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Placebo 3 - the study of the phenomenon

How do you test the placebo effect, without giving a placebo?

as we have seen In the first part, within the clinical trials the placebo effect is causes a disturbance, a nuisance, measurement noise, a phenomenon that interferes with evaluating the effectiveness of the new treatment at hand. The operators of the clinical trial try to minimize the effect and clean up its effect.

After the shock he suffered the placebo effect In the second part, we continue, as promised, to check what were the findings of the studies that focused on the placebo effect itself.

In order to isolate it and learn about its characteristics and the mechanisms behind it, the researchers developed new and different experimental structures. Here are two sample trial forms:

Overt versus covert treatment (or placebo trial without placebo)
For years, the strength of the placebo effect has been evaluated by comparing a group of subjects who received a "real" treatment and a group of subjects who only believed that they were receiving a real treatment (but received a sham treatment).
So the idea came up to perform the comparison in a different way, without the need to provide a sham treatment at all: as part of such a study, two groups receive some kind of "real" treatment. Members of one group receive the treatment in the usual way while being aware of receiving it, while members of the other group receive the same treatment without their knowledge. It is important to note that the recipients of the covert treatment know that they will receive it at one stage or another, they only Don't know when it will happen.

For example, one group receives an injection of a substance from the nurse while explaining its essence, while a second group receives the substance through an infusion to which they are continuously connected in a computer-controlled manner, at an unknown time. This form of research is called "open-hidden study design".
The purpose of this type of research is to quantify the psychological-social component of the treatment, which comes close to expression in the overt treatment but is absent from the covert treatment. And what do they discover in such experiments? Will a real but covert treatment work less than an overt real treatment?

It was found that treatment undercover in common painkillers Much less effective than giving them openly. These findings have increased Even among healthy subjects in whom pain is artificially induced, and also among subjects who suffered from post-operative pain and were required Prescribe much smaller painkillers if these were given overtly.

Similar findings Elevated in the treatment of anxiety and after treatment Deep stimulation of the brain in Parkinson's patients.

Here's an example From the field of painkillers. The same chemical substance, given in the same amount, is twice as effective and even more so if the patient sees that the substance is being given to him, compared to a situation where he receives it without the "granting ceremony"!

In other words, it is very difficult to separate the placebo effect from the "real" effect of the treatment, even when a completely "real" treatment is given! The very knowledge that the treatment is given affects the patient's experience.

A balanced placebo trial
Another structure of an experiment is called Balanced Placebo Design, according to which the subjects are divided into four groups:

  1. give treatment Plasibo + They say they give treatment True (a lie)
  2. give treatment Plasibo + They say they give treatment Plasibo (Truth)
  3. give treatment True + They say they give treatment True (Truth)
  4. give treatment True + They say they give treatment Plasibo (a lie)

In this way it is easy to isolate the influence of what the people Think they get it, compared to the effect of what they are Really get it.
Here is a video that summarizes many strange findings about the placebo effect, as shown by studies:

The mechanisms of action of the placebo

Why is this happening? and how?

Many experiments have been carried out in an attempt to establish the nature of the placebo effect and reveal the mechanisms behind it.
Gradually, the picture became clearer - it is Dover in a family of different and separate phenomena, which work in different doses and combinations, under different conditions.

The expected experience - the conscious component
The experience of what is expected (Expectancy, Expectations) plays a decisive role in everything related to placebo. Remember the people who passed out when they drank a glass of plain water given to them by a nail, just expecting that to happen?
You have already read The amazing story about the N rays?
From a series of experiments that have been carried out, it appears that awareness expectations mainly affect experienced pain And on mechanical abilities. for example in pain experiments, subjects who received a highly praised placebo responded quite differently than subjects who were told that the placebo was ineffective in relieving pain. Differences following the planting of different expectations among the subjects were also observed regarding Motor skills in Parkinson's patients, and emotions.

intensification of the effect

As we saw in the video, studies in the field of pain have shown that every detail in the positioning of the drug can affect its effectiveness as reported by the users.
מחיר The drug, for example, raises expectations regarding its quality (=its effectiveness), just as it happens with other consumer products such as a home theater system, a garment or a bottle of wine. Dan Arieli describes in his book "Irrational and not coincidental” experiments he conducted in this field. in experiments Tested the level of sensitivity of subjects to pain as a result of electric shocks of different intensities, before and after receiving a "famous" placebo pill for pain relief. The price of the pill was $2.5. almost everything Subjects rated their pain levels as a minority after taking the pill.
But when they took down the מחיר The pill for 10 cents, only About half Some of the subjects reported an improvement in pain levels!
Similar experiments showed that apart from the price, also צבע the pills, size the pills, And the amount of praise and the scientific citations (the fakes) attached to the drugs affected the magnitude of the placebo effect (Sources 57-63).
More generally, it seems thatThe more dramatic the treatment and the greater the expectation, the placebo effect increases accordingly.
An instructive example of the viewing component can be found In this experiment with pain:
Three groups of patients recovering from a certain type of surgery were given a strong dose of pain reliever according to their choice. At the same time, an infusion with a normal saline solution was injected into their veins.
One group was told that the infusion was Strong pain reliever, the second group was told that it was Either with a strong pain reliever or a placebo and to the third group Nothing was said. The extent of the placebo infusion's effect on the pain they experienced was determined by measuring the consumption of the real painkiller: during the three days of the experiment, the group that was told that the infusion contained a placebo supplier of painkiller consumed 20% less, while The group that was assured it was a strong pain reliever consumed 34% less of the real substance, compared to those who were not told anything!
The following story will sharpen the point. We return for a moment to the clinical trials.
During the testing of a new drug for migraines, compare its effect to an existing drug on the market whose effectiveness has been proven, and in addition - to placebo. The original plan was to divide the subjects into three groups of equal size - a proven drug, a new drug and a placebo, but the ethics committee ruled that The number of subjects who will receive a placebo must be reduced To expose as few subjects as possible to the ineffectiveness of the placebo treatment. The results of the experiment were surprising: no significant advantage was found Neither drug About the placebo treatment, not even the one whose effectiveness has been proven in the past!
Where did the effect of the approved drug dissipate? The hypothesis was that the mere knowledge of the subjects that the chance of receiving a placebo is extremely low (1:16), significantly increased their expectations of the treatment, compared to subjects who participated in studies in which the chance of receiving real treatment was announced as only 50%. Indeed, this hypothesis was confirmed In a super review of all the studies done on drugs from this family.
not simple! Every nuance in the form of the experiment affects the results.

Reversing the effect
Not only can placebo potency be manipulated by expectancy, it can even be reverse direction In which he influences!
placebo described As a muscle relaxant it caused muscle relaxation, but if it was described as having the opposite effect - it did cause muscle tension. A placebo described as a stimulant increased heart rate and blood pressure, but when given as a sedative caused the opposite effect.

The power of a soothing word or - the doctor himself as a placebo
in a simple experiment And fascinatingly, 200 people who complained about one or another symptom but were not diagnosed with any specific medical problem, were divided into four groups. Here is what was said and given (or not given) to the members of each group. The same doctor treated them all:
Group A"You will feel better in a few days. There is no need for treatment".
group b"You will feel better in a few days, and the treatment I will give you will make you feel better"+ Placebo treatment is given.
Group C"I don't know what's wrong with you, so I don't give you any treatment. Get back to me if there is no improvement in a few days"
group d"I don't know what's wrong with you, and therefore I do not know if the treatment I will give you will be useful. Get back to me if there is no improvement in a few days"+ Placebo treatment is given.
Two weeks later, 64% of the recipients of the positive diagnosis reported an improvement in their condition (groups A+B), compared to only 39% of the recipients of the uncertain diagnosis (groups C+D). There was no difference between those who received the placebo treatment and those who did not. I mean, the effect was For things that were said, And not For treatment himself.
Here is an instructive experiment added that made use of in sham acupuncture As a powerful placebo, and tried to separate the flu The placebo awarding ceremony itself and the flu therapist-patient relationship surrounded him.
262 subjects who suffered from irritable bowel syndrome received sham acupuncture using special needles that were recently developed especially for this purpose: these needles do not penetrate the skin at all, but give a light stab and are pushed out, into the plastic handle in which they are located. (The principle is similar to the special knives used in the film industry, where the blade does not penetrate the actor's body of course, but is pushed spring-like into the handle).
The subjects received treatments twice a week, for three weeks. Half of them won for a business-related relationship on the part of the therapist (an exchange of about 5 minutes in the first visit), while the subjects in the second group who won for a long introductory conversation 45 minutes with the therapist, during which he showed interest in their situation, empathy, and even instilled in them positive expectations regarding the treatment.
At the end of the study period, the subjects evaluated the degree of improvement in their symptoms and quality of life. The results were amazing: among a group of waiting people who did not receive any treatment, 28% reported an improvement in their condition, among those who received the "sham acupuncture ceremony" alone, 44% reported an improvement in their condition, and among those who received an encouraging and empathetic introductory conversation, the rate rose to 62%!
In other words, if we subtract the 28% that can be attributed to components unrelated to the treatment itself (such as a natural temporary improvement), we get that One conversation at the beginning of the treatment series doubled the treatment success rate! And remember that In both cases, sham treatment is given!
It is interesting to note that significant differences were found between different therapists. This is not surprising if you understand that half of the achieved effect originates from one conversation. Food for thought.
And how exactly does the expected experience occur?
banditti (Beneditti) talks about two mechanisms: the first mechanism is The reduction in anxiety. a mere statement like "I'm about to give you a strong painkiller” is a statement that reduces anxiety. The second mechanism is The reward mechanism. On a neurological level, this is a very specific area of ​​the brain that secretes dopamine when the person Expect a reward something in the form of food, water, sex, money, etc. When the person receives any treatment (real or placebo), the treatment itself is the reward - the expectation that in a short time relief will come.

Classical conditioning - the unconscious component
A different mechanism from the expectation mechanism is the classical conditioning mechanism.

Pavlov (Wikipedia)

In classical conditioning, a repeated association between a neutral stimulus and an active drug component can manifest itself in the fact that later, the neutral stimulus himself will cause a reaction of the medicinal component to which it is matched during the "learning", without it actually being given.
Already at the end of the 19th century, Pavlov noticed that dogs salivate not only at the sight of food, but also at the sight of the person who regularly feeds them. He called drooling at the sight of food a natural reaction or Unconditioned response, and drooling at the sight of the louse feeder conditioned response. The conditioned response results from a link we will learn that takes place between the feeder and the food. In a famous experiment, Pavlov conditioned the dogs to salivate at the sound of a bell ringing (the conditioning was created after enough times in which he rang the bell at the same time as feeding them). Pavlov received a Nobel Prize for his discovery in 1904.
Here is a short video that includes original footage of Pavlov's experiments:

In placebo experiments it was found that the conditioning mechanism works mainly when it comes to unconscious physiological functions such as the secretion of hormones and the functioning of the immune system.

Beneditti tries to illustrate in a somewhat picturesque way The difference between a mechanism the conditioning the unknown to the mechanism the expectation the conscious We talked about it earlier: if the doctor tells the patient "Now I'm giving you a medicine that will increase your growth hormone levels” and giving him a placebo, there was no change in the growth hormone levels in his blood. Expectation has no effect in this case.

In another scenario, the doctor gives the patient a drug that increases the production of growth hormone for several days in a row and indeed higher levels of the hormone are measured in his blood. This is not really surprising either. But the next day, the doctor gives the patient a placebo. At this stage the placebo does work, because conditioning of the treatment with the response has taken place. The placebo action occurs regardless of the patient's expectations. If at this stage the doctor tells the patient "I am giving you medicine now that downloads the hormone levels” – the hormone levels will rise nonetheless.

A similar state of affairs occurs with regard to the immune system - the placebo can work through a conditioning mechanism and not through expectation mechanisms.

That is, in some cases a placebo reaction will occur even without attributing symbolic meanings to the treatment, and this at the most basic biological level, as a result of classical conditioning. (You can read more about this
HERE, HERE, And here).

Combining mechanisms and the snowball effect
In many cases it is difficult to separate the conscious component of the expected experience from the unconscious component of classical conditioning. It seems that both factors exist in their own right and reinforce each other (see for example HERE וHERE) and also the effect of each different mechanism according to the medical conditions in question.

For conditioning to occur, there must be a positive link between the administration of a placebo and a feeling of improvement in the condition. In laboratory experiments, this connection is created by providing an effective treatment several times at the same time as placebo stimulation, and only then, when the conditioning has taken place, can the active agent be removed. But what can create such conditioning in natural situations, in a series of treatments where a placebo is given from the very first treatment?

It is possible that the "experience of the expected" mechanism is what starts the process, and after a certain initial success, the conditioning mechanism begins to operate. This mechanism reinforces the effect, which of course raises expectations the next few times. Both mechanisms lead to the strengthening of the effect and thus reinforce each other.

But in fact it is not even required that the initial expectations lead to improvement. It is enough that an improvement occurred for a reason accidental any If the person attributes the improvement to the treatment, this will strengthen their conscious expectations of future success, thus establishing a process of conditioning. From there the process will continue to strengthen as described above.

Such a process-dynamic view demonstrates the importance of initial conditions. This explains why the patient will be informed about the treatment he is about to receive, and the accompanying superlatives can make a huge difference - they are the ones that will make the first treatment succeed, even to some extent, and from there the snowball will start rolling. This sensitivity to the starting conditions can also explain the great difference in the strength of the placebo response in different cases and for different people.

Another condition can be The general acquired link between a visit to a doctor and a benefit in feeling following the treatment he gives. After enough successful events like this, we may feel relieved of symptoms (such as pain) just because of the visit, similar to the saliva that a dog drools when it hears the sound of the bell.

The placebo effect as a learning process

Sometimes it is enough for people to see positive reactions in others In order to start this vicious circle.
in a fascinating experiment The subjects received painful stimuli and were asked to rate the intensity of the pain on a scale of 0 to 10. The researchers tried to create a learned link between the intensity of the pain and the on or off state of a green light (the placebo in this experiment).

The subjects were divided into three groups. For subjects in the first group just said Because they can expect a reduction in pain in the event that the green light comes on. The subjects in the second group Go through a phase of conditioning During this, every time the light was turned on, the intensity of the stimulus was reduced. The members of the third group Just watch another person (cooperating with the researchers) who acted as if turning on the green light reduced his pain.
After that came the experimental phase in which the subjects evaluated the intensity of the pain that was "given" to them when the green light was on compared to the times when it was off. Of course, the intensity of the stimulus was constant, regardless of the bulb state.

The results: The effectiveness of the green light was little for the subjects who received a verbal promise, but significant for those who went through the conditioning phase. The interesting thing was that the members of the third group Just watched others Those who seemed to respond well to the green light felt a reduction in pain to an almost identical extent as those who underwent conditioning on their flesh!

Researchers talk about a combination of these three elements in a more general learning process, which probably underlies the placebo effect:

  1. Learning from information, relying on language skills, without an experiential element.
  2. Associative learning (conditioning) - creating associative links between factors From personal experience.
  3. social learning, from observing others.

At least in this particular context, it seems that people do learn from the experience of others.
An interesting point to which we will return later, concerns what happens when The subjects were told that they had received a placebo.
in an experiment in which pain was reduced under placebo conditioning, The effect was completely canceled As soon as they discovered to the subjects that they had "worked on them", that is, that in the conditioning process the pain stimulus was weakened to make them believe that the placebo treatment they received at the same time was working. This result strengthens the "expected experience" model and shows that the power of this mechanism cancel the conditioning mechanism, at least in some cases (and this is in contrast to the hormonal experiment in which expectations do not have the power to prevail over conditioning).

Neurobiological mechanisms - the place where subjective and objective meet

So far we have mainly talked about the psychological mechanisms that underlie the placebo response. But in the end, at least according to the approaches prevalent today in neuroscience, every subjective-psychological process also has an expression at the level of brain function, whether at the chemical, electrical or structural level. The difficulty is to locate and isolate the physical factors associated with any psychological experience, but they are there.
When you look at things from this angle, the placebo study is actually the study of the way in which beliefs and expectations affect processes in the brain that are related to perception and feeling, and ultimately mental and physical health.

The neurological study of the placebo effect was founded in 1978 In the work of Levin and his colleagues.
To understand what we are talking about, we will start with a brief explanation about Opioids (opioids). This is a group of compounds that bind to the opioid receptors (opioid receptors) whose role is to transmit pain sensations and other sensory signals to the brain. The binding of opioids to these receptors creates an analgesic effect.
Substances from the opioid family can be given find in nature (in the opium poppy for example. Morphine, known as a pain reliever, is the main component of opium), They can be distilled from natural sources (for example heroin which is synthesized from morphine) or produce them artificially (methadone, tramadol, pethidine and others). But the opioids that will interest us in the context of the placebo are the endogenous opioids - they are secreted by the body and appear naturally in the brain. Their role is to monitor emotional behaviors related to pain, anxiety and fear. The best known among these substances belong to the endorphin family.

Levin's research showed that it is possible cancel the pain-relieving effect of placebo treatment By giving an anti-opioid agent called Naloxone. This indicated that the pain relief caused by the placebo administration was carried out through the secretion of natural opioids in the body.
Many studies that followed strengthened the findings and expanded them. Different placebo mechanisms have been found to work in different chemical ways. Some work by secreting opioids, and some by secreting substances from other families, depending on the specific conditions in which the placebo response was induced.

In recent years, they began to investigate the placebo response in Parkinson's patients as well, and it was discovered that patients achieve Improvement in motor ability A few minutes after they received a placebo that was announced as a strong medicine for their condition. It was found that the action of the placebo is manifested in the release of dopamine.
In addition, they measured electrical activity among individual neurons with an electrode inserted into the brains of Parkinson's patients, and compared the level of electrical activity before and after the administration of the placebo. Not all patients responded to the placebo. Those who did not respond reported a subjective experience of lack of improvement in their condition and no change in their neural activity was measured. In contrast, in those who reported that they felt much better following the sham treatment, a significant decrease in the level of neural activity of the neurons in the specific areas that were monitored was measured!

That is, A clear match was found between the subjective feelings reported by the patients, and the neural activity in certain areas of their brain, in response to the placebo treatment.
In various simulations, the researchers were also able to "see" the placebo reaction taking place in the patients' minds.

The following video shows the effect of the placebo on brain activity related to pain perception:

The research in the field is still in its infancy and the research in the field is very technical and detailed, so I will not delve further into the neurological angle, at this stage. More details for those interested can be read for example HERE, HERE (p. 688), fHERE (pp. 576-582).

So is there Bo or Invo?!

At this point, the reader is probably a little confused. Is the placebo a myth or a powerful phenomenon?
On the one hand We met researchers who showed that when all the biases and factors of natural recovery are removed there is almost no difference left between those receiving sham treatment and those who received no treatment at all, meaning the placebo effect is only a myth.

On the other hand, we reviewed at length a series of studies that showed that classical conditioning, expectation and different learning mechanisms have the power to create impressive effects for placebo treatments.

What is going on here?
In the next entry I will try to make order in the mess and reconcile the contradictions, as much as possible.

3 תגובות

  1. Chinese acupuncture and all the old-fashioned medicines work this way

    There is no doubt that it helps, but what makes the phenomenon worse is that in the last hundred years, medicine has improved so much and people believe more and more in the abilities of science, and this is how positive feedback is created that the drugs do help

    Paradoxically, the improvement of existing drugs strengthened the placebo effect

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