When was the placebo effect discovered?

The healing power of nothing

Placebo effect

The healing power of nothing

By Bettina Sauer, Berlin


Actually, they shouldn't work at all, those tablets that only consist of starch. You do it anyway. Why? How can drugs help patients without affecting disease symptoms? Answers from placebo research were given at the German Pain Congress.


The experimenter drops one milliliter of the red, watery, bitter tincture onto a cotton swab, hands it to the patient with chronic back pain and repeats: "You are now testing a strong pain reliever with a mobility-enhancing component." The patient pushes the cotton swab into her Cheek pocket, rub it several times over the oral mucosa and let the tincture take effect briefly.


Then she demonstrates exercises that can be used to determine the functionality of back pain patients. She picks up a coin from the floor. She changes from lying down to sitting down. She puts on socks and takes them off again. She completes the test palette faster and more skillfully than before taking the tincture. This is confirmed by video recordings that independent scientists subsequently evaluate. The woman herself feels more flexible and feels less pain at rest and during exercises. The "opioid" works.


Effect without active ingredient


Purely physiologically, this is not possible at all. Because the solution consists only of water, color and quinine for the bitter taste. There is no active ingredient. In this regard, the woman and the other test participants sit on a conscious deception. In truth, the study on a total of 72 patients with chronic back pain is not aimed at developing a new drug, but for placebo research. It forms part of the doctoral thesis that Jens Tretrop from the Department of Psychology at the University of Hamburg published this year. His results show, among other things, that patients' expectations alone are sufficient to alleviate chronic back pain and increase their mobility.


"Since its discovery, the placebo effect has been mystified or viewed with disdain," said Tretrop in a lecture at the German Pain Congress at the end of October in Berlin. "And although it is attracting more and more scientific interest, there is still something very mysterious about it."


Tretrop described the meta-analysis "The Powerful Placebo" published in 1955 by Henry Beecher in the "Journal of the American Medical Association" as a "classic" of placebo research. This is a joint evaluation of 15 placebo-controlled studies, according to which approximately every third of the 1082 patients on the dummy drug had a satisfactory effect. Taking this knowledge into account, it has since been considered the standard to compare the effectiveness of a drug therapy with a placebo. And in most clinical studies, placebos have shown beneficial effects.


Against pain in all its facets


"This is confirmed by current meta-analyzes, particularly in relation to the most diverse facets of pain," said Professor Dr. Paul Enck. In the Department of Psychosomatic Medicine at the Tübingen University Hospital, the psychologist is researching the placebo effect in painful intestinal diseases in particular. "With them it is even in the order of 40 percent," said Enck, "regardless of whether they are more psychological, such as irritable bowel syndrome, or a serious organic cause, such as chronic intestinal inflammation, Crohn's disease."


The placebo effect is not only limited to different forms of drug administration, but also contributes to the healing success of other medical treatments. For example, sham acupuncture has a better pain-relieving effect than placebo pills. Dr. Ted Kaptchuk and his colleagues from Harvard University in Boston only last year based on 270 patients with chronic forearm pain in the British Medical Journal. Some of them were treated with needles that pretended to go into the skin. Instead, they pushed together as soon as they were punctured. Kaptchuk and colleagues consider the ritual associated with it to be the reason for the superiority of sham acupuncture, which is far more time-consuming and care-intensive than taking a pill.


"Realistically," said Enck in his lecture, "the placebo effect is partly due to statistical errors in the test evaluation." However, according to the current state of research, it is also based on two psychological mechanisms that presumably interact: "Suggestion and conditioning."


The latter is a kind of physical learning process based on positive experiences with drugs or medical treatments. Several scientists have proven the phenomenon in humans, including Dr. Fabrizio Benedetti, who and his team at the University of Turin have been working on placebo effects for many years. Among other things, he published a study in the "Journal of Neuroscience" in 1999, according to which a placebo alleviates pain significantly better if test participants were previously given the strong pain reliever morphine several times.


Healthy hope


According to the second psychological mechanism, placebos work because patients or test participants expect them to have a beneficial effect. It is possible that doctors or investigators only really stimulate this hope, as psychologists working with Dr. Lene Vase from the University of Aarhus, Denmark, was given a double meta-analysis in the journal »Pain« in 2002. In it, they compared 23 clinical studies in which placebos were only used as a control with 14 studies on people who looked at the mechanisms of action of placebos. "In the second case, the dummy medication relieved pain about six times as effectively as in the first," said Tretrop, "probably because the investigators aroused expectations in their test subjects." As he did with the back pain patients for his doctoral thesis.


Benedetti also carried out a similar deception and published it in »Pain« in 2001. After an operation, patients were given an infusion with active substance-free saline solution. When Benedetti told them there was a strong pain reliever in it, they would ask for about a third fewer additional opioids over the next few days than the control group, which had not received the misinformation.


As early as the 1990s, Benedetti was also able to prove that the hope of a cure leads to an increased release of endorphins in the brain. These endogenous opioids bind to receptors in the pain-conducting nervous system, reduce its activity and thus ultimately suppress the perception of pain in the cerebrum. To confirm this assumption, Benedetti secretly administered naloxone, an opioid antagonist that blocks endorphin receptors, to pain patients. In most cases, the placebos then had no effect.


The influence of dopamine


"The involvement of endorphins has also been confirmed by brain images over the past five years," said Enck. Accordingly, the administration of a placebo and the associated expectations activate brain regions that otherwise also release endogenous opioids in the course of pain relief. These include above all the cingulum, which is part of the limbic system responsible for processing feelings, and an area of ​​the cerebral cortex behind the forehead.


In addition to the opioid, the brain's dopamine system probably also contributes to the mediation of placebo effects. At least several studies that have appeared since the turn of the millennium show that placebos stimulate the release of this neurotransmitter in the reward center as well as in the basal ganglia and thus improve the mobility of Parkinson's patients. Some again come from the Benedetti family.


Even mind-body interactions seem to be occurring. Among other things, Professor Dr. Manfred Schedlowski and his colleagues in the »FASEB Journal« in 2002 that the human immune system can be conditioned and then reacts to placebos. To do this, the scientists administered a taste-intensive sugar solution to healthy test subjects several times, as well as the drug ciclosporin A, which strongly suppresses the immune system. After a blood sample and a break for a few days, the test subjects were given the sugar solution to drink again, but this time in combination with a placebo. Then blood was drawn again. The laboratory analysis of the samples showed that after conditioning, the taste stimulus alone suppressed the rate of division of white blood cells and the release of messenger substances of the immune system, namely interleukin-2 and interferon-gamma, to a similar extent as ciclosporin.


"The placebo research should still hold many surprises," said Tretrop. But health professionals could already learn a lot from this for their practical work. "By communicating optimistic information about drugs and treatment methods, their effect can be increased considerably." If the doctor, therapist or pharmacist, on the other hand, shows skepticism, be it in facial expression, in body language or in sentences such as "This has already helped some", weakness it can significantly reduce the effect of a drug. In general, the interpersonal level also contributes to the success of most therapies, added Enck: "If health professionals could spend as much time, patience and empathy with their patients as is done in clinical studies, many drugs would most likely work much better."