A RESEARCH ON PLACEBO DRUGS AND THEIR EFFECTS
Psychology is a discipline that attaches importance to new diagnosis and communication and treatment methods, but it is also known as an important discipline, especially with its systematic development in the last century. Placebo drugs and methods, one of these developments, are expected to regain their effect in this period when necessary or unnecessary drug use is increasing, and it is thought that the importance of studies conducted on this method is also increasing.
While this study tries to explain the development and evolution of placebo drugs from past to present, the benefits of these drugs to society, the individual, medicine and psychology will be explained, and comments and discussions on the use of these drugs will be put forward.
It is aimed that the related study will contribute to the knowledge and interest of the researcher on the subject and help scientists who want to reach a comprehensive introduction and introductory research on placebo drugs.
Although there are studies in the literature in this context, it is noteworthy that there is no study that addresses the increasing psychological and physiological problems in the post-COVID-19 period. The related study will share the developments and achievements of the last century in general terms, and will also include a COVID-19 section that is expected to contribute to the literature.
Among the most important limitations of the research, it can be shown that the sources that the researcher has access to are second-hand sources. Although the relevant research will benefit from peer-reviewed journals and academic resources, it can of course be considered remarkable that it does not include any experiments or field studies. In order to overcome this limitation, the study will include many sources and research.
The related research has adopted the literature review model as the research model. In this way, the claims and researches about placebo treatment and placebo drugs, especially in the last 40 years, will be compiled and it will be aimed to create a comprehensive idea of the subject. For this purpose, the study cited many academic and scientific sources as references.
The data were collected after searching various academic and scientific sources and priority was given to national and international online, local libraries, online article portals and general internet algorithm.
Analysis of Data
The collected data were analyzed in a systematic way, and at least 2 scientific and academic sources were tried to be given to each alleged phenomenon. In this way, the study was able to follow a linear route from the history of the subject to the current discussions and justify it by underlining each part.
Findings and Comments
- Placebo Concept, Treatment and Development of Drugs
It is known that Sir Thomas Percival mentioned the use of placebo for the first time in history (Clark, 1994). Percival mentioned the use of placebo in 1803 in his publication titled Medical Ethics, and as the definition and use became increasingly widespread, the definition of placebo was also included in the Hooper medical dictionary in 1811 (Clark, 1994). Towards the end of the 19th century, physicians began to become aware of the placebo effects and to study these effects systematically. They started to benefit from this in treatments, but as a result of the dominant views and practices of influential scientists of the time such as Lous Pasteur, the presence of bacteria causing certain diseases reduced the interest in placebos, beliefs, and brain-body interactions in medical practice (Clark, 1994). With the positive developments experienced after the Second World War, interest in placebo increased again in the 1950s.
In the related years, important scientists such as Beecher, Pepper and Lasagna pioneered the researches about placebo and played an important role in gaining the current meaning of this systematic. The interest in placebo, which has become increasingly important on the ground of discussion, has brought along the differences of opinion and consensus of opinion. In the 60s, physicians who did not work in the field of psychiatry, in particular, supported the use of placebo in their treatment, while psychiatrists were divided into two camps as those who opposed the use of placebo or supported the use of placebo (Shapiro, 1960). It can be argued that physicians who were against placebo were close to the approach of the period that took less psychological factors into account and centered surgical and pharmacological applications as valid treatments, and therefore they were also against placebo applications, the benefit of which could not be clearly demonstrated (Shapiro, 1960).
As can be seen, the debates about how placebo and the placebo effect emerged have been going on for a long time in the history of modern medicine, because the perspective on placebo and its effect varies according to the perspective on the disease. The fact that the existence of two types of diseases has been accepted in the history of medicine from past to present has been effective in the emergence of this situation. First of all, he sees the disease as a unique and independent field of existence and argues that it should be handled with this understanding. hypocratic” understanding, as another approach, is based on the life history of the patient rather than the disease. physiological medicine ” approach. Hippocratic medicine took into account the disease existing in man, physiological medicine took into account the human in the disease. Until today, there has been a disagreement between medical scientists who advocate these two approaches, but with the developments offered by modern medicine, hippocratic medicine has gained an important acceptance against physiological medicine.
Therefore, hippocratic medicine sees the disease as a special entity and focuses on investigating the specific factor of that disease in the relevant treatment. This understanding of medicine is functional, specific in the context of the desired treatment. specific) focuses only on cause-focused treatment methods that exclude non-existent factors – with the spread of this understanding, the interest and respect for placebos is also increasing.
Placebos are used for many reasons other than to increase the effect of a chemical substance or to increase the current mechanism of action of the chemical, but among the most common areas of use, they are used instead of drugs for the courage and morale of the patient who has no treatment or whose treatment is not deemed necessary by the physician. There are some factors that are more important than placebo in creating the placebo effect. These;
- Positive beliefs and expectations of patients,
- positive belief, dynamic and good relationships with the physician or health work, and,
- It can be explained as finding suitable patients and diseases.
Considering the use of placebos, it is understood that placebo treatment covers a wide area from surgery to taking patient history. Beecher (1961), who pioneered the placebo effect in 1955; Placebo determined the effect in 35% of events such as mental changes caused by drugs, anxiety, postoperative wound pain, seasickness, cold, pain and cough. Recently, the effect of placebo on the mortality of asthma, chest angina, coronary artery and congestive heart failure diseases has been mentioned. For example; In one study, it was noted that 66% of bronchial asthma diseases treated with placebo, and in another study, 80% of patients with herpes simplex virus showed signs of recovery (Kayaalp, 1987). However, the patient’s mental state, attitudes and behaviors towards the disease, level of excitement, pain, anxiety, depression and loss of appetite etc. some of the symptoms and autonomic nervous system disorders respond well to placebo; It has been reported that somatic conditions such as fever, organic disorders, and mydriasis do not respond to placebo (Beecher, 1961).
For these reasons, it is necessary to address the factors that affect the response of patients to placebo.
Researchers have found that placebo response rates are associated with traits such as higher levels of social support and higher levels of health-related and self-assessed mental and physical functioning (Turner, 1994).
The study also showed that patients’ response to placebo was related to their perception of the safety of the treatment, their trust in their doctor, and their own beliefs about the effectiveness of the treatment.
At the same time, the researchers found that patients’ response to placebo was related to their level of treatment expectation, their trust in their doctor, and their beliefs about the drug’s efficacy. It is also stated that the response of patients to placebo is not related to the severity of their depressive symptoms (Wager & Atlas, 2015).
It can be determined that patients who do not have prejudices about the reality and functionality of placebo treatment are more likely to respond to treatment. Along the same lines, another result showed that patients who were more skeptical of placebo treatment were less likely to respond to treatment.
It is possible that other factors, such as the patient’s level of motivation, also influence the patient’s response to placebo. In the light of all these studies, the factors affecting the response to placebo treatment can be listed as follows (Turner, 1994 & Wager & Atlas, 2015);
• Genetic and related psychological variables.
• Environmental factors. Among these factors;
• Physician-patient interaction,
• Perceptions influenced by experiences, and,
• There is the environment and place where the treatment is done.
• Treatment process.
• Clinician’s and patient’s expectations from treatment.
• Factors belonging to the person administering the placebo.
• Being moderate.
• Disease factors (eg pain characteristic).
Placebo, which is defined as a drug that has no pharmacological effect or has no effect for the situation in which it is applied, is perceived by the patient as a therapeutic agent, although it is considered ineffective in terms of the medical world. This drug, which can be referred to as a counterfeit drug, clearly demonstrates that it is effective for many pathological conditions (Rentchnick, 1985). This effect has been utilized to a great extent in cases where medical knowledge and facilities have difficulty in producing results or in applications performed completely unconsciously.
It should be noted that there are different studies in the literature examining the factors affecting the placebo response. Among these studies, one of the studies expected to explain the placebo treatment well focused on the psychological suggestion used in the treatment as a factor in the placebo effect; Among the two aerobic exercise groups, the members of the first group were advised that the training program would both increase their aerobic capacity and be psychologically good. To the second group, only the biological effects of the program were mentioned. After a ten-week training program, only the first group’s own views were found to have a significant positive effect. According to this research, psychological changes occur before biological changes and expectations increase the effects of exercise (Ojanen, 1995).
Another comprehensive study was conducted in Norway in 1998 as a study examining the effect of drug information to be presented during drug administration on the placebo response. In this context, 6 different groups of patients with muscle spasm were given Carisoprodol as a muscle relaxant and lactose as a placebo. According to the results obtained from the patients who were given different matrix information such as stimulant or muscle relaxant together with the drug and placebo application; The drug information to be presented while giving the drug to the patient can create the placebo effect, in other words, it realizes the physiological change expected from the drug (Flaten, 1999).
A study on another important issue, gender, revealed whether the response to these placebo drugs would differ in this context. The related study investigating the effect of gender on the placebo effect was conducted in the USA in 2001 in 501 female and 375 male patients with major depressive disorders. According to the results of the research conducted as double blind; The response to fluoxetine and placebo is not different for males and females (Casper et al., 2001).
For an inert substance, a placebo effect is considered to be the complete improvement in a particular symptom or disease, whereas in the case of an effective substance, a placebo effect represents the difference between the observed change and the expected result from the pharmacological effect of the drug. In other words, the effect resulting from the treatment can be expressed as the effect that occurs by the sum of the pharmacological and placebo effects. The placebo effect can mimic, hide, potentiate, or hinder positive returns from drugs. Individual differences in the pharmaceutical world, the patient’s failure to comply with the treatment plan, the effect of a different drug or substance taken together, the response to the drug should be alert.
In the light of all these data, it is possible to summarize the historical reasons for placebo use as follows:
- It is necessary for the control of nonspecific effects of new drugs, drug efficacy studies.
- It can be used to test the effectiveness of treatments.
- Physicians are used to recognize the effects of drugs used in the treatment of psychological diseases on the patient.
- When placebos are used in the unknown, they are tools that eliminate patient and observer bias.
- Placebos distinguish changes due to the natural course of the disease from those due to drug effects.
- It is an important tool in the study of the mechanisms of action of drugs.
- Term Meaning of Placebo and Expanding the Concept
The Latin word ‘placebo’ means ” i will please ” means; It implies the subjectively positive effect of a concept taken for medicine or cure. The opposite of this concept is expressed as ‘nocebo’, “ i will hurt” and refers to a negative subjective experience (Gotzsche, 1994).
Brody (1982) argued that there are 4 definitions of the placebo effect. While one of them is the specific and non-specific effects in the treatment mentioned above, other definitions also contain meanings close to this narrative. These;
- The effect that results in the treatment elicited by the medically ineffective drug,
- The therapeutic effect not explained by the pharmacological property of a drug, and
- It can be expressed as a common effect for all treatments.
Brody (1982), as a comprehensive definition that includes these 4 definitions; It is a medical form of treatment or an attempt made to accelerate the treatment, which is believed to have no special efficacy for the condition being treated and is used for its symbolic effect.
Making this definition more comprehensive and known as a sociologist, Forrester (1997) stated that medicine for testing the claims of empirical scientific medicine” Although it is widely used in medicine, the placebo effect is never limited to this definition. Modern medical practices and acceptances indicate that Forrester is quite right in this critique, as it is clear that a placebo control group was used even in animal experiments (Dachir et al., 1993 & Sachdev et al., 1993) without even needing to define the placebo effect. According to Forrester, the placebo effect should also include the atmosphere of the physician or clinic, the way the physician thinks about the problems they face, efforts to restrain or calm the patient, and especially the trust and understanding created by the physician.
Forrester also argues that the placebo effect is also linked to power relations. According to him, making the patient feel better also plays an important role in the placebo effect. Based on Spiro (1986), who has done many studies on this subject, Forrester argues that not only physician and patient relationships, but also developing and changing high technology should be included in the placebo effect. According to him, since in order for the placebo effect to be in question, individuals who are described as patients must be absolutely unaware of the procedure to be done to them, this situation is associated with cheating, lying and deception. Is any treatment method that requires the patient to be treated with fraud justified?”This led to the discussion of the placebo effect from a different perspective.
It would not be accurate to state that Forrester is the only scientist who has given weight to the ethical debates about placebo treatments, since it can be assumed that he himself was influenced by the debates that lasted for decades.
- Relation of Placebo and Ethics
Ever since the medical and psychological sciences determined that placebo is a respectable, or at least acceptable, treatment method, there has been debate about the ethical problems of this method. For example, does viewing placebo as a medical treatment modality with its potential efficacy and toxicity justify the practice of placebo from an ethical viewpoint, or does placebo reflect the generally self-critical expression in clinical trial results? medicine x is no better than placebo so medicine x is useless) deserve it?
Today, placebo and the placebo effect appear as a biologically and pharmacologically winged and indisputable fact – placebo is a treatment method that is applied not only for patient satisfaction but also for benefit (Wager & Atlas, 2015).
At this stage, it should be noted that in the context of the Helsinki Agreement, which first came into force in 1964 as an international agreement on the treatment processes that physicians will apply on humans, and with the amendment made in 1996, the articles on placebo and the placebo and ethical debates, which are still valid today, were also mentioned. So, placebo; “ In studies where there is no proven diagnosis and treatment method, the use of placebo is not excluded.”, but with the changes made in recent history, “ Even if there is a proven treatment, in cases where it is necessary to conduct scientific studies to determine the safety and effectiveness of the researched method, and in cases where the failure to apply the best proven treatment will not cause additional serious or irreversible harm to the patient; a less effective intervention than the best proven intervention, or the use of placebo or no intervention” has found a place for itself with its scope (Çelik & Karataş, 2022).
As it can be understood from the relevant contract, one of the areas where ethical discussions lose their importance is clinical researches and dangerous diseases that can be the subject of these researches. In clinical studies, if there is already a good drug that can be accepted as a reference for the disease in question and the disease is not benign, it is necessary not to deprive the patient of this drug. For example; cardiotonicaccepted as a reference drug in drug studies. digoxin Although there is a placebo drug, giving the patient is not beneficial, on the contrary, it creates a harmful attitude (Schulz, 1975). However, when there is no accepted treatment method for this disease or if the disease has a benign nature, placebo administration can be accepted as an appropriate practice (Reynaud, 1987).
Therefore, it appears that placebo should not present any danger to the patient – the benefit to the patient should far outweigh the harms. The boundary between acceptable hazards and unacceptable hazards should be determined by an academic committee that has no interest in the work to which it is associated (Spriet, 1986).
When patients are given information about the study they are included in, they are told that they can take a placebo, which causes distrust even against pharmacological drugs and a decrease in the effectiveness of the drug in these patients.
Another reason for opposition to the use of placebo in daily clinical practice is the fraudulent use of placebo. According to these viewers, fraudulent practices are, by their very nature, tempting to evade the normal limitations of liability, and therefore they can easily become widespread. Pressure from pharmaceutical companies, aspiring patients, and busy physicians to increase necessary unnecessary drug use has led to an increase in placebo use, resulting in an increase in drug toxicity as impure rather than pure placebos are used in clinical practice, a more general incentive for other forms of fraud in medicine, and a lack of trust between patient-physician. may lead to its disappearance (Bourne, 1978).
It can be seen that placebo drugs in daily practice are unconscious, worthy of criticism, and can be abused to extremes. However, in the absence of other treatment options, the benefits of placebo in potentiating the effect of the current active drug and in many functional disorders cannot be ignored.
- Characteristics of the Placebo Effect
Just like every drug or treatment method, it is expected to give various reactions in the individual when applied. Thus, a placebo reaction, or reaction to a placebo drug, means the sum of the changes observed in the placebo-administered individual. While these changes are positive, negative effects (such as undesirable effects or severe symptoms) nocebo ) can also have consequences. Cases where no change is observed are expressed as Iplacebo resistance. However, the objectivity of the assessment in the case of placebo resistance should be questionable, since placebo therapy has some effect on almost all diseases (Giraud, 1984).
The positive effects of placebo can also be observed in very serious pathological conditions. In general, it has been found that placebo has a beneficial effect of 26-58% on symptoms in various diseases, and this rate can be accepted as 30% on average to increase the ease of treatment (Rentchnick, 1985). In cases that can be described as more specific such as psychosomatic and functional disorders, this rate can reach up to 60% (Marie, 1972). It is accepted that the placebo effect has a very important place in psychiatry, especially in anxiety treatments. In acute depression, on the other hand, recovery due to placebo effect or spontaneous recovery has been recorded around 45% (Wager, 2011) – although it is very difficult to distinguish the differences between these two reasons, it can be said that the importance of placebo treatment in such processes cannot be denied.
It is thought that there are some features that distinguish placebo effects from pharmacological effects, even where the results may be similar. Although the effect of placebo treatment increased with modern medicine, placebo was not included in pharmacology due to reasons such as the effect of these treatment methods was short, decreased and disappeared over time, and there were no side effects, especially in the first half of the last century. However, in some studies and researches, it has been suggested that this effect may be long-lasting and may show side effects and undesirable effects with a rate of 40%. To date, it is accepted that placebo exhibits a number of pharmacological properties similar to drugs – perhaps the most important difference being the severity of the effect.
Just like any other treatment method, placebo treatments can cause undesirable effects; may cause minor or multiple and severe side effects. Nocebo effects are generally between 7-36%, at the same time, placebo given after an effective substance is highly likely to mimic the supplement in undesirable effects (Rentchnick, 1985). Although quite common nocebo effects are fatigue, drowsiness, concentration impairment, nausea, vomiting, headache, nausea, dermatitis with tremor, angioneurotic edema, cases of dependence on placebo have also been recorded, although they are not very common. This type of addiction is very rare and explained by personality traits (Flaten, 2020).
In addition, there may be reactions between the drug in use and placebo. The same placebo solution can have a tranquilizing or psychostimulant effect due to suggestion.
- Who, How, Why: The Placebo Mechanism of Action
Although the teaching and practice of placebo drugs and placebo treatments are increasingly important, the effect of the widely used placebo is still not fully understood; It has been generally accepted that this is psychological, existing in nature, and it has been argued that personality traits are the determining features. However, it can be accepted within the shared explanations that it is not possible for all patients to benefit from placebo at the same rate. When evaluating the response to placebo, it is possible to talk about two types of patients.
- Responders to placebo: It is suggested that these placebo-sensitive individuals are more sensitive to the messages they receive from the environment.
- Those who do not respond to placebo: It is suggested that these placebo-resistant cases are more skeptical and insecure individuals.
The international scientific world has carried out various studies based on the psychological characteristics and differences of groups that are significantly opposite to each other in order to understand the placebo effect mechanism, but no results that can be recognized as evaluation have been obtained. It should be noted that individuals who respond positively or negatively to a placebo given treatment process do not always give the same reactions in the treatment of the same disease or in the treatment of other diseases over time.
It should be noted that the importance of two important factors in curing the disease cannot be ignored: the patient’s recovery and the physician’s desire to heal. When examined in this context, it is generally known that the highest level of response to the placebo effect will be obtained with the contribution of the physician to the patient’s request for treatment.
Although the response to placebo is slightly affected by age, gender and social status factors, it is assumed that the effect of the patient’s psychological state is much greater. The placebo effect also depends on the physician and the environment – the fact that medical teams using the same method in a double-blind manner did not achieve the same results, and the determinant effect of the environment factor on the placebo effect was understood. At the same time, it has been noted that the responses of patients who are hospitalized and treated under the control of a physician are very different from those who receive outpatient treatment (Chadha, 1977).
Regardless of the mechanism in question, the following two conditions are absolutely necessary in order to talk about the existence of the placebo effect:
- The disease process or symptoms vary over time or from patient to patient. Apart from very serious disorders that impair the individual’s defense mechanism, some psychological factors that affect the patient’s defense mechanism and recovery power directly on the causes of the disease or on the central nervous system under the control of the disease can play an active role in changing the course of the disease. Therefore, being able to fight the disease already constitutes one of the conditions (Burge, 1978).
- There should always be a patient doctor relationship. Patients can, of course, give placebo responses to various drugs without the intervention of the physician – it may be clearer to give an example of the immediate relief of a headache after taking aspirin, before the drug is yet absorbed, but it is the real dynamic relationship between patient-physician that maximizes the placebo effect. The common point of almost all patients is fear, and the common point of patients and physicians is hope. The concept of psychoanalytic transference can be given as an example of this; the patient can transfer his past feelings towards some objects (parent, teacher) to new objects (nurse, pill, needle or an EKG monitor). The reason why placebo has less positive or negative effects in control individuals than it does in real patients may be that the patient uses transference as a defense mechanism when under stress (Burge, 1978). Therefore, the presence of a physician whom the patient trusts or respects his authority and the existence of a patient-physician relationship with this physician can be determined as the second condition.
Although one of the most important elements of the placebo effect is psychological acceptance and process, it is not correct to explain the placebo effect on psychological grounds alone, physiological research and studies should be done – studies have shown that it is possible to abolish the analgesic effect of placebo with the morphine antagonist naloxone (Field, 1984). ).
There are three theories for the placebo effect mechanism covering all these discussions, but it would not be appropriate to consider each of these theories alone, because it is reported that each model focuses on a feature of the placebo effect, in other words, there is a coexistence of models in the placebo effect mechanism.
Models that explain the placebo effect are described below:
- opioid ( Narcotic) pattern.
- Conditioning Model.
- Model of Meaning.
Opioid (Narcotic) Model
Placebo is not a model to explain the onset of effect. This model associates the analgesic placebo effect (Placebogenic effect) with the analgesic property of the placebo effect. It has been reported that endorphin levels are higher in those who respond to placebo than those who do not. By examining the peaks of endorphins in the cerebrospinal fluids of patients with chronic pain, it was understood that there is a direct relationship between internal narcotic secretion and placebogenic effect. However, although there is a relationship between the endochronological framework and the placebo effect, the opioid model can neither illuminate the onset of the placebogenic effect nor the nonanalgesic placebo effects (Field, 1984).
According to this model, placebo effects appear either classically or ‘operant’ conditional on the treatment situation—a former experience conditioning stimulant that has successfully resolved a past health problem. For example, factors such as the attitude and behavior of the physician towards the patient, the white coat, the physician’s office, the atmosphere of this office are sufficient for the placebo effect to begin. In addition, the view advocated by this model is supported by experimentally obtained placebo effect findings from animals. However, this model cannot explain why the expected placebo response in individuals sometimes does not occur.
Model of Signification
In this model of Brody (1982), placebo effects are initiated through the cultural and symbolic effects of the therapeutic situation. For example, complex components of the clinical setting have a potential meaning in inducing the placebo effect, and this meaning is based on the signals embedded in patient-doctor communication and the patient’s interpretation of these signals. The model is described broadly and conceptually coherent – although it is still pointed out that it is difficult to test empirically.
It should be noted that, independent of the three theories briefly summarized above, two other views can find their place in the literature (Hrobjartsson, 1996). According to the first of these, although a placebo drug has an effect, the patient’s psychological characteristics initiate the placebo effect; The complexity of the placebogenic situation includes the clinical setting in which physician-patient relationships take place, as well as the personality traits of the physician or patient. The second view is that although patient anxiety plays a role in the onset of the placebo effect, the placebo effect does not occur in every anxious patient, but any therapeutic meeting between a conscious patient and a physician has the potential to initiate the placebo effect. However, administering a placebo is neither necessary nor sufficient for the initiation of the effect (Hrobjartsson, 1996).
- Pain and Placebo
Understanding the relationship between placebo and pain plays an important role in having a fruitful experience in this field, as the placebo phenomenon, as understood in modern medicine, was first revealed by study or research in the field of pain (Beecher, 1955). Even today, studies on placebo still play an important role in pain; Especially after the developments and advances in neuroimaging methods, many brain regions that have a place in the feeling and control of pain have been defined. The fact that these brain regions are also associated with emotional processing and thinking on people explains the occurrence of more than one psychological and physiological effect in the person during the period of pain (Melzack, 2005).
In the same studies, it was determined that the pain reliever effect (Placebogenic) of placebo, just like the effect of morphine, is antagonized by the morphine antagonist, naloxone. These results also explain why some herbal products have been used as medicine by humans for centuries (Melzack, 2005).
In an experimental method with a heat-induced pain model, the neurophysiological effects of opioid and placebo analgesics were compared in healthy volunteers by examining the activated brain regions by positron emission tomography, and the same brain regions were activated in the group that received both placebo and remifentanil, which is an opioid agonist. Atlas, 2015). Wager (2015), in their functional magnetic resonance imaging study, revealed that with a placebo cream applied to the forearm after electric shock, the pain experienced by the patients decreased, and the activation of the dorsolateral prefrontal cortex, medial prefrontal cortex and periaqueductal gray region brain regions, which are responsible for the emotional regulation of pain, increased, and pain was felt. It was found that there were decreases in the activation of the thalamus, posterior insular cortex and anterior cingulate cortex, which are directly related regions. Likewise, he determined the regulatory role of the dorsolateral prefrontal cortex from the emotional response of pain, and it was revealed that changes in other brain regions were managed through this region. In a similar study, Price (2007) observed that some changes occurred in the activation of the same brain regions after the administration of placebo in patients with irritable colon syndrome (Price, 2007).
As can be seen, placebo drugs and placebo effect have taken their place in modern medicine as an extremely effective treatment method in relieving pain that occurs as a symptom or result of various diseases.
- Modern Medical Science and Placebo Treatment
Although the relationship between pain and placebo is perhaps one of the most important research topics about placebo in practical and theoretical terms, it corresponds to a much wider area than pain treatment, which is used in modern medicine, because today in all branches of medicine, definition difficulties and unknowns are encountered. Despite its content, the existence of a placebo effect is generally accepted. The only element of discussion at this point is only what level of efficacy the placebo has for which disorder and which drug.
In fact, there have been findings showing that the placebo effect has a positive effect on the patient even in diseases requiring surgical intervention. In 1959, intramammary artery ligation was believed to be a cure for coronary disease, but studies showed that angina was treatable in 56% only with skin incision, and 63% when this method, which proved to be faulty, was applied (Spiro 1986). It is also said that the placebo effect plays a major role in coronary bypass operations, because even if the sutured veins do not hold in the operation, improvement can be observed in some cases (Vlades 1979).
In general, if diseases and conditions that can be combated with placebo occur, it is possible to say that drugs that are expected to be effective for this disease and condition are only more effective than placebo at certain rates, or that placebo efficacy constitutes a very high rate in treatment efficacy. So much so that the placebo effect in the treatment of asthma, shingles and ulcers has been reported to be 66% (Roberts, 1993. It should be noted that the expectation for placebo is not fixed and does not express a certainty, but this is true not only for placebo but also for the effective drug – because the variability of the effect is also present. may not be fully revealed.
It should be noted that the placebo effect not only varies from disease to disease or patient to patient, but also varies from country to country and even from region to region within the same country (Forrester 1997). Even the viewpoints and beliefs of physicians about placebo play a role in the placebo effect, and the application of the relevant treatment method by physicians who approach placebo moderately increases the likelihood of the patient responding to treatment (Spiro, 1986).
Another interesting situation in placebo applications is the side effects caused by these treatments and drugs, because side effects were higher in placebo control groups in many studies. A meta-analysis of 109 double-blind studies found that placebo side effects were more intense, on average 19%. The most common of these side effects are; insomnia, headache, nervousness and nausea. Placebo has a peak, aggregation and sagging effect just like drugs; It is known that large capsules and injections have a much stronger effect, yellow capsules have a stimulating and antidepressant effect, and white capsules are more effective as analgesics (News 1994).
The most useful model for illustrating how placebos work and their neurophysiology is the pain model. Although neurophysiologically, a relationship between bodily pain and endorphins has been demonstrated, the relationship of endorphins with the HPA axis, GABA and opioid receptors has not been adequately explained until now. Our current knowledge shows that the placebo effect has a multidimensional and self-regulating aspect. It is stated that the placebo comes into play to compensate for the hyperexcitability caused by environmental threats in the HPA axis (Oh, 1994). Placebo was found to be more effective in clinical pain rather than experimental pain, and more effective in severe pain than mild pain; “sex,” “suggestion,” and “ intelligence The relationship of ” with placebo could not be demonstrated; It has not been demonstrated that there are “placebo reactors” that regularly respond to placebos. For all these reasons, it is therefore not possible to say which patients would benefit from placebo (Oh 1994).
The Role of Dopamine in the Placebo Effect, Expectation and Reward Models
It should be reminded again that the placebo effect is a phenomenon that occurs when a patient’s expectations about a drug or treatment affect his response to treatment. The strength of the placebo effect is well documented in clinical studies, where patients who took a placebo generally reported feeling better than those who did not.
The mechanisms behind the placebo effect are not fully understood, but it is thought that dopamine, the brain’s own chemical messenger, may play a role. Dopamine plays a role in many processes in the brain, including learning, motivation, and pleasure. Studies have shown that when people expect to receive a reward, their brains release dopamine in anticipation of that reward. This dopamine release has been associated with the placebo effect, as it can help create positive anticipation that leads to a beneficial response.
While the role of dopamine in the placebo effect is still under investigation, it’s clear that this brain chemical plays an important role in many areas of our lives. Dopamine is essential for our survival, and its dysregulation has been associated with many diseases and disorders, including addiction, depression, and schizophrenia. Understanding how dopamine works is expected to help develop more effective treatments for these conditions and others.
Within the scope of these studies, how placebo is effective in Parkinson’s disease has been an interesting subject. As with placebo analgesia, it has been reported that positive expectation causes dopamine release in the nigrostriatal pathway in Parkinson’s patients, and this may be related to the reward model (Fuente, 2002). These findings were supported by a PET study showing that the level of positive expectation was correlated with striatal dopaminergic transmission (Lidstone. 2010). In the measurements made with PET labeled with raclopride, a dopaminergic receptor antagonist, in patients with Parkinson’s, there was a significant release of endogenous dopamine, possibly from the caudate nucleus and putamen, after saline solution injection in patients, and these dopamine removed raclopride from dopaminergic receptors. Endogenous dopamine release was especially higher in the placebo-responsive group (Fuente, 2002).
In another study, when patients with subthalamic stimulators were told that the stimulator was working even though it was not working, better motor performance improved and there was an increase in subthalamic firing rates in relation to the placebo effect (Pollo, 2002). At the same time, it was stated that dopamine signaling could be a marker for the difference between expected and actual reward on the effect of placebo, and it was claimed that dopamine release during reward expectation in a pay game task is related to dopamine released from the same region as placebo analgesia (Irizarry, 2005). It has been stated that this signaling decreases as the duration of expectation increases, and it has been evaluated that this explains the difference between single-dose or long-term dosing (Faria, 2012).
These findings suggest that the effect of placebo may affect the dopaminergic pathway.
Positive expectation leads to tonic activation of dopaminergic neurons in the dorsal striatum, ventral striatum and prefrontal cortex; The expectation of reward induced by placebo is explained by the effect of excitatory glutamate and inhibitory GABA impulses on dopaminergic neurons in the body (Fuente, 2004). It has been evaluated that the presence of phasic activation such as tonic activation in dopaminergic neurons, positive expectation increases prefrontal cortex activation and thus causes an increase in dopamine flow in the ventral tegmentum from the medial fascicle. It is thought that positive expectation regulates the stress response and affects the placebo response (Teixeira, 2010). On the contrary, it has been observed that negative statements cause anticipatory anxiety and increase pain, that there is a decrease in endogenous opioids and hyperalgesia develops after the activation of the cholecystokinergic system (Oken, 2008).
- Placebo in Psychology and Psychiatric Sciences
Although it can now be observed that placebo drugs and treatments have important effects in all diseases and patients, psychology and psychiatry in particular think that diseases are closely related to placebo and focus on studies in this area (Lapierre, 1995). Research results also support this idea; For example, responses to placebo have been shown to be generally effective in acute schizophrenia, sometimes even superior to drugs used in the treatment of the disease (Chouinard, 1990). Likewise, the response rates to placebo in long-term schizophrenia are around 30-45% (Ruskin and Nyman, 1991), and placebo was effective in the prevention of bipolar relapses by 30% (Klein, 1992). While this rate increases up to 65% in the treatment of generalized anxiety, this rate remains around 22% in panic disorders (Black et al., 1993). Studies conducted to date have reported that, unlike other mental illnesses, there is a serious resistance to placebo in obsessive-compulsive disorders, and response rates are around 3-13% in this direction (Greist et al., 1990).
Understandably, the relationship between psychiatry and psychology and placebo effects is still not fully understood, but it is clear that placebo effects may play a role in psychiatric treatment. In some cases, placebo effects may be beneficial, while in other cases they may be harmful.
It is important to remember that psychiatric disorders are complex and often involve more than one factor. Placebo effects can be one of many factors that influence the course of a disorder. Therefore, it is important to consider all available evidence when making treatment decisions.
Overall, evidence suggests that placebo effects may play a role in psychiatric treatment, but the effect may be different for different disorders. More research is needed to fully understand the relationship between psychiatry and placebo effects. However, it is clear that placebo effects are an important factor to consider when making treatment decisions for psychiatric disorders.
Considered one of the experts in research with placebo, Brown has an interesting study and commentary on this relationship. Brown (1994), who conducted research on the effect of placebo in the treatment of long-term depression, saw that the placebo effect gave high-efficiency results, and strongly recommended the administration of placebo drugs for the first six weeks in the treatment of depressions other than those that became chronic or had a biological appearance. Brown, in response to criticism of this study; He expressed that he could not understand the high reactions shown in the face of the scientific placebo treatment he suggested, while there is so much interest in unproven treatment methods such as massage, homeopathy, spiritual healing, and mega vitamin.
The fact that the psychological (emotional, thought and behavioral) effects of psychiatric drugs are not fully known and the criticisms made about the fact that known ones carry methodologically erroneous information (Jacops & Cohen, 1999) are also one of the reasons why placebo has gained more importance in psychiatry. In addition, it should be kept in mind that the contribution of placebo is determined by the interest and curiosity of the physician, especially in field studies in primary care, while investigating the effect of psychiatric drugs, because insufficient knowledge, misdiagnosis, inadequate and inappropriate treatment are seen too much in this field (Laporte & Figuras, 1994).
The Placebo Effect in Depressive Disorder
The best example we have today to discuss the placebo problem in psychiatry; Depression is the reason that most of the discussions are made on this disorder. The placebo in the treatment of depression has been studied more frequently, well researched and a discussion that can be made for many disorders of psychiatry, especially in the context of depression.
It was found that among those who responded to placebo in depression, those who had their first episode and women were more common than those who did not respond, and these people had lower Hamilton Depression Scale depression total scores, psychomotor retardation, and somatic anxiety scores (Bialik et al., 1995). However, it should be noted that there is another study that reported quite contradictory results to these results and had the same importance in the literature (Wilcox et al., 1992); According to this study, men, married people, and those older than 65 were relatively more likely to respond to placebo. The common point of these two studies, which included differences in gender and age, was that the best indicator of response to placebo in both studies was the low Hamilton Depression Scale scores. These studies, which were conducted to determine the characteristics of those who responded to placebo in depression, show how variable, mixed, empirical ( empiricist) can be claimed to indicate that it is a difficult subject to obtain information consistent with research.
More recently, Enserink (1999) and Oh (1994) have brought up the discussion about the use of placebo in the treatment of depression. In particular, Enserink made an important contribution to the literature and practice by bringing the concept of time-dependent sensitization to the evaluation of the placebo effect. According to Enserink, in order to reveal the placebo effect, a third control group is required from those who do not take drugs, but only in the natural process, because placebos are just like drugs because of time-dependent sensitization, which expresses the primitive reactions of the organism against any substance that it sees as foreign and stressful. cause reactions. In this context, it is necessary to reconsider the late responses to treatment, especially in antidepressant treatment.
Oh (1994), on the other hand, stated that it is possible to use placebos not only in the treatment of depression, but also in the pain states, autonomic sensory disorders and disorders in neuro-humoral control, which have proven to be the most effective, when the treatment is both ineffective and expensive. Oh (1994) also drew attention to the link between the placebo effect on mental and physical health, and emphasized that placebo could not be adequately developed clinically due to the dominance of modern chemotherapy.
As a result of the antidepressant and placebo treatment given to patients with major depression, brain activity was examined by quantitative electroencephalography compared to pre-treatment, and a significant increase was reported in the prefrontal chord, which is the measurement unit of electroencephalography activity and which reveals a strong correlation with blood flow, in the group that responded to placebo (Leuchter, 2002). ). In another similar study, fluoxetine was compared with placebo. PET measurements of the placebo-responsive group revealed an increase in glucose metabolism in the prefrontal cortex, anterior cingulate, parietal cortex, posterior insular cortex, and a decrease in metabolism in the subgenual cingulate, thalamus, and parahippocampus (Mayberg, 2002). The presence of similar metabolic changes in the fluoxetine group was interpreted as that placebo caused an increase in serotonin with a high probability. In the light of all these findings, it was determined that placebo activates endogenous opiates and pain-regulating pathways with the effect of positive expectation in patients with pain, and that it activates neurons in the subthalamic nucleus by increasing dopamine release in the striae; In the case of depression, it was thought that it had serotonin-related effects in some brain lobes (Benedetti, 2007).
Placebo Effect in Anxiety
In studies investigating and examining the placebo effect on anxiety, images that cause dissatisfaction were shown to healthy volunteers and emotional perception was tried to be measured (Petrovic, 2005). Medication containing the active substance was administered to some of the patients and placebo was administered to some of them. An increase in activation in the right anterior cingular cortex and orbitofrontal cortex was detected in patients with a decrease in placebo-induced anxiety during emotional regulation. It is known that these regions also have a regulatory role in placebo-induced analgesia. In addition, it has been determined that pre-existing treatment expectancy and placebo-induced activation in the ventral striatum are correlated, which is in line with the placebo reward model in emotion regulation (Petrovic, 2005).
The results of these studies show that the antidepressive and anxiolytic effect of placebo is regulated by some regions in the prefrontal cortex.
Especially in the context of anxiety, the expectation model has a very important place in the placebo effect. The ventral striatum’s involvement reflects the antidepressant and anxiolytic effect associated with possible reward expectation. There was a correlation between excess dopamine release in the dorsal striatum (caudate and putamen) and an excess of clinical placebo effect, but not in the ventral striatum, as the ventral striatum is less associated with motor performance than the dorsal striatum—therefore, it is more strongly associated with expectation of reward rather than reward realization (Phillips). , 2002).
More recent studies on the evaluation functions of the dorsal anterior cingulate cortex; It has been stated that the right anterior cingulate cortex is effective in the regulation functions (Etkin, 2011). It has been suggested that placebo reduces the negative affective dimension of pain by causing a decrease in the activation of the dorsal anterior cingulate cortex in the placebo response. This indicates that the sensory process plays a large role in the placebo response. Consistent with this finding, it was concluded that the activity changes in the sensory process circuits in the placebo analgesia response were important in determining the placebo response, and it was stated that anticipatory anxiety was associated with a low placebo response (Wager, 2011).
Hypnosis and Placebo
There are some similarities between the placebo effect and the effect of hypnosis. This situation has been expressed as the placebo’s ability to create a hypnotic process on patients, but unlike hypnosis, although the “misleading patients” factor is involved in placebo, the expectation of improvement in both placebo and hypnosis response has a significant effect and this situation is closely related to suggestion.
In a study with PET, activation occurred in the occipital, parietal, prefrontal, and cingulate cortex when hypnotized people asked them to recall their happy memories; On the other hand, when the same people wanted to remember the same memories while they were awake, activation occurred in both temporal lobes and basal forebrain regions (Maquet, 1999).
This is an indication that there is a difference in the functioning of the brain under hypnosis and in wakefulness.
When healthy people are hypnotized and suggested to feel pain, these people not only feel pain, but also increase activation in the thalamus, anterior cingulate cortex, insula, prefrontal and parietal cortices (Derbyshire, 2004). These brain areas are also activated when actually exposed to pain. When people with chronic pain are hypnotized, the pain they feel increases even more (Derbyshire, 2009). However, when suggestion is made during hypnosis in these patients, the pain they feel decreases in correlation with the activation in the brain (Derbyshire, 2009).
Hypnosis not only reduces the intensity of pain, but also affects the emotional response to pain. The anterior cingulate cortex has an active role in regulating emotional response. During hypnosis, when pain-related dissatisfaction increases or decreases due to suggestion, changes occur parallel to anterior cingulate cortex activation. However, the expected activation changes in the primary somatosensory cortex and secondary somatosensory cortex do not occur (Rainville, 1997). On the contrary, when there is an activation change in the primary somatosensory cortex and secondary somatosensory cortex, which is correlated with an increase or decrease in the intensity of hypnotic pain, there is no change in the anterior cingulate cortex. In fibromyalgia patients, hemodynamic responses develop along with the decrease in the pain felt during hypnosis, an increase in bilateral orbitofrontal, right thalamus, left inferior parietal cortex blood flow; bilateral cingulate cortex blood flow decreases (Wik, 1999). Related studies and findings point to important conclusions that the effect of suggestion in hypnosis on pain control is through cortical regulations in the brain.
It should be noted again that there are differences in perception and expectation in individuals associated with hypnosis. In patients who have more than one chronic pain and have a high susceptibility to suggestion, it is observed that there is a very significant improvement in pain during hypnosis, depending on the expectation, but the pain reappears after a while after hypnosis. This link between hypnosis and placebo produces similar changes in the brain, both of which are related to suggestion and expectation. Admittedly, it is an interesting area that patients are affected by hypnosis and placebo to varying degrees in different situations.
- Use of Placebo Drugs in Clinical Trials: Methods
As mentioned in the previous sections, a placebo treatment can be applied to a patient, but if there is no reference treatment accepted in clinical studies, or when the disease is a benign disease, placebo use is acceptable. But sometimes some studies require placebo drugs and treatments in clinical trials themselves to meet scientific experimentation requirements.
The use of placebo drugs is common in clinical trials. Placebo drugs are inactive substances given to patients in order to compare the results of the active drug tested. In some cases, patients may not be aware that they are taking a placebo.
There are ethical concerns regarding the use of placebo drugs in clinical trials. Some argue that it is unethical to give patients an inactive substance when an active treatment is available. Others argue that the use of a placebo is necessary to accurately compare the results of the active drug tested.
The use of placebo drugs is regulated by the FDA. Placebo drugs should be clearly labeled as such and their use should be justified in the protocol of the clinical trial. Informed consent should be obtained from all patients who will receive placebo drugs.
Some clinical studies use active-placebo comparisons. In these studies, patients are given both the experimental drug and an inactive placebo. Then the results of the two groups are compared. Active-placebo comparisons are generally considered more ethical than placebo drug use alone.
The use of placebo drugs is controversial. Some argue that ethics is necessary to conduct clinical trials. Others argue that the use of placebo drugs is unethical and that active-placebo comparisons should be used instead. Ultimately, the decision on whether to use placebo drugs should be made on a case-by-case basis.
The use of placebo drugs in clinical trials can only be carried out in the following ways, within the scope of established rules and principles in today’s accepted legal, ethical and practice;
- Use of placebo versus tested substance. The aim of this relatively simple research model is to