities can influence the psyche." For example, the development of depression is also discussed against the background of inflammation. They do not always have to arise from the biography, but could also have immunological reasons.

Classical psychosomatics is limited to researching psychological causes of physical illnesses, but not the reverse. Schubert cites so-called sickness behavior as an example of the reverse mechanism: social withdrawal, increased need for sleep, loss of appetite and listlessness, as virtually everyone is familiar with from colds. "Not so long ago, this behavior was thought to be nonspecific. Today, we know that the immune system releases certain cytokines that set 'highly strategic' effects in the brain to make us change psychologically." These changes, such as just fatigue and the need to withdraw, were aimed at the body channeling its energy into pathogen defense; they were not an expression of general weakness, he said. Chronic inflammations such as rheumatic diseases can therefore also cause or intensify depression.

It is similar with the hormonal system. Here, too, interactions with psychological and immunological stresses can occur. Schubert reports of a patient in whom the mere anticipation of stress was enough to stimulate the release of cortisol. "The lady was already confronted with the stressful event before it had already occurred in real terms. The anticipation of the stress is the real stressor." So the same thing happens as with a nocebo effect. The expectation is enough for the organism to react in a very real way.

The realization of these connections, even though they are far from being fully researched, is being put into practice in psychooncology, for example. Breast cancer patients who receive psychotherapy suffer less from anxiety and disease-related stress, which improves their prognosis. The clinic clown, which now exists in many hospitals, also relies on good humor to speed up recovery, because laughter has been shown to strengthen the immune system. It increases the concentration of T cells, killer cells and antibodies.

Research into the transmission pathways and interrelationships between the psyche, immune system, nerves and hormones could still yield exciting results and help to bring about placebo effects without placebo. /

Sources:

(1) Moseley, J. B., et al., A Controlled Trial of Arthroscopic Surgery for Osteoarthritis of the Knee. N. Engl. J. Med. 347 (2002) 81-88.

(2) Linde, K., et al., Acupuncture for tension-type headache. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No. CD007587; doi: 10.1002/14651858.CD007587.

(3) Ader, R., Cohen, N., Behaviorally conditioned immunosuppression. Psychosomatic Med., Vol 37, Nr. 4 (1975) 333-340.

(4) Pressemitteilung der Deutschen Gesellschaft zum Studium des Schmerzes e. V., ­ 25. 10. 2007. (Press release of the German Society for the Study of Pain e. V., 25. 10. 2007.)

(5) Eippert, F., et al., Direct Evidence for Spinal Cord Involvement in Placebo Analgesia. Science, Vol. 326 (2009) doi: 10.1126/ science.1180142.

(6) Tilburt, J. C., et al., Prescribing placebo treatments: results of national survey of US internists and rheumatologists. BMJ 2008; 337:a1938, doi: 10.1136/bmj.a1938.

(7) Lichtenberg, P., The Role of Placebo in Clinical Practice. MJM 11, Nr. 2 (2008) 215-216.

(8) Benedetti, F., et al., The Biochemical and Neuroendocrine Bases of the Hyperalgesic Nocebo Effect. J. Neuroscience, Bd. 26, S. 2014; doi: 10.1523/JNEUROSCI.2947-06.2006.

(9) Furmark, Th., et al., A Link between Serotonin-Related Gene Polymorphisms, Amygdala Activity, and Placebo-Induced Relief from Social Anxiety. J. Neuroscience 28 ; Nr. 49 (2008) 13066-13074 ; doi: 10.1523/JNEUROSCI.2534-08.

(10) Leuchter, A., et al., Monoamine Oxidase A and Catechol-O-Methyltransferase Functional Polymorphisms and the Placebo Response in Major Depressive Disorder. J. Clin. Psychopharmacology, August 2009, doi: 10.1097/JCP.obo13e3181ac4aaf.

(11) Webseite des Deutschen Kolloquiums für psychosomatische Medizin. - Interviews  mit Professores Dr. Manfred Schedlowski, Dr. Paul Enck und Dr. Dr. Christian Schubert. (Website of the German Colloquium for Psychosomatic Medicine - Interviews mit den Professoren Dr. Manfred Schedlowski, Dr. Paul Enck und Dr. Dr. Christian Schubert.)

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