See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/318877045 PLACEBO and THE PLACEBO EFFECT IN CLINICAL TRIAL IS IT a BIOCHEMICAL and PHARMACOLOGIC BLUFF? Conference Paper · September 2004 CITATIONS READS 0 58 2 authors: Nuket Örnek Büken Hacettepe University Erhan Buken 41 PUBLICATIONS 417 CITATIONS 109 PUBLICATIONS 353 CITATIONS SEE PROFILE SEE PROFILE All content following this page was uploaded by Nuket Örnek Büken on 03 August 2017. The user has requested enhancement of the downloaded file. PLACEBO and THE PLACEBO EFFECT IN CLINICAL TRIAL Buken NO., Buken E. “Plasebo and Plasebo Effect in Clinical Trial” (The Role of Placebo in Clinical Trial), 39th ISHM Congress (39th International Congress on the History of Medicine), Bari, Italy, Proceedings book pg: 149-160, Edit. By: Alfredo Musajo - Somma, 5-10 September 2004, Oral presentation. IS IT a BIOCHEMICAL and PHARMACOLOGIC BLUFF? This paper will discuss the placebo, a subject that has been reflected in scientific literature with its confusion of concepts and whose characteristics have been discussed throughout medical history. First we will look at the concept of placebo from the point of view of medical history, then we will attempt to define placebo and the placebo effect. We will discuss the subject of the use of placebo with research subjects. We will examine placebos in clinical drug trials, placebos in psychiatry, the ethical problems that arise with placebo use, and topics for discussion such as, can the placebo effect of holistic medicine methods (alternative medicine methods) be explained? Placebo in Medical History The discussion related to what a placebo is and how the placebo effect occurs goes back into the distant past of medical history. The way placebo and placebo effect were looked at varied with the understanding of disease. There are roughly two types of understanding of disease in medical history that continue today: The "Hippocratic" or "ontologic medicine" approach by those who see disease as an ontologic entity, particular to itself, taking on an independent identity or the "physiologic medicine" approach that emphasizes the individual patient's biography in light of the illness. The Hippocratic type sees disease as a specific entity, is directed at looking for the specific effect of that disease in treatment, and completely ignores factors not a result of the actual treatment (societal and environmental factors, factors specific to the individual, dimensions and smell of the medication), and has the understanding of only treating the specific cause (1). The discussion of specific and nonspecific effects that has lasted for years in clinical pharmacology is in fact directly related to placebo, because, according to the Hippocratic medical understanding, the placebo is seen as one and the same with nonspecific factors. Of course when seen this way, nonspecific factors, that is, the placebo effect, will be discredited; they will be considered worthless, of no account, and instead of them, all hope will be invested in one treatment that can be completely explained by specific effects (1,2). What is a Placebo? The word "placebo" comes from the Latin meaning "I will be pleased" and suggests the positive effect of a medication or a specific thing that is taken as a remedy. "Nocebo" is the exact opposite concept and means "I will be harmed" and is used for a specific negative period of life. They are substances that do not have any biologic affect that are used in the care of patients for their psychological effects or as a control agent in research. So in this situation is a placebo a kind of biochemical and pharmacologic bluff? There are four basic definitions of the placebo effect that have been proposed (1,3). 1. 2. 3. 4. A nonspecific effect that occurs with a specific effect of a treatment, The treatment effect that a drug gives that is biomedically ineffective, A treatment effect or side effect that cannot be explained by the pharmacologic characteristics of a medication, The combined effect of all treatments. What is the Placebo Effect? The accuracy of the suggestion, “When a pain killer is taken pain ceases” is indebted to two factors. The first is that when a medication is taken the feeling of pain begins to leave from the pain-alleviating pharmacologic effect of the medication; the second is with the "I took the medication, now it will stop" thinking, the pain ceases. Together with the medication's pharmacologic effect there is the "placebo effect" that is thought to be psychological. The placebo effect not only supports the medication's effect, in medication research it works independently. When a medication's pharmacologic effects are investigated, the subjects, or a portion of the subjects, are given a substance that does not contain a medication. Substances, like sugar, that do not have a therapeutic effect are put in the form of a medication and used in the control group, then the subjects' reactions to the actual medication and compared to those given the placebo and the effect of the medication are measured. In research conducted with placebos, it has been discovered that there is even an effect from the color of the placebo medication given to subjects. Yellow placebo tablets have been shown to have an antidepressant effect, blue tablets have a calming effect and red tablets have an analgesic effect (4). The confusion about the concept of placebos is reflected in the scientific literature; in a review of the last 20 years of scientific journals, only one fourth of the journals used the correct meaning of placebo. The journals discuss cases in which a wrong medication was given or no treatment was given with the term "placebo." A psychologist summarizes the situation as, "when the meaning of the term placebo is confused even in the head of scholars, it states that, in fact, they do not have the intention of understanding." Another psychologist states that the negative approach to placebo is due to the fact that the medical world is dependent on the financial support of the pharmaceutical companies; nobody would give a patent to medications that contain sugar. In some research studies it has been defended that the placebo effect can also be revealed with biochemical events in one day. However in biochemical research related to the brain's immune system, the form taken by the brain biochemical substances continues and biochemical studies on this subject are continuing. Even though the details of how the placebo mechanism works remains a secret, a good starting point for investigating these secrets would be Pavlov's dogs. Pavlov was able to measure the effect on salivary glands of dogs that had been made to identify food with a bell. Researchers, following in Pavlov's footsteps have trained research animals to be conditioned to the effect of narcotic or poisonous substances and have observed them curl up and die in pain when given placebos. However the placebo effect in human situations is a conditioning that occurs throughout life; with every aspirin that is swallowed whether we like it or not we are being conditioned to feel better with a white pill. Medications do not only have pharmacologic effects, however, because a substance is taken as a medication or with the expectation of healing, some of patients' symptoms can be alleviated or the patients' opinion of them can be made to be positive. In addition even if a medication is completely ineffective, during its use the disease and the seriousness of the pathologic process that caused it, as a natural course may show a decrease or lessening; and this can be interpreted incorrectly to be a result of the medication. For these reasons preparations in placebo form can show therapeutic activity to a certain extent and usually for a temporary period of time. Researchers state that placebos' activity on subjects show a success rate between 0 and 100% compared to the actual medication. It is impossible to predict which patients will have a positive response to placebo therapy or which placebo will have the best effect on diseases. In the majority of interventions, placebo injections are more effective than placebo capsules, and capsules are more effective than pills (3,4). In placebo intervention, individuals are said to be responsive to placebo who state that their complaints have been alleviated even when there is no objective change, or who state that there has been a change in their physical and/or emotional state. People who are responsive to placebo are generally those who are responsive to suggestion. In psychological tests that have been done, in general they are seen to be neurotic individuals with low self-confidence. Tablets or other pharmacological forms that can be used as placebos are not available specifically in pharmacies. In medication trials the placebos are generally prepared specifically for the pharmaceutical production company in the form that imitates the medication that will be studied. Discussion of the Use of Placebos with Subjects in Research An English research group examined the placebo effect on a group on patients who were having their wisdom teeth pulled. To treat the swelling in the chins of the patients whose teeth had been pulled the patients' cheeks were massaged with an ultrasonic type of instrument that is used in gynecology. When the swollen chins that had the treatment were compared with the control group, 35% were successfully healed. Of course there was no therapeutic activity from the ultrasound waves behind this success. In fact the researchers pulled the plug of the ultrasonic instrument without telling the dentists or the patients who had it used on them. This experiment is an indicator of how successful methods that are based on medical persuasion can be in even difficult conditions in patient treatment (4). So can patients be treated with medications that do not contain any active substances or instead of doing nothing, by a variety of practices that give an appearance of treatment? Ask about the physicians' responsibility for not misleading their patients. Will this bluff be effective if patients are informed about the situation? The question is a topic of daily discussion. This and similar questions are making more difficult the contest between a secret placebo treatment and an honest, effective medication treatment. An Australian psychologist, Nicholas Voudouris, recommends a solution to this dilemma in which the strong therapeutic potential of placebos can be used without misleading people. In a research conducted on volunteer students a fake anesthetic cream was shown to lesson the pain of a mild electric shock that was given. The students benefited from the cream even when they had been informed that they were being misled. According to Voudouris the important point of this study is that the students were convinced to be conditioned to feel less pain with the cream, and were like Pavlov's dogs that had been conditioned to the bell with food. Voudouris is now carrying out studies with this method on real humans with chronic pain. Placebo tablets are added coincidentally amongst the potential analgesic doses that are given to the patients. In this way the patients take less medication, are subjected to fewer side effects and have lower medication expenses. Today, it is not legally possible for physicians to use placebos other than for the purpose of research. A corollary to this is that placebo is not a therapeutic method that is misunderstood; it creates a tool that shows that patients' complaints are a figment of their imagination. Placebos in Medicine Today the presence of the placebo effect is accepted in all branches of medicine in spite of difficulty defining it and its mysterious contents; the only issue for discussion is the percentage of effectiveness with which diseases and which medications. The placebo effect has even been discovered with surgical discomfort. In general it is possible to say that effective medications are only 1.3 times more effective than placebos or that a very significant placebo effect is created in therapeautic activity. The basic difficulty talking about the placebo effect creates its variability. The placebo effect doesn't just vary from illness to illness; it also can show variability between countries and even between regions. Even if the physician believes in placebos he plays a role in the placebo effect and increases it. Another interesting aspect of placebos is the side effects that they cause. In many studies more side effects from the placebo control have been found. Some of the most frequently reported are sleeplessness, headache, nervousness and nausea. Placebos in Psychiatry It is thought that placebo is tied more to psychiatric illnesses than all the other illnesses. The reason that placebos have earned special importance in psychiatry though is really a very interesting subject. For this reason according to whomever the origin of psychiatric disturbances is unknown. Nonpharmacologic placebos, such as "suggestion", "persuasion", "positive thinking", "trust", and "belief", for whatever reason are believed to play a central role in psychiatry. Thus, when developing an opinion to explain the etiology of psychiatric disturbances, of course it plays a big part in the lack of clarity of the place and position of psychotherapies in theories of psychology and psychiatric treatment (5). Criticisms about the fact that the exact psychological effects of psychiatric medications (feelings, thoughts and behaviors) are not known and what is known has inaccurate information about mechanism of action is one of the reasons why placebo has gained importance in psychiatry. The best example today of an issue for discussion regarding placebos in psychiatry is depression. The place of placebos in the treatment of depression has been studied more and has been well researched and a discussion that can be made for many psychiatric disturbances is only continuing in the context of depression. Among those who respond to placebo in depression, there were more who were having their first attack and women than there were those who did not respond. However according to a research that gives quite opposite results to this, men, married people and those who were over 65 years old responded slightly more to placebo. These studies, that were conducted to determine the characteristics of those who respond to placebo in depression, are merely clear evidence of just how difficult placebos are as factors with complex, empiric research as a subject for getting consistent information. When Brown, who conducted research about the role of placebos in the treatment of depression, saw significant results with the effect of placebo, he made serious recommendations that, other than in chronic cases, placebo be given in the first 6 weeks of the treatment of depression. In the issue in which Brown's article was published there were also several criticisms from different viewpoints. When Brown responded to these criticisms he stated that when there is so much interest in alternative therapies such as "massage", "homeopathy", "spiritual healing", "megavitamins" he does not understand the indignation shown towards scientific placebo therapy that those who remain silent recommend (6). Use of Placebos in Clinical Drug Trials In clinical drug trials directed at comparing the clinical effectiveness and safety (side effects) of medications, the placebo is used in the control group patients; the alternatives to placebo in the control group are giving no medication, giving a formerly tested, accepted medication that has known effect to patients, or giving the new medication at a very low, ineffective dose. The principle reasons for giving placebos in clinical drug trials are (7,8): • To determine a medication's part in the actual effect of a medication on the improvement in symptoms of a disease that has been tested with psychological effect of participating in a clinical trial and with the psychological effect of taking any kind of medication, • To determine if adverse effects are from the medication being tested or from natural course of the disease process, spontaneous changes or for reasons unrelated to the medication, • When it is absolutely necessary to ensure the random sampling of the volunteer and treatment groups and that the treatment be given blindly, • To bring to light the clinical effectiveness of a new medication in comparison with another effective medication in a clearer and faster manner that requires fewer subjects and in this way to ensure that results are more clearly evident. On the other hand in the control group in clinical drug trials the use of a placebo in the place of a medication that is effective and has been used for a long time means that this group is receiving no treatment and the patients are left face to face with the disease; for this reason in some situations important ethical problems arise. To keep these problems to the minimum in the control group, the placebo should be used (7,8): • In trials of short duration or one dose (for example, to test the acute analgesic effect of a new medication in painful conditions or to test the hypnotic effect of a new sleep medication in sleep disorders), • In diseases and clinical conditions that do not have a standard treatment or even if there is a standard treatment it is ineffective or its effectiveness has not been proven, • In special patient groups where standard treatment is inappropriate or contraindicated, • In drug trials for acute and chronic diseases that have benign symptoms that are not progressive, • In the treatment of conditions and psychological disorders that are strongly influenced subjectively when it is necessary to control for or to determine the degree of influence from suggestion. In contrast to this in the case of serious illnesses, because in conditions of advanced disease that is not ameliorated with medication and in diseases with no adequately effective alternative medication, giving the control group placebo could be "punishing" the patients, this practice is objectionable on ethical grounds. In some situations to eliminate the objections the placebo is given in addition to an effective, accepted medication and the treatment group is given the new medication with this accepted medication in combination and the additional effectiveness of the new drug is evaluated in contrast to the placebo. Permission can be given for placebo medication or false treatment intervention in control groups, when the researcher-clinicians understand that there is little efficacy of the standard treatment. A good general rule is that placebo or false treatment is not used without informed consent from all patients in the research. These interventions must not be harmful when they involve giving a foreign substance to a living being or disrupting the body's integrity. For that reason they must be based on rights and must be unequivocally harmless. In addition these interventions cannot be used to the same degree for every individual because of differences in patient age, severity of illness, etc. (9). In the fifth version of the Helsinki Declaration (October, 2000, Edinburgh) that has been accepted as the foundation of medical research ethics the use of placebo in clinical trials is not encouraged and, because it requires researchers to offer the "best proven" treatment to participants at the conclusion of the trial, it continues to receive a lot of varied reactions. In the 29th paragraph of the Helsinki Declaration these are clearly defined: new treatments should not be compared to placebo but to the "best current" treatment, placebo should only be used when no proven treatment exists. Some researchers and bioethics specialists think that there is no place for recommendations for the use of placebo and it is unnecessary and that it will be an obstacle to future research. In the US, the FDA (Food and Drug Administration) and DHHS (Department of Health and Human Services) are neutral on the subject of support for this requirement in the declaration. The standards of the ICH (International Conference on Harmonization), which is an international consortium of institutions responsible for regulations about medications, are being shown as an alternative model. According to the ICH "whether placebo use is problematic or not is related to what is the normal treatment that is being used for individuals." Said another way, if the individual will not be harmed placebo can be given. However the interpretations of these types of general and comprehensive statements and their meanings in practice are cloudy. The days ahead are pregnant with new arguments from this viewpoint (10,11). Ethical Issues that Result from the Use of Placebos Because there can be a placebo effect the patient must be completely uninformed about what it is and in fact in the most reliable use of placebo effect, together with the patient, the physician or the other professional expert as well should all be uninformed about it. This characteristic of placebo being related to a "trick", "deception" and "lie" frequently raises the question of the context of telling the truth in medicine. The placebo effect, particularly from the aspect of having to deceive, as it relates to medical ethics has come to the focus recently. However there is a need for discussion of the ethics of this question: Can it be right in any kind of medical treatment for there to be a necessity of the patient being deceived? In particular while the complex questions about definition of placebo and what it means continue doesn't the scope of this question need to be broadened? In reality placebo use generates serious ethical issues. It is not possible to hinder placebo from being separated from real medications that have been mixed up and given to real patients for a long time. Even if the patient arrives at the decision that he/she did not get well with the real medication, it is even more difficult to arrive at a conclusion about the false medications. Before everything else, when it is possible to treat patients with real medications, how ethical it is to use placebo must be discussed. However those on the side of placebo propose that contrary to placebo being seen as unethical today, tomorrow the high price and side effects of real medications will be unethical. Can the Effect of Alternative Medicine Methods Be Explained with Placebos? Proving the placebo effect has helped in the explanation of alternative medicine methods and the effectiveness of medications that don't have any active substances. These observations explain why some medications and plant products, that have been shown to be ineffective by modern pharmacologic techniques, have been used by people as medications for years, in fact hundreds of years. However the subject for researchers to discuss today is whether or not placebo will be used alone as a medication. As can be guessed every illness will not swallow this "bluff". While it is known that placebo is effective in conditions such as pain with psychological origins, anorexia, psychological depression, fever, organic disorders and cardiac insufficiency are not responsive to placebo. Today do all modern physicians hold the belief that traditional treatments that have continued for thousands of years, even decades, are treatments that are not beneficial to patients but harmful? Today which physician would dare to treat patients with the Nobel prize winning (in in its time) "malaria fever treatment" or "insulin coma treatment"? Another question that comes to mind is: "Although they are not using these treatments which were beneficial to people for thousands of years, what was it that healed them?" In the answer to this question there will certainly by found the “placebo effect" with the understanding of contentment (1). If the concept of contentment is limited and if it can be defined scientifically, while talking about placebo effect, factors such as "hope" and "expectation" which are concepts that are frequently discussed but are distant from science can also be evaluated and brought under the same roof. The reason can be explained why those who have more expectations of getting well and hope are able to benefit more from treatment than those who do not (1). Conclusion There are, essentially, two sides: to correct all the treatments of the specific processes that lie under conditions of disease and to show the demoralizing effects of nonspecific diseases. Placebo has a part in the treatment of the person that is helped by bringing together factors that are related to trust, emotional unloading, rationalizing, conceptual schemes or myths, and ritualistic factors. For this reason placebo, which feeds the patient's hope for recovery, participates in fighting the demoralizing factors with symbolic communication and it wouldn't be wrong to see it as a kind of psychotherapy. Placebo includes all of the things that are interpreted as the stimulants that affect the contentment systems in our bodies and all the factors that a patient interprets as hope for recovery from the strength of the institution to ensure treatment to the interest of the physician in the form of a medication. Because the placebo effect opens the way to contentment in the body, as the effect of a drug in medicine as a last resort, it shows itself as a regulating substance in the body. It also has the meaning of bringing improvement to human illnesses and for the healing of these diseases. Every person, because they are human, makes this inescapable interpretation. Both the medication that is taken or the technique that is implemented and the physician-patient relationship or anything that contributes to the treatment process with "it will be good" thinking (this is a value that ensures contentment in the individual's specific world) that is a strong factor in the meaning web and are defined as placebo effect. The meaning web, that is the physician who believes that the treatment implementation "will be good", increases the placebo effect of the treatment team and the patient's next of kin in a measurable way. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 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