Homeopathy, placebo and Nanopurga

The effect of absence, or Emptiness matters

Valery Yudin, "Weekly Pharmacy" www.apteka.ua

If it were, it would be nothing. If, of course, it was.
But since it's not, it's not like that. That's the logic of things!
Lewis Carroll. Alice through the Looking Glass

Previously, this word was used in religious rituals, but today almost everyone listens to the songs of the band with this name. Doctors and pharmacists meet this word in specialized literature and pronounce it in communication with colleagues, trying to describe a phenomenon whose mystery has not been fully disclosed. But at the same time, some, using the mythological side, are trying to actively use it on a par with conventional medicines. ...We could continue to give you hints, but we are sure that you will never guess what we want to tell you today.

And in order to keep the intrigue a little longer, let's start our story from afar, with the story of how this word appeared, which migrated to the medical dictionary.

In the eighth century, when the Roman Catholic Church established funeral rituals, an Officio Mortuorum was created - a set of rules providing for the singing of psalms during the funeral procession, in which such a line was repeated like a chorus (Ps 114:9): "Placebo Domino in regione vivorum" – "I will be pleasing to the Lord in the land of the living." Later, this line was corrected many times and in the last official version approved by Pope John Paul II in 1979, the word "placebo" disappeared, and the line sounds different: "Ambulabo coram Domino in regione vivorum" ("I will walk before the Lord in the land of the living")

And so, seeing such a procession in the city, the poor joined the procession, starting to sing along in chorus. Mourners were often called to funerals for the same purpose. Both of them received financial compensation from the relatives of the deceased or were invited to the wake. This is how the concept of "singing a placebo" arose – to seek benefits in artificiality, fake, insincerity, sycophancy. Already in the Canterbury tales of Geoffrey Chaucer (about 1343-1400), the name Placebo is a crafty, insincere character: "One praised him, the other blasphemed, and now – often because the sudden fervor of a friendly conversation leads to a quarrel – a heated argument between the two arose soon and only by the end of the meeting subsided. Placebo was the name of one of them."

Of course, everyone has already realized that it will be about him – about the placebo.

It is assumed that the first to use "placebo" as a medical term was the Scottish physician and researcher William Cullen (1710-1790). In his "Clinical Lectures" (1772), along with the idea of the existence of the law of similarity – which then pushed Samuel Hahnemann (Christian Friedrich Samuel Hahnemann; 1755-1843) to create homeopathy – the idea of a placebo was also contained (Vasilenko V.V., 2012). However, not quite in the sense in which we use it today. As noted by the American historian of science and medicine Guenter B. Risse, W. Cullen called the word "placebo" drugs with a low content of active substances. He used such drugs primarily in incurable patients, whom he wanted to calm down somehow or just support. It is noteworthy that even then, by doing so, he used what today we call an active placebo (as opposed to an inactive one – tablets containing an indifferent substance like milk sugar). At the same time, in the Medical Dictionary (1811) by Robert Hooper (1773-1835), placebo is characterized as "any remedy more calculated to please the patient than to have a therapeutic effect" (Kerr C., Milne I., Kaptchuk T., 2008).

In professional medical reference books, the term "placebo" is found in the second edition of the New Medical Dictionary (1785) by George Motherby (1732-1793). He gives the following explanation of this concept: "A well-known method of treatment or therapeutic practice." How later the meaning of the term "placebo" became completely opposite, today continues to lead many historians to perplexity. Thus, Arthur Shapiro, a researcher of the history of the placebo phenomenon, still considers the true reasons for such a twisting of the meaning of the word unknown (Shapiro A.K., 1968).

Anyway, the idea of using a placebo in the form of low-dose drugs persists in the XIX century, but along with this, it gradually acquires the importance of a pharmacologically inert substance (for example, in the form of bread pills or lactose). Already at that time (the first half of the XIX century), inert substances were beginning to be used in comparative clinical studies (studies by Cuming R., 1805 and Forbes J., 1846). This gives further impetus to the fact that the term "placebo" by the end of the XIX – beginning of the XX century finally secured an unambiguous interpretation and began to be used as an element of pharmacological experiments (Kaptchuk T.J., 1998).

According to Catherine Kerr, such a shift in meaning probably reflects the emergence of new accents in medicine at that time – in connection with scientific discoveries in chemistry and pharmacology, molecules of active substances of active preparations, and not some mystical substances, begin to occupy a central place. At the same time, obtaining positive results with the use of any other means began to be considered as a non-specific, or placebo effect.

It's always nice not to come where you're expected
(Oscar Wilde)

What is a placebo in its modern medical meaning?
Placebo is a substance without obvious medicinal properties, used as a medicinal product, the therapeutic effect of which is associated with the patient's own belief in the efficacy of the drug.
The placebo effect is a measurable, noticeable or perceived change in the physical or psychological state that occurs in response to therapeutically inert external influence.

At the same time, a placebo may not necessarily be some kind of inert drug (sugar tablets or injection of water with a syringe), but also an inert physical effect (for example, radiation), as well as surgical intervention (in which a superficial incision is made, which is immediately sewn up).

The modern history of placebo dates back to 1946, when Cornell University (USA) held the first symposium on the effects of placebo on patients. However, the peak of interest in placebo was in 1955, when the Boston doctor Henry Beecher (Henry K. Beecher; 1904-1976) analyzed the results of 15 clinical studies that dealt with the treatment of various diseases. The researcher found that out of 1082 patients, recovery was noted among 35% who used placebo. He published the results of these studies in the Journal of the American Medical Association in the article "The Almighty Placebo" ("The Powerful Placebo", 1955). Of course, at that time it had the effect of an exploding bomb, and many other researchers who undertook to study this question noted that the number of people responding to placebo was even greater. In their studies, placebo gave a positive result in 50-60% of patients, depending on what they tried to "treat": pain, depression, some cardiac diseases, stomach ulcers and other gastrointestinal diseases.

The truth is rarely pure and never simple
(Oscar Wilde)

The pursuit of sensation, as it often happens, played a cruel joke with the researchers: the placebo probably really has such a metaphysical ability that its effect is manifested not only in the subjects, but also in the researchers themselves. 40 years later, in 1997, two German researchers – Gunver Sophia Kienle and Helmut Kiene – decided to "recalculate" the data of the most cited study regarding the placebo effect. Their results, published in the Journal of Clinical Epidemiology (article "The powerful placebo effect. Fact or fiction?" ("The Powerful Placebo Effect. Fact or Fiction"), were stunning: the design of the studies analyzed by G. Beecher had errors, so we can talk about completely different reasons for the improvements observed in patients, but this had nothing to do with the placebo effect.

The false impression of the placebo effect could be obtained in various ways: spontaneous improvement of the condition of patients, fluctuations in symptoms, regression of symptoms to the norm, rounding of results, the use of additional therapies by patients, researchers' bias, patients' assessment of therapy as positive out of politeness to the researcher, psychosomatic phenomena, misinterpretation of results, etc. "All these factors according to- they are still common in modern literature describing the placebo effect," the German researchers conclude.

Re - analysis of the study of G. Beecher showed that there are many factors that can influence the course of therapy, as well as how, in the end, the results of this treatment will be evaluated. All this does not allow us to be absolutely sure that therapy brings improvement or its results are evaluated adequately. We must also take into account the influence of "hindrances", such as the natural course of the disease (spontaneity, when patients may feel worse or better regardless of whether they do something for this); the fact that patients behave differently when they participate in an experiment than when they pass conventional therapy; the desire of patients to arouse the disposition of researchers to themselves by giving "correct" answers… Actually, this is true not only in the case of some medical experiments, but also for life in general: we try to be liked, we try to look better than we are, we want to get the favor of others – all this is quite natural for a person.

In May 2001, an article was published in The New England Journal of Medicine, in which the ability of placebo to exert any influence on the condition of patients was questioned at all. In the article "Is placebo really powerless?" ("Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment") Danish researchers Asbjørn Hróbjartsson and Peter C. Götzsche indicated that "they found little evidence that placebo is capable of showing significant clinical effects." After conducting a meta-analysis of 114 studies, they found that "compared to the absence of treatment, placebo does not significantly affect binary results, regardless of whether they are subjective or objective. In trials with continuous results, placebo shows a positive effect, but it decreases with an increase in the sample, indicating possible errors associated with the consequences of small studies." Most of the studies analyzed by Danish scientists were few: in 82 of them, the average group size was 27 people, and in the other 32 studies – 51.

"The high level of the placebo effect, which has been repeatedly reported in many articles, in our opinion, is the result of shortcomings in the research methodology," concluded A. Hrobjartsson.

In order for the reader to understand that to assess the effect of placebo (actually, as well as for conducting clinical trials), more advanced techniques are needed, and conclusions require balance and caution, let's give one example.

40 years ago, a young cardiologist Leonard Cobb from Seattle (Australia) conducted a unique study to evaluate the procedure, which was widely used in patients with angina at that time. The doctor made small incisions in the chest area, after which he applied ligatures to 2 arteries, which, it was believed, allowed increasing blood flow to the heart. Previously, this technique was popular – 90% of patients after such a procedure noted an improvement. However, when L. Cobb compared this method with placebo surgery (in which he made incisions, but did not connect the arteries), it turned out that both methods were the same in their effectiveness. Soon, such a procedure was abandoned (Talbot M., 2000).

So what did L. Cobb's research actually show? That such a surgical procedure had a placebo effect? Or did he demonstrate that there was no need for surgical intervention, because most patients return to their original state anyway?

In order to exclude the influence of factors such as the natural course of the disease or the return to the initial state on the results, many researchers use the third (control) group, which does not receive treatment at all. In the event that the placebo group demonstrates comparatively better results, they talk about the effectiveness of the placebo. However, A. Hrobjartsson and P. Getzsche believe that most of these studies are also not without drawbacks, mainly due to a small sample, and researchers select such participants whose answers will suit them in advance.

In an editorial accompanying the material of Danish researchers, John C. Bailar III noted: "Those who claim that the placebo effect exists will have to prove it." Those who are going to do this need a large, carefully planned study that would clearly identify and measure the effects of drugs and treatments, not only compared to placebo, but also compared to no intervention at all. These studies should clearly distinguish between objective measurements (e.g. blood pressure, cholesterol levels, etc.) and subjective (e.g. pain reports or evaluative observations).

However, several such studies have been conducted. Antonella Pollo and her colleagues from the University of Turin (Università degli Studi di Torino) have shown that placebo can help with severe pain. Thus, in the article "The feeling of hope in the placebo group and its clinical significance in analgesia" ("Response expectations in placebo analgesia and their clinical relevance"), analgesia of patients who underwent thoracotomy with buprenorphine was considered on demand for 3 consecutive days in parallel with the main intravenous administration of isotonic solution. However, this was reported differently to all patients. So, group No. 1 did not know that they were being injected with some kind of analgesic (the natural course of the disease); group No. 2 was informed that the injected isotonic solution was either a powerful analgesic or a placebo (classic double blindness). Group No. 3 was informed that the injected solution is a powerful analgesic (deceptive message). Thus, while the analgesic therapy in all 3 groups was exactly the same, the information about what was administered was different. The results were measured by recording the number of required doses of buprenorphine during 3 days of treatment. The researchers noted that in group No. 2, requests for the administration of buprenorphine were lower compared to group No. 1. However, this decrease was even greater in group No. 3. In general, after 3 days, group No. 1 received 11.55 mg of buprenorphine, group No. 2 – 9.15 mg, and group No. 3 – 7.65 mg. Despite such significant differences, anesthesia was the same in all 3 groups. These results show that different oral awareness, setting patients to clear or uncertain expectations, gave a different placebo effect. That, in turn, caused a sharp change in behavior, which contributed to a reduction in the consumption of analgesic. Thus, patients who thought they were using a powerful analgesic asked for 34% less buprenorphine than patients who were not told anything, and 16% less than those who were told they were taking either painkillers or placebo. Each group eventually received the same amount of painkiller, but their requests for such a drug differed dramatically.

Summing up, it is important to note that the patient's attitude includes treatment by medical personnel in a medical institution, which means motivation for healing, as well as the belief that therapy will be effective. The different awareness of patients in the study that we described above led to different expectations. And we saw that their faith, motivation, and expectations were essential to the placebo effect. All together, this is called the subjective expectation effect. The classic conditioned reflex development and the suggestion of an authoritative healer seem to be the trigger of the placebo effect.

What is the reason for the placebo effect?Some scientists believe that it has a purely psychological basis.

For example, psychologist Irving Kirsch from the University of Connecticut is confident that the effectiveness of antidepressants can be almost completely explained by the placebo effect. He and Guy Sapirstein analyzed 19 clinical studies of the effectiveness of antidepressants and came to the conclusion that in 75% of cases improvement occurred not due to changes in neurotransmitter activity of the brain, but due to the placebo effect. "Our belief that something is going to happen is critical. At the same time, if the patient notes some positive changes, drugs are not necessarily involved in this," he believes.

But be that as it may, faith and attitude to change plus suggestibility – all this can lead to changes in biochemical processes. Sensory experiences and thoughts can affect neurochemical processes, which, in turn, affect other biochemical systems, including hormonal and immune. Thus, the placebo effect can be explained with the help of modern knowledge, which suggests that a positive attitude and faith are very important for physical health, as well as healing. But all this does not mean that you can do nothing in terms of treatment and be healed by faith alone, and also that if a person does not believe in healing, he will not recover.

However, there is an opinion that the placebo effect may not consist in influencing the body, but in influencing existing behavioral stereotypes - changing the patient's attitude to his own actions and words about well–being can affect chemical processes in the brain.

The second theory that could explain the placebo effect is that the treatment process itself, in which the patient is given attention, care, benevolent attitude, etc., may be the cause of somatic changes that contribute to healing. After all, the mood of the patient changing during such an attitude in turn initiates the release of endorphins, catecholamines, cortisol or adrenaline. This helps to reduce the level of distress due to the appearance of hope or the reduction of doubts that relate to treatment methods or its possible outcomes. The elimination of a stressful state helps to prevent harmful changes in the body or to slow them down.

Since the placebo effect demonstrates variability in different types of people, some researchers are looking for evidence of a genetic predisposition that would cause susceptibility to placebo. So, Professor Andrew Leuchter from the Semel Institute for Neuroscience and Human Behavior at the University of California (UCLA Semel Institute for Neuroscience and Human Behavior; Los Angeles, USA), believes that placebo acts through central pathways modulated by monoamines, which are under strong genetic control.

He and his colleagues studied 2 genes: catechol-O-methyltransferase (COMT) and monoamine oxidase A (MAO-A). Both genes have a so-called polymorphic site, which varies in structure, and some variations enhance the work of the enzyme, while others, on the contrary, weaken. It turned out that in patients with gene variations supporting high activity of the MAO-A enzyme, placebo showed the least effect than in patients with other genotypes. Patients with genetically determined low activity of the COMT enzyme were less sensitive to placebo than those with other gene variants. However, the researchers emphasize that genetics is not the only explanation for the response to placebo. There are probably several biological and psychosocial factors involved.

Important–no matter... no matter–important…
(Lewis Carroll. Alice in Wonderland)

Whatever the reason for the changes when taking a placebo, nevertheless, the question remains: how ethical is its use? Is it possible to "deceive" patients with severe pain by giving them a placebo, or is it necessary to reduce the severity of their pain and suffering with a drug with proven efficacy? Is it possible to use a placebo to benefit the patient? Is it really unethical for a doctor to prescribe a placebo without informing the patient about it? If informing the patient reduces the effectiveness of the placebo, is it possible to justify "deception" if it (deception) guarantees benefit?

Some foreign experts believe that the practice of prescribing a placebo is justified in cases where you can count on benefits and there is no danger of causing significant harm to health or worsening the condition. Others believe that it is unethical to hide the true essence of treatment from the patient and that the practice of informed consent requires informing the patient that he is taking a placebo. Finally, the third – representatives of complementary (non–traditional) and alternative medicine - do not delve into whether their approaches lead to a placebo effect or not. The opinion of many of them is that as long as their therapy methods form a sense of effectiveness in patients, it is absolutely not necessary to establish the true nature of these changes. At the same time, now this attitude is changing and a different extreme is spreading: some advocates of non-traditional methods admit that their approaches are based on the placebo effect and that is why (in their opinion) complementary medicine methods are better than traditional ones.

However, while many representatives of Western traditional medicine are trying to find a solution to the ethical dilemma regarding the use of placebo, representatives of alternative approaches seem to consider their methods ethical a priori, since they believe in the energy of qi, chakras, Prana, vata, pitta, aura, water memory and other unobservable processes that they are happy to offer as magical funds or bring an evidence base under them.

For example, earlier modern supporters of homeopathy tended to believe that the mechanism of this approach is based on the memory of water (according to this theory, water at the molecular level has a memory of the substance once dissolved in it, and retains the properties of the original solution after not a single molecule of the substance remains in it). But not so long ago there was a theory that, at its core, homeopathy is... nanomedicine.

At least, this is what is discussed in the article 2 of Indian researchers entitled "Homeopathy becomes nanomedicine" ("Homeopathy emerging as nanomedicine"), published in the journal "International Journal of High Dilution Research" (Upadhyay R.P., Nayak C., 2011). They associate this with the technology of preparation of homeopathic medicines, which consists in the serial dilution of matrix tinctures in glass vessels, accompanied by active shaking (so-called potentiation). As a result, the nanoparticles of the glass vessels pass into the solution and "remember" the information from the active substance molecule, which is then transmitted during the preparation of each subsequent dilution to other similar particles. The idea that homeopathy is essentially a nanomedicine is also found among some supporters of the homeopathic movement. However, our homeopaths do not specify the subtleties or mechanisms yet.

Since we are distracted by homeopathy, what do the studies corresponding to the principles of evidence-based medicine say about its effectiveness? In 2005, at the University of Berne (Switzerland), a team of authors carried out a meta-analysis of studies of homeopathic remedies and studies of the effectiveness of allopathic drugs. As a result, no significant differences were found between the effects of homeopathic drugs and placebo (8 studies), whereas significant efficacy was demonstrated in studies of allopathic medicines (6 studies) (Shang A., Huwiler-Müntener K., Nartey L. et al., 2005).

My favorite color, my favorite size…the form of release matters: a beautiful capsule has a greater effect than a tablet, and an injection is greater than a capsule;

• size matters: a large placebo pill is more effective than a small one;
• dosage matters: 2 placebo tablets are more effective than 1;
• the intake scheme matters: 2 tablets 1 time a day have a greater effect than 1 tablet 2 times a day;
• color matters: blue placebo pills are suitable as a sedative, yellow – as an antidepressant;
• the brand matters: a placebo with a name and in a package is better than without them.

Like is treated likeHowever, let's return to science and traditional medicine, where the idea of the placebo effect is actively used just to debunk myths and test the properties of new drugs.

In the first case, we can recall the role of placebo in debunking the myths about animal magnetism, invented by Friedrich Anton Mesmer (1734-1815) and the magnetization of water by the method of Charles d'Eslon (Charles d'Eslon, 1739-1786) (the latter almost unchanged successfully began to be used 200 years later by Alan Chumak), and in the second – to to study the effectiveness of "Perkins' Patent Tractors" (1796).

In modern medicine, the role of placebo fully corresponds to the proverb "a wedge is knocked out with a wedge" – thanks to its use and comparison of results, we can get rid of ineffective drugs whose effectiveness does not exceed placebo. After all, how else can you find out if a new drug really has an effect, or if the changes reported by the patient are just a figment of his imagination, since the desired is given out for reality? It is on this comparison that evidence-based medicine is based today. The idea is simple: several groups of patients are given tablets of the same color and shape, but some contain the substance being studied, and others are inert. Comparing the results obtained, we can talk about how effective the drug is.

Ideally, a study that meets the principles of evidence-based medicine should have a large sample of patients, as well as be a double-blind randomized placebo-controlled multicenter.

Blind examination means that patients do not know whether they are taking a placebo or a drug; double blindness also excludes the awareness of medical personnel. Randomization involves a random distribution of patients into groups, which excludes the impact on the results of researchers. Multicenter studies are conducted in several clinics (from different cities or even countries) that do not know about each other (Vodovozov A., 2010).

Finally, only the question of placebo safety remains unresolved: if it includes indifferent substances, can we talk about its absolute safety?

If we do not talk about the use of placebo in clinical trials, then it can hardly be considered safe, no matter how supporters of chiropractic, astrology, homeopathy try to convince us of this.

The biggest danger is that patients can become addicted to all these unscientific methods: a placebo can open the way for charlatans. On the one hand, such patients can be convinced that they are susceptible to some diseases that have been identified, for example, by photographing the aura. In the worst case, patients who turn to psychics, but really need medical help, can wait a long time for a miracle of healing without seeking medical help, while missing precious time.

Another of the downsides of placebo is the nocebo effect, when the patient believes in a negative outcome of treatment, despite the fact that he is injected with an indifferent substance.

So, in one of the experiments, patients with bronchial asthma were given to inhale steam, while being informed that it was an irritating chemical or allergen. After that, about half of the participants had breathing problems. To eliminate an asthma attack, they were given another remedy, allegedly a drug with bronchodilating properties, and asthma symptoms disappeared. In fact, in both the first and second cases, a solution of seawater was sprayed on the subjects. In another study, about 20% of patients taking placebo in one of the clinical trials reported developing side effects (www.health.harvard.edu ). Adverse reactions were formed in a similar way when an anti-influenza vaccine and a conventional isotonic solution were administered as a placebo. However, if the reaction at the injection site was expected to be more pronounced during vaccination, then general symptoms (fever, runny nose, cough, sore throat, headache, weakness, etc.) were noted in the placebo group not much less often (Figure) (Ohmit S.E., Victor J.C., Teich E.R. et al., 2008).

Local and systemic adverse reactions on day 7
after the introduction of the influenza vaccine and placebo in 1917 subjects

The results of such simple studies show not only how the human brain functions, but also how easy it is to manipulate consciousness. However, how easily this can be done and whether such manipulation will be for our benefit or harm depends largely on our knowledge.

Portal "Eternal youth" http://vechnayamolodost.ru30.08.2012