What we know about placebo and its effects
Fool me if you can
Oleg Lischuk, N+1
Recently, researchers from Northwestern University in Chicago received another confirmation that the placebo effect is not just a subjective reaction, but a phenomenon associated with well-defined changes in brain functions. In this regard, we decided to recall what kind of effect it is, how it was treated at different times, how it works and what we know about it in general.
What is in your term
For the first time, the word "placebo" (from the Latin placebo – "I will like it", "I will make it nice") appeared in everyday use in the XIV century. Then they were called hired mourners at funerals – when burying the deceased, they often began with a line of incorrectly translated into Latin psalm 114 "Placebo Domino in regione vivorum", which means "I will please the Lord in the land of the living" (in synodal translation, this line looks like this: "I will walk before the Lord in the land of the living"). In this context, placebo meant devaluation and substitution of true grief.
The first mention of the term in a medical source dates back to 1785, when in the "New Medical Dictionary" by George Motherby, it was interpreted as "an ordinary technique or medicine". However, already in the 1811 edition of the Quincy Dictionary of Medicine, a placebo is defined as "any medicine designed to please the patient rather than help him."
In the modern sense, a placebo is any deliberate simulation of treatment without the patient's knowledge, which improves his condition. It is any – placebo is not limited to the usual "dummy pill", it can be an injection of isotonic saline solution, imitation of physiotherapy, electrical stimulation, acupuncture, any other manipulations and even surgical operations.
The improvement of the patient's condition when using a technique that does not have a real physiological effect is called the placebo effect. Here it is worth paying attention to the fact that placebo and placebo effect are not identical in meaning: placebo by definition is inert and cannot have any effect in itself, and the effect can be registered and evaluated qualitatively and quantitatively, that's why it is an effect. This often gives rise to a "war of concepts" and attempts to ideologically rework the attitude towards placebo. For example, in 2002, Americans Daniel Moerman and Wayne Jonas conducted a "deconstruction" of the placebo effect and proposed the formulation "meaning response", which, in their opinion, shifts attention from an insignificant "dummy" to the meaning that the patient attaches to it and which is responsible for the effect itself. However, such research strongly smacks of a terminological game that has no significant practical significance.
The reverse of the placebo effect, when the simulation of treatment worsens the condition, was called the nocebo effect (from the Latin nocebo – "I will cause harm").
Hypothesis versus hypothesis
Despite the fact that hundreds of scientific papers have been devoted to placebo and that it is actively used in treatment and in clinical trials, there is still no complete understanding of the mechanisms of its action. Moreover, the views of experts on its significance and its very existence are often diametrically opposed.
Currently, there are two main hypotheses describing the placebo effect. The first of them explains it by the patient's expectations – a person expects to get an effect and gets it. This hypothesis well explains why the placebo effect is stronger in conditions when expectations are high (for example, with a preliminary story about the effectiveness of a drug or method, when prescribing a "dummy" under the guise of an advertised and proven drug, etc.), as well as the correspondence of the placebo action to the expected (for example, the same "pacifier" can cause both a quickening and slowing of the pulse, depending on whether it is called a stimulant or a sedative). However, the concept of expectations poorly explains the development of side effects during treatment simulation (the so-called placebo-nocebo effect) and the presence of a placebo effect in healthy people, and also does not explain at all the possibility of causing it in animals.
The second hypothesis considers the placebo effect as a conditioned reflex. If in Pavlov's dogs, the bell during feeding began to cause salivation and in the absence of food, then for placebo, the appearance of pills, syringes, a "white coat", the environment of a medical institution and similar factors become such a "call". Animal experiments speak in favor of the conditioned reflex hypothesis, in which the imitation of treatment was able to cause a physiological response (in one of the vivid experiments after the administration of the immunosuppressant cyclophosphamide to rats in a flavored saccharin solution, the same solution without the drug caused a weakening of immunity). The weakness of this hypothesis is that it cannot explain the different effectiveness of placebo in different people (and it differs very much) and the influence of expectations on it.
Some aspects of the placebo effect can be equally explained by any of the hypotheses. For example, they fit equally well with the fact that large tablets work better than small ones, capsules are better than tablets, and injections are better than capsules.
As a rule, these hypotheses are opposed to each other. However, in 2004, Steve Stewart-Williams (Steve Stewart-Williams) and John Podd (John Podd) from Massey University of New Zealand, in their detailed analysis of both points of view, proposed to consider them as complementary. Their concept is that the placebo effect is based on the unconscious fixation of the conditioned reflex, which leads to the development of physiological and subjective effects through conscious expectations. These expectations, in turn, depend on awareness, personal qualities and other factors. At the same time, in each specific case, the share of the influence of conditioned reflexes and expectations differs, which can explain both the individuality of the placebo effect and the development of side effects accompanying it.
At the same time, the authors of several meta-analyses of clinical trials in which treatment control was carried out not only by prescribing a placebo, but also by the complete absence of treatment, came to the conclusion that the placebo effect is greatly overestimated, mainly affects the subjective perception of pain and has no special clinical significance. According to critics of placebo, the action that is usually attributed to it, in most cases, can be explained by irregularities in the natural course of the disease, additional treatment, subjectivity of assessments, lifestyle correction during treatment and many other factors.
Other researchers, including Stewart-Williams and Podd, point out significant shortcomings of these meta-analyses, primarily related to the significant heterogeneity of the included diagnoses (several dozen conditions from asthma to purely psychological family problems) and the insufficient number of studies devoted to non-pain in the sample.
Biochemistry and anatomy
The presence and some mechanisms of the development of the placebo effect have been shown in a number of physiological studies. Most of them are devoted to pain relief, since imitation of treatment works better on pain than on other symptoms, and it is most often used with it (the second place belongs to depression).
The first of these studies, conducted in 1978, showed that the introduction of the opioid receptor antagonist naloxone blocks the analgesic effect of placebo. This is how the understanding was born that the mechanisms of the placebo effect involve an antinociceptive (reducing the perception of pain) system, the main neurotransmitters of which are endogenous opioids. The effect of these substances can also be explained by such changes in physiological parameters as a slowing of the heart rate or a decrease in the release of the hormone cortisol by the adrenal glands, which is responsible for the stress response and regulation of immunity.
A number of subsequent studies have confirmed that endogenous opioids, as well as dopamine, serotonin, endocannabinoids and some other neurotransmitters and hormones are involved in the development of placebo and nocebo effects, that is, the administration of placebo causes changes in brain (and not only) biochemical processes. Moreover, with different types of pain, the contribution of different mediators may vary. For example, endogenous opioids are most important if the patient's expectations are high or a placebo is prescribed after synthetic opioids.
Similar changes in the biochemistry of the brain have been shown in a small number of studies on other conditions, in particular, depression, Parkinsonism, asthma and others.
The use of modern imaging methods, such as positron emission and functional magnetic resonance imaging, made it possible to study changes in the activity of various parts of the brain under the influence of placebo. One of its key effects was the activation of the anterior cingulate cortex, which participates in the regulation of a number of physiological (for example, blood pressure and heart rate) and higher nervous (sense of pleasure, emotions, impulsivity, decision-making) functions.
Also involved in the formation of the placebo effect are parts of the brain closely related to the anterior cingulate cortex, such as the prefrontal cortex (responsible for complex cognitive functions, personality traits and expectations; a decrease in its functions in Alzheimer's disease levels the placebo effect), and various structures responsible for emotions, motivation and pain perception (amygdala, nucleus accumbens, hypothalamus and others). Changes in their activity were associated with analgesic and antidepressant effects. Involvement in placebo analgesia of the spinal cord has also been shown. A recent study, with which we started the story, pointed to another area of the brain involved in the formation of the placebo effect - it turned out to be the right middle frontal gyrus, which switches attention between external and internal stimuli.
Research in this area is actively continuing, so we will soon learn a lot about the mechanisms of the placebo effect. For example, neurophysiologists may be able to explain why in some cases a placebo can help (reduce discomfort with irritable bowel syndrome or migraine pain), even if patients know that they are taking a "pacifier".
Tablet or substance
Until the 1950s, medicines and other therapeutic methods were recognized as effective on the basis of the pathophysiological justification of their action given by experts in the relevant field. Comparative studies were practically not carried out.
Despite this, experiments to separate the real effect of treatment from the placebo effect were carried out at that time. The first experience of this kind can be called the work of the British physician John Haygarth, who in 1801 decided to test the effectiveness of the then popular technique of Elisha Perkins (Elisha Perkins). The essence of this "treatment" was to apply rods made of "special alloys" (actually steel and bronze) to the sore spot, which "pull out painful electrical fluids underlying suffering" (by the way, this "invention" received the first patent for a medical device in the history of the United States). Haygarth conducted a study on five patients, using either metal or masked wooden rods, and was convinced that their effect was indistinguishable.
A much larger placebo-controlled trial was conducted at the beginning of the XX century by the German physician Adolf Bingel (Adolf Bingel). He injected 937 patients with diphtheria with either pure horse serum or containing diphtheria antitoxin, and concluded that the antitoxin content did not affect the effect.
In the 1930s, several clinical trials were conducted in the United States and Great Britain, the authors of which prescribed placebo to some patients, calling it by their name in the publication and justifying the meaning of such control by saying that the patient could get better simply from believing in the medicine. In one of these studies, placebo control helped to prove the ineffectiveness of the cold vaccine, although patients noted subjective improvement.
In 1955, Harvard researcher Henry Beecher conducted a review of 15 controlled trials and concluded that placebo was effective in more than a third of cases. Although this work was not without drawbacks, it drew attention to the placebo effect as a significant therapeutic effect and contributed to its being taken into account in the maximum number of scientific papers.
In modern evidence-based medicine, placebo control is an integral part of all clinical trials where it is applicable in any way. If we are talking about trials of a drug or other therapeutic effect, for the proper quality of the results, they must also be randomized (that is, patients are selected into an experimental or control group absolutely randomly) and double-blind (when neither the patient nor the doctor knows what is used in each case to exclude the subjectivity of the specialist when registering the effect). The only exception is the work in which the use of placebo is directly contrary to ethics, for example, when testing a promising treatment that can significantly prolong the life of cancer patients. Placebo or its analogues are used not only in clinical, but also in physiological and psychological studies, if this is possible in principle.
Recently, there have been more and more proposals to introduce a third group into clinical trials that does not receive either experimental treatment or a placebo. According to a number of researchers, this is necessary to distinguish the real placebo effect (associated only with the use of placebo) from the imaginary one, which is a combination of the real effect and the influence of various unaccounted factors, which is automatically attributed to placebo. It was on such studies that scientists relied, who did not find a significant effect in placebo (they were mentioned above).
Times and mores
Historically, doctors have used placebo very widely. In 1807, U.S. President Thomas Jefferson described an example of a "salvation lie" when one of the most successful practitioners of medicine confessed to him that he uses bread pills, drops of tinted water and powders from pecan ash more than all other drugs combined. About a century later, Richard Cabot, a lecturer at Harvard Medical School, wrote that he, "like, I think, any other doctor, was accustomed to using a placebo," but opposed misleading patients.
Nevertheless, in general, the medical ethics of those times considered the use of placebo as a completely acceptable "inevitable deception". In the understanding of doctors, it was supposed to increase the comfort of the patient without any impact on the pathophysiology of the disease. Moreover, it was believed that the more ignorant the patient, the more pronounced his placebo effect.
Currently, there is no consensus on the ethics of using placebo. Some experts consider it unacceptable quackery, discrediting medicine, while others, on the contrary, speak in favor of a deeper study of the effect with a view to its wide application. For example, Harvard placebo specialist Ted Kaptchuk stated: "We have been trying for years to increase the effect of drugs, but no one has even tried to increase the effectiveness of placebo."
The American expert on evidence–based medicine David Newman in his book "The Shadow of Hippocrates" called the current state of affairs the "placebo paradox": on the one hand it looks like an unethical deception of the patient, and on the other - it is unethical not to use any tool that helps. From his point of view, medicine should accept the use of a placebo, provided that the prescribing doctor is "honest, open and believes in its therapeutic potential."
While there is an ongoing ethical debate around placebo, practitioners use it as they see fit. Surveys conducted among Danish and Israeli general practitioners showed that, respectively, 48 and 60 percent of them use placebo systematically. Most often, "pacifiers" were prescribed as "antibiotics" for viral infections, "vitamins" for increased fatigue, as well as to "reject" the patient's requests for an unnecessary drug and reduce the degree of anxiety about the disease. In a similar American survey, it turned out that 24 percent of doctors are ready to prescribe a placebo, just if the patient wants to be treated, 58 percent are against such a practice, and for the remaining 18 percent it depends on the circumstances.
In general, follow the doctor's orders, do not self-medicate.
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16.11.2016