PLACEBOandTHEPLACEBOEFFECTINCLINICALTRIAL

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PLACEBO and THE PLACEBO EFFECT IN CLINICAL TRIAL IS IT a BIOCHEMICAL
and PHARMACOLOGIC BLUFF?
Conference Paper · September 2004
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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. A nonspecific effect that occurs with a specific effect of a treatment,
2. The treatment effect that a drug gives that is biomedically ineffective,
3. A treatment effect or side effect that cannot be explained by the pharmacologic
characteristics of a medication,
4. 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.