Placebo Effects in Clinical Trials and Conditions

18390451026,School Of Pharmacy, DBU
PROJECT REPORT ON
“PLACEBO : BOON TO RESEARCH, BANE TO THERAPY”
SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENT
FOR THE AWARD OF THE DEGREE OF
BACHELOR
OF
PHARMACY
SUBMITTED BY:
RAHUL RATHOR
UNDER THE SUPERVISION OF
Ms. PARAMJIT KAUR
(ASSOCIATE PROFESSOR)

1
CERTIFICATE
This is to certify that RAHUL RATHOR has completed Dissertation project report, entitled
“PLACEBO: BOON TO RESEARCH, BANE TO THERAPY.”
under my guidance and supervision. To the best of my knowledge, the present work is the
result of their original investigation and study .No part of the report has ever been submitted
for any other degree at any university.
This report is well for submission and the partial fulfilment of the conditions for the
award of BACHELOR OF PHARMACY.
Date: April 29,.2022 Supervisor Signature
MS. PARAMJIT KAUR
(ASSOCIATE PROFESSOR)

2
DECLARATION
I hereby declare that this article entitled “PLACEBO: BOON TO RESEARCH, BANE TO
THERAPY” is an authentic record of my own work carried out at DESH BHAGAT
UNIVERSITY, MANDI GOBINDGARH. (PUNJAB) for the partial fulfilment of the
award of Bachelor Of Pharmacy under the guidance of Ms. PARAMJIT KAUR (Associate
Professor ). This work is my original and has not been submitted for any degree/diploma in
this or any other University. The information furnished in this dissertation is genuine to the
best of my knowledge and belief.
Place: DBU RAHUL RATHOR
Date: April 29, 2022

3
ACKNOWLEDGEMENT
It gives me immense pleasure to acknowledge my indebtedness with due respect to
Ms. PARAMJIT KAUR, for whose continuous efforts made it possible for me to present my
project.
Moreover, I wish to reciprocate my full kindness to Dr. POOJA GULATI
(Principal), who had guided me with their timely advice & constant inspiration which ended
the task of completing this project report. They have not only made our present work a
possibility but inspired me greatly to work for a better future. I have been fortunate enough to
have a chance to undergo their guidance.
Last but not the least, sincere thanks to my parents for whose constant motivation
ended the task of completing this report.
Date: April 29, 2022 RAHUL RATHOR
Place: DBU

4
ABSTRACT
Placebos are boon and bane to medical theory and clinical practice. On the one hand,
randomized controlled trials employ concealed allocations of placebo to control for effects
not due to specific pharmacological mechanisms. As a result, nearly all of evidence-based
medicine derives from principles and practices based on placebo. On the other hand, medical
researchers and physicians have tended to ignore, minimize, or deride placebos and placebo
effects, perhaps due to values emphasizing scientific understanding of mechanistic pathways.
Placebo effects are beneficial health outcomes not related to the relatively direct biological
effects of an intervention and can be elicited by an agent that, by itself, is inert.
Understanding these placebo effects will help to improve clinical trial design, especially for
interventions such as surgery, CNS-active drugs and behavioural interventions which are
often non-blinded. A literature review was performed to retrieve articles discussing placebo
implications of clinical trials, the neurobiology of placebo effects and the implications of
placebo effect for several disorders of neurological relevance. Recent research in placebo
analgesia and other conditions has demonstrated that several neurotransmitter systems, such
as opiate and dopamine, are involved with the placebo effect. Brain regions including anterior
cingulate cortex, dorsolateral prefrontal cortex and basal ganglia have been activated
following administration of placebo. A patient’s expectancy of improvement may influence
outcomes as much as some active interventions and this effect may be greater for novel
interventions and for procedures. Maximizing this expectancy effect is important for
clinicians to optimize the health of their patient. There have been many relatively acute
placebo studies that are now being extended into clinically relevant models of placebo effect.
Keywords: placebo effects; expectancy; cognition; clinical trials methods.

5
INDEX
S.NO. TABLE OF CONTENT PAGES
1
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16
17.
18.
INTRODUCTION
ORIGINATION OF PLACEBO
DEFINATIONS OF PLACEBO
PLACEBO EFFECT ON HUMAN BEING
HISTORY OF PLACEBOS
PLACEBOS IN MEDICINE
PLACEBO IN PSYCHIATRY
PLACEOS IN PAIN
PLACEBO IN DEPRESSION
A MODEL OF PLACEBO RESPONSE IN
ANTIDEPRESSANT CLINICAL TRIALS
Future Directions: Maximizing and Minimizing Placebo
Response in the Treatment of Depression
STRESS RESPONSE AND PLACEBO EFFECTS
PLACEBO IN CLINICAL TRIALS
PLACEBO STUDIES IN CLINICAL CONDITIONS
PAIN
PARKINSON’S DISEASE
MULTIPLE SCLEROSIS
EPILEPSY
CONCLUSION
REFERENCES
6
7
7
8
10
11
12
13
14
15
17
21
22
24
25
26
27
28
29

INTRODUCTION 2022
6
INTRODUCTION
Placebo effect, also called nonspecific effect, psychological or psychophysiological
improvement attributed to therapy with an inert substance or a simulated (sham) procedure.
There is no clear explanation for why some persons experience measurable improvement
when given an inert substance for treatment. Research has indicated that the effect may be
caused by the person’s expectations about the treatment rather than being a direct effect of
the treatment itself. Research has indicated that the effect may be caused by the person’s
expectations about the treatment rather than being a direct effect of the treatment itself.
Your mind can be a powerful healing tool when given the chance. The idea that your brain
can convince your body a fake treatment is the real thing — the so-called placebo effect —
and thus stimulate healing has been around for millennia. Now science has found that under
the right circumstances, a placebo can be just as effective as traditional treatments. The
placebo effect is more than positive thinking — believing a treatment or procedure will work.
It's about creating a stronger connection between the brain and body and how they work
together.

ORIGINATION OF PLACEBO 2022
7
ORIGINATION OF 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?
DEFINITIONS OF PLACEBO
A Placebo is usually pharmacologically inert preparation prescribed more for the mental
relief of the patient than for its actual effect on a disorder
 A nonspecific effect that occurs with a specific effect of a treatment,
 The treatment effect that a drug gives that is biomedical ineffective.
 A treatment effect or side effect that cannot be explained by the pharmacologic
characteristics of a medication.
 The combined effect of all treatments.

THE PLACEBO EFFECT ON HUMAN BEING 2022
8
THE PLACEBO EFFECT ON HUMAN BEING
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.(1)
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.
The colour 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. 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."
The 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

9
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 . 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.

HISTORY OF PLACEBO 2022
10
HISTORY OF PLACEBO
The word placebo was used in a medicinal context in the late 18th century to describe a
"common place method or medicine" and in 1811 it was defined as "any medicine adapted
more to please than to benefit the patient". Although this definition contained a derogatory
implication, it did not necessarily imply that the remedy had no effect.
Henry K. Beecher published an influential paper entitled The Powerful Placebo which
proposed idea that placebo effects were clinically important. Subsequent re-analysis of his
materials, however, found in them no evidence of any "placebo effect".
Placebos have featured in medical use until well into the twentieth century. In 1955
Homeopathy (18th century) Samuel Hahnemann (1755-1843) created a new type of medicine
that broke with the previous traditions.
The theory in homeopathic medicine is that “like cures like”, and that only a tiny amount of a
substance is needed to produce the desired effect. Homeopathy aims to restore the balance
between the life forces that have become altered in the patient's body by providing a
minuscule amount of a substance that will elicit a chain of reactions within the body that will
in turn cause it to heal. A report drawn up by the Science and Technology Committee of the
British House of Commons maintains that the effect of homeopathic remedies is similar to
that of placebos.

PLACEBOS IN MEDICINE 2022
11
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 therapeutic 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 2022
12
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. Non pharmacologic 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. 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 thpies such as era"massage".

PLACEBOS IN PAIN 2022
13
PLACEBOS IN PAIN
Physiological mechanisms involved in the placebo effect (meaning response) are perhaps best
understood in the area of pain. In the 1950s, Beecher and others reported evidence that the
administration of a placebo could lead to lower levels of reported pain.(54;95;96) Other
studies followed. In 1964, Egbert et al. published “The reduction of post-operative pain by
encouragement and instruction of patients.”(51) In 1978, only a few years after Hughes et al.
discovered endogenous opioids,97 Levine et al. published “The mechanism of placebo
analgesia,” demonstrating that the opioid-blocking drug naloxone could block the “non-
specific” effects of placebo analgesia.98 Further studies using blinded infusions of placebo or
naloxone, controlled by concealed pumps and timing devices, confirmed that the pain-
relieving properties of placebo operated through mechanisms involving opioid
receptors.(92;99;100) More recently, Benedetti and colleagues have confirmed and extended
these findings, demonstrating beyond reasonable doubt that awareness of actual or potential
treatment can reduce pain, and that opioid-related mechanisms are indeed involved in the
causal pathway. Various reviews have estimated the magnitude for various forms of placebo
analgesia, with estimates of effect size ranging from 10% to 75%.106-111 Combining data
from 44 pain trials (2,833 participants), Hrobjartsson and Gotzsche reported the pooled
standardized mean difference for placebo compared to no treatment at 0.25 (95% CI 0.16 to
0.35).(88) Most recently, Hoffman et al. have reviewed the research on placebo pain
response, concluding that evidence is strong , and that biological pathways are beginning to
be known in some detail.

PLACEBOS IN DEPRESSION 2022
14
PLACEBOS IN DEPRESSION
RCTs testing antidepressant treatments provide some of the best evidence regarding placebo
effects and meaning responses. A recent meta-analysis including data from 75 trials
representing more than 6,000 patients found that “the mean proportion of patients in the
placebo group who responded was 29.7%.”84 This study also found that placebo response
was greater in studies published in more recent years, and concluded that “the response to
placebo in published trials of antidepressant medication for [major depression] is highly
variable and often substantial and has increased significantly in recent years.”84 As the mean
proportion of responding patients in the active medication groups was 50.1%, it may be
concluded that the majority of apparent response to antidepressant medications comes from
placebo effect rather than from specific pharmacological mechanisms (0.297/0.501 = 59.3%).
A meta-analysis including only those trials with both no treatment and placebo groups
concluded that “23 percent of the response to antidepressant medication is due to spontaneous
remission, 27% is due to the drug, and 50% is due to expectancy.” A more recent and
comprehensive meta-analysis of all antidepressant drug studies submitted to the FDA
(published and unpublished) suggests that as much as 80% of effects from antidepressants
can be attributed to the placebo effect. Other systematic reviews of placebo effect in
depression have provided similar findings and interpretation.

MODEL OF PLACEBO RESPONSE IN ANTIDEPRESSANT 2022
15
A MODEL OF PLACEBO RESPONSE IN ANTIDEPRESSANT
CLINICAL TRIALS
Placebo response in antidepressant clinical trials has recently captured the attention of
psychiatric researchers, clinicians, and the lay public. Scientific interest focuses on the
influence of placebo response on signal detection in clinical trials and what its physiologic
mechanisms reveal about the pathophysiology of major depressive disorder.
The public would like to know whether responses to antidepressants are caused by specific
effects of the medications or are “just” placebo effects. Clinicians may view placebo response
as a challenge to their decisions to prescribe antidepressants and as a potential tool for
improving patient care. Complicating much of this discourse has been a murky understanding
of what contributes to placebo response in clinical trials. In this review, we present a model
of placebo response in order to aid in the interpretation of randomized controlled trial results
and their application to clinical practice, set an agenda for future research, and provide
information to help clinicians speak with their patients about antidepressant treatments.
Relationship of Placebo Response to Medication Response in Antidepressant Clinical Trials.
A fascinating and important question in pharmacologic treatments is how to conceptualize the
contribution of placebo response to medication response. “Medication response” denotes the
change in symptoms occurring during a clinical trial in patients randomized to receive
medication. In contrast, the “medication effect” is the specific physiologic effect of the
medication being studied on the target disorder (e.g., the effect of serotonin reuptake
inhibition on major depressive disorder). By extension from Figure 1, medication response
represents a combination of the specific medication effect with the previously described
sources of placebo response (expectancy-based placebo effects, effects of the therapeutic
setting, measurement factors, and natural history factors). The simplest and most common
way to understand the nature of this combination is to assume that medication effects are
additive with placebo response (i.e., placebo response is the same in the medication and
placebo groups). In other words, if the observed placebo response rate in a clinical trial is
30% and the observed medication response rate is 50%, then the specific effects of the
medication account for 50%–30%=20% response rate. If the specific effects of medication
are relatively constant between similar patient samples, differences in observed medication
response between different types of antidepressant studies (e.g. placebo-controlled,
comparator, open) would presumably be caused by differences in expectancy-based placebo
effects and other non pharmacologic factors.

MODEL OF PLACEBO RESPONSE IN ANTIDEPRESSANT 2022
16
Fig.1 Placebo Response in Anti-Depressant Table 1. Sources Of Placebo Response in
Anti-Depressant Clinical Trials Clinical Trials

DIRECTIONS 2022
17
Future Directions: Maximizing and Minimizing Placebo Response
in the Treatment of Depression
Valid evaluation of putative antidepressant agents requires that placebo response be
minimized in the drug development setting, while the best care for patients with depression
may involve maximizing placebo response in clinical treatments. Data presented in this
review suggest that the next generation of research aimed at reducing placebo response
should focus on limiting patient expectancy and the intensity of therapeutic contact in
antidepressant clinical trials (Table 2). More research is needed to elucidate how
antidepressant study design, the content and process of informed consent discussions, and
clinician attitudes affect patient expectancy and treatment outcome. Designs in which patients
have a higher probability of receiving placebo (i.e., 50%) may be preferable to designs in
which patients are randomized to multiple active treatment arms and placebo. In terms of
therapeutic contact intensity, future studies should examine whether clinical trials could be
made more efficient and generalizable to clinical practice by reducing the amount of contact
with health care staff to levels resembling those associated with treatment in the community.
However, it must be determined whether acceptable attrition rates and patient safety can be
maintained while reducing placebo response.
TABLE 2.Study Design Features Influencing Placebo Response in
Antidepressant Clinical Trials-
Increase Placebo Response Decrease Placebo Response Strength Of evidence
More Study Sites
Poor Rater Binder
Multiple active treatment
arms
Lower probability of
receiving placebo
Single baseline rating
Briefer duration of illness in
current episode
More study visits
Sample of Symptomatic
Volunteers
Optimistic/enthusiastic
clinicians
Fewer study sites
Good rater blinding with
blind assessment
Good rater blinding with
blind assessment
Higher probability of
receiving placebo
Multiple baseline ratings
Longer duration of illness in
current episode
Fewer study visits
Sample of self-referred
patients
Pessimistic/neutral clinicians
Strong
Strong
Strong
Strong
Medium
Medium
Medium
Weak
Weak

DIRECTIONS 2022
18
Neurobiology of placebo effects
There has been increasing research on the neurobiology of placebo effects (26;27). Placebo
effects presumably have multiple and different effectors depending on the specific context
and type of learned anticipation. The placebo response systems need to be different to be able
to produce analgesia through release of endogenous opioids (15), dopamine release in the
basal ganglia or reduced sub thalamic nucleus firing in Parkinson’s disease (123),
anticipatory vomiting from chemotherapy (101), objective changes in pulmonary function in
asthmatic adults , anti-tussive activity or improvements in reaction time and mood with
administration of placebo in amphetamine like stimulant drug experiments (34). Additionally,
there are likely further downstream effects. For example, placebo analgesia may be
associated with decreased b-adrenergic activity of the heart as measured by decreased heart
rate and low frequency heart rate variability (69).
Different patterns of neural activation during anticipation and during the placebo response
have been demonstrated (80;102) and there are likely different processes during the time
period of acquisition of expectancy compared with the period when a beneficial clinical
response occurs. The currently best understood placebo effect is in analgesic responses. The
placebo analgesia research relies heavily on modulation of sensory processing often assessed
by subjective perception on acute experimental pain models in healthy subjects, but this
research still sheds light on the underlying mechanisms of clinically relevant placebo effects.
There are many brain systems that contribute to the placebo effect. The dopamine system has
several elements relevant for placebo effect (43); (60). Dopamine is critical in associating an
environmental stimulus to the anticipation of a reward (79) as well as being released during
behavior to obtain a reward (70). Dopamine release in the striatum was enhanced with a
placebo dopaminergic agent in a group of Parkinson’s patients as determined by raclopride
PET scanning (37). It is uncertain if this effect was specific to the dopaminergic deficit in
neostriatal motor pathways in Parkinson’s disease or if it was a more general expectancy
related to dopamine changes in the nucleus accumbens or other nearby modulatory regions
that are less specifically associated with Parkinson’s disease. In a small study of placebo
analgesia, there was a correlation between striatal dopamine receptor binding potential and
pain thresholds but not with placebo induced elevations of pain thresholds (65).
Dopamine release in the nucleus accumbens as demonstrated with raclopride PET scanning
was found to be directly correlated with degree of placebo analgesia (83). It has been
theorized that dopamine signaling as a marker for discrepancy between predicted and actual
reward may be the critical aspect for its role in the placebo effect (61). Dopamine release in
the anterior cingulate cortex (ACC) associated with expectancy of reward in a monetary
gaming task has been associated with dopamine release in the same region with placebo
analgesia (85). The temporal course of this signaling is discounted for longer periods to the
expected reward, highlighting the potential differences between a clinical intervention given
as a single dose or over a longer time period. Additionally, the anterior cingulate, an area rich
in dopamine receptors as well as opioid receptors has been activated by placebo analgesia
(see subsequently). The endogenous opioid system is critically important for placebo
analgesia and likely plays a role for other placebo effects. The role of opioids has been
demonstrated by the ability of naloxone, an opioid receptor blocker, to antagonize placebo
analgesia (65;15).Additionally, the opioid- mediated analgesic placebo response is enhanced

DIRECTIONS 2022
19
with proglimide a cholecystokinin antagonist that modulates opioid activity, even though
proglumide has no analgesic effect on its own (23). The involvement of the opioid system has
been documented by neuroimaging with PET visualizing activation of mu-opiod receptor
mediated neurotransmission with placebo analgesia (109;110). The key role of the opioid
system in pain signaling is highlighted by overlap between brain areas activated by pain and
by placebo analgesia (e.g. ACC) and by correlations between cortical activation areas and
subcortical regions, such as periaqueductal grey, which are more clearly related to pain (71;
118). The endogenous opioid system may be relevant for many other neural functions than
signaling related to pain (78), and has already been postulated to have a more general role in
placebo effects (122). Another projection system that may relate to the placebo effect is the
serotonin system through its relationship with mood and stress (119). One trial found that
changes in brain glucose metabolism using PET were in similar brain regions of patients
responding to placebo and to fluoxetine during treatment of depression, including increases in
prefrontal, anterior cingulate and other cortical and sub cortical regions (121).
Unfortunately, the placebo arm contained some counseling or other active intervention. This
highlights the difficulty of evaluating placebo effects in depression because of the reliance on
data from placebo arms of clinical trials that do not have an adequate control group for
studying placebo effects. Neuroimaging techniques have implicated specific brain regions in
placebo effect. The ACC is an important anatomical component of the dopaminergic as well
as opioid system and has been activated during placebo analgesia (71; 114; 115,116; 30; 117;
112), placebo anxiety relief , mood improvement in the placebo arm of an antidepressant trial
and improvements in mood associated with administration of placebo. Using an analysis
technique to evaluated are correlated with activation in periaqueductal grey (70;30). The two-
way communication between the brain and the immune system (14), contributes to aspects of
the placebo response, both in its potential relationship to conditioning and in relationships
mediated by stress and HPA axis activity (13).
A beneficial immunosuppressive effect was obtained with placebo through conditioning of
administration of cyclophosphamide with saccharine in a murine systemic erythematosus
model (14). Even a commonly used clinical immune marker, the tuberculin reaction, can be
significantly diminished through conditioning (88).A small study suggested that conditioning
can play a role in the treatment of neurological illness in humans. Pairing cyclophosphamide
treatment for multiple sclerosis with a gustatory stimulus (anise-flavoured syrup) on five
occasions resulted in the lowering of peripheral leucocyte counts in 8 of 10 subjects simply
with administration of the anise-flavoured syrup (113).

DIRECTIONS 2022
20
CURRENT EXPERIMENTAL METHODOLOGIES FOR PLACEBO
RESEARCH
Studying placebo effects requires a control for the placebo condition. These studies require
some deception, ranging from simply not informing subjects of the intention of the study to
overt deception about the drug they are receiving. There are ethical guidelines guiding
deception in a research study. These guidelines include the study should be minimal risk,
there is no other way to answer the scientific question and there is a debriefing at the end of
the study where subjects are told about the deception and they have the right to withhold their
data (National Bioethics Advisory Commission, 2001; American Psychological Association,
2002). Research on acute placebo analgesia often uses a control condition where nothing is
administered although other controls have been used.
Much has been learned with this experimental paradigm although the application of
knowledge learned from acute experimental pain in healthy subjects to the clinical condition
is not straightforward . There are limited numbers of studies where anticipation of analgesia
is developed by pill-taking over weeks (114). Another paradigm for studying placebo effects
uses hidden versus open administration of active agents (26) in postoperative patients with
pain as well as in Parkinson’s disease and in anxiety. While this is clearly relevant to the
clinical situation, it is important to note that longer term administration of placebos in
conventional clinical trials may produce less of an effect than that observed in many of the
experimental placebo studies simply evaluating the immediate placebo effect (57). It has been
observed that a clinical response from a placebo may be less sustainable than a response from
an active agent (39;76), and the sustainability of the placebo response remains to be explored.

STRESS RESPONSE AND PLACEBO EFFECTS 2022
21
STRESS RESPONSE AND PLACEBO EFFECTS
A clinical intervention may provide cognitive benefits due to stress reduction, decreased
anxiety or improvement of mood. Mesolimbic and mesocortical modulations of the stress
may be one mechanism of the clinically beneficial expectancy effect (43). Level of anxiety
correlated with placebo analgesia effect and this relationship was independent of the opioid
system . Reduction in negative emotions may be a critical component of placebo analgesia
and perceived stress may impact placebo responsiveness to cognitive enhancement (68).
Cortisol has also been altered by experimental manipulation of expectancy in placebo
analgesia studies (28). A formal meta-analysis suggested that non-suppression of cortisol on a
dexamethasone suppression test predicted poorer response to placebo (79). Many aspects of
psychoneuroimmunology (14) may also contribute to aspects of the placebo response, both in
its potential relationship to conditioning and in relationships mediated by stress that are
affected by many facets of medical provider–patient interactions.

PLACEBO IN CLINICAL TRIALS 2022
22
PLACEBO IN CLINICAL TRIALS
The placebo, a pharmaceutically inert substance (typically a sugar pill), is the clinical
researcher's analogue to the scientist's control experiment. To prove a new treatment effective
above and beyond the psychological results of a simple belief in the ability of the drug to
cure, a researcher compares the results of the experimental treatment for an illness with those
obtained from the placebo. The placebo-controlled trial “is widely regarded as the gold
standard for testing the efficacy of new treatments.(17)
Interest in placebo effects began only with the widespread adoption of the placebo-controlled
clinical trials after World War II. The randomized clinical trial was a major methodological
breakthrough in medicine and the best evidence for new treatment came from randomized
placebo-controlled (RCT) double-blind studies. It was noticed that patients improved,
sometimes dramatically, in placebo control arms. Henry Beecher popularized this observation
in his famous proto-meta-analysis which claimed that about 35% of the patients responded
positively to placebo treatment.
In randomized clinical trials, for conditions having no effective treatment, the control
regimen with which the new treatment is compared, is warranted to establish the evidence.
However, when an effective treatment already exists, it is unethical to create a placebo group
that will receive no treatment. In other words, patients are deprived from an already existing
effective therapy. The objective of testing such drugs to establish whether the new drug is
better in efficacy or safety when compared to the existing drug/s placebo controlled trial
considered unethical.
The association of placebo effects with RCTs has caused confusion because the response in
the placebo arm is not necessarily a genuine psychosocial response to the simulation of
treatment. In fact, the observed response to placebo in RCTs may reflect the natural course of
the disease, fluctuations in symptoms, regression to the mean, response bias with respect to
the patient's reporting of subjective symptoms and other concurrent treatments.

PLACEBO IN CLINICAL TRIALS 2022
23
THE PLACEBOS RESPONSE IN CLINICAL TRIALS

PLACEBO STUDIES IN CLINICAL CONDITIONS PLAIN 2022
24
PLACEBO STUDIES IN CLINICAL CONDITIONS
PAIN
The pain system is the best-studied model of placebo effect . Following removal of impacted
third mandibular molars, the reduction in pain perception from an inert substance experienced
by placebo responder subjects could be attenuated with administration of naloxone while
others without a placebo response had no change in pain when administered naloxone
(65;52). The latency of the improvement in pain ratings following intravenous administration
of inert drug was 45 min. The response to placebo was greater in subjects who had higher
initial pain ratings (66). While naloxone may reverse placebo analgesia, there is another
component of the placebo analgesic effect that is not blocked with naloxone (Gracely et al.,
1983). From more recent research it appears that only some of the placebo analgesic effect is
mediated via opioid pathways (23; 24).
In an ischaemic arm pain model in healthy humans, subjects were given either an opiate
(morphine) or NSAID (ketorolac). Analgesia observed on the following day when subjects
were given saline but told it was an active drug is presumably related to placebo effect. This
improvement, postulated to be partially related to conditioning, can be blocked completely
with naloxone following morphine days but not following ketorolac (15). In another study
using the same experimental pain model, subjects were given either open or hidden injections
of analgesic. Subjects had greater pain tolerance following open injection compared with
hidden injections of analgesics and the greater pain tolerance in the open condition was
associated with a significantly greater variability (16).
Administration of naloxone following open administration of ketorolac decreased the
analgesic response to be the same as that following hidden administration, suggesting that the
improvement in analgesic response in the open condition compared with the hidden condition
was mediated through opioid pathways. The authors reached similar conclusions in patients
post thoracotomy who could not be given naloxone . The variability being greater in the open
condition is important: the measure being evaluated, total analgesic dose required by the
patients, was significantly lower in the open than hidden condition but still had a greater
variance. In some sense, responsiveness to placebo varied more across subjects than truly
blinded (i.e. not knowing whether any medication was administered) response to analgesics.
In addition to opioids, cholecystokinin has been related to placebo analgesic effect (24).
Proglumide, a cholecystokinin antagonist, has been shown to increase the placebo effect in
an experimental pain condition (23). Of some interest, this effect was only seen in placebo
responders and placebo non responders had no change in pain with proglumide. As
mentioned earlier, PET and fMRI studies in healthy subjects during experimental pain have
demonstrated that areas of activation by opioid and placebo analgesia were similar.

PARKINSON’S DISEASE 2022
25
PARKINSON’S DISEASE
Using a conservative definition of what would constitute a clinically relevant, objective
placebo response in a clinical trial, researchers observed that one-sixth of subjects improved
on placebo treatment .(35) There was not a no-treatment control group in these studies. Also,
the objective improvement on the Unified Parkinson’s Disease Rating Scale was not related
to improvements in subjective changes raising the question of examiner biases. In a
systematic review of the placebo effect in Parkinson’s disease, responsiveness to placebo did
not relate to age, gender, religion, level of education or duration of Parkinson’s disease
(90;49). Patients with Parkinson’s disease had PET scans using raclopride PET scanning
without administration of any drugs and following blinded administration of placebo or Apo
morphine. Subjects receiving placebo demonstrated significant decrease in raclopride binding
in the neostriatum consistent with endogenous dopamine release. The raclopride binding
changes reflecting dopamine release in the caudate and putamen were 20%(40). Motor testing
was not performed at the same time since changes in motor performance would directly alter
the PET scanning, so it is unclear how the PET results directly relate to motor improvements.
Expectancy effects related to surgery in Parkinson’s disease have produced effects
comparable with the surgery itself. Subjects believing they received real surgery had better
outcomes than those believing it was sham surgery, whether or not they actually received the
real or sham surgery (72). In a small number of Parkinson’s disease patients who had sub
thalamic stimulators in place, there was better motor performance when subjects believed the
stimulator was functioning compared with being told the stimulator was being turned down
(65) and there appeared to be increased sub thalamic firing rates related to the placebo effect
(26).

MULTIPLES SCLEROSIS 2022
26
MULTIPLE SCLEROSIS
Some intervention studies have had more than one assessment prior to beginning active
treatment so the placebo effect can be partially evaluated by comparing the placebo treatment
data to the baseline period data. The placebo control group in one interferon b-1a study had a
20% decrease in MRI lesion number compared with the baseline period (OWIMS, 1999). In
another interferon b-1a trial with just a single baseline assessment there was also a placebo-
group improvement in MRI, as assessed by the number of gadolinium-enhanced lesions (62).
However, given the unpredictable course of the disease, it is difficult to clearly differentiate
placebo effect from natural history in the published multiple sclerosis trials.

EPILEPSY 2022
27
EPILEPSY
Significant improvements in frequency of seizures, usually defined as a 450% reduction, are
not uncommon in placebo arms of anticonvulsant trials (29;64). However, as with multiple
sclerosis, the disease course is relatively unpredictable and no trials have directly evaluated
the placebo effect with a natural history control. Most current anticonvulsant trials are addon
or comparison trials so further data on placebo effect may be limited. Patients with non-
epileptic seizures of psychogenic origin, may have their typical spells induced by placebo
(saline injection, tilt table manoeuvre or simple suggestion) but a high false positive rate
should preclude its routine clinical use (22).

28
CONCLUSION
There are factors related to a clinical interaction that may produce improvement in patient
outcomes without directly affecting the underlying pathophysiology of a disease. 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.

REFERENCES 2022
29
REFERENCES
1. Göka, E. “Plasebo Kavramı ve Plasebo Etkisi (The Placebo Concept and Placebo
Effect)”. Türk Psikiyatri Dergisi, 13(1): 58-64 (2002).
2. Shepherd M. “The Placebo: from specificity to the non-specific and back”.
Psychological Medicine, 23: 569-578 (1993).
3. Büken NÖ. Büken E. “Plasebo ve Plasebo Etkisi (Placebo and the Placebo Effect)”,
Sendrom, 16(3): 98-103 (2004).
4. Phıl C. “Biyokimyasal Bir Blöf : Plasebo (A Biochemical Bluff: Placebo)”. Çev.:
Kurtuluş Ö. Bilim ve Teknik, 341; 54-55 (1996).
5. Laporte JR, Figuras A. “Placebo effects in psychiatry”, Lancet, 344(29): 1206-1208
(1994).
6. Brown WA “Placebo as a treatment of depression”. Neuropsychopharmacology,
10(4):265-269 (1994).
7. Kayaalp, O. Klinik Farmakolojinin Esasları (Principles of Clinical Pharmacology),
Ankara, 1996.
8. Büken NÖ, Denek ve Hasta Hakları Açısından Klinik İlaç Araştırmaları (Clinical
Drug Trials from the Aspect of Subjects and Patient Rights), A.Ü. Sağlık Bilimleri
Enstitüsü Yayınlanmamış Doktora Tezi, Ankara, 2000.
9. Vastag B, Helsinki anlaşmazlığı? Tartışmalı bir bildirge (Helsinki misunderstanding?
A declaration for discussion), JAMA, 14(8): 395-397 (2001).
10. Dünya Tabipler Birliği Helsinki Bildirgesi (İnsan Deneklerle İlgili Tıbbi
Araştırmalarda Ahlaki İlkeler) /World Medical Association Declaration of Helsinki
(Ethical Principles for Medical Research Involving Human Subjects), JAMA, 14(8):
398-400 (2001).
11. Büken NÖ., Büken E. The Rights Experimental of Subjects and Patients in Clinical
Drug Research. FABAD Journal of Pharmaceutical Sciences, 27: 173-185 (2002).
12. Ader R. The placebo effect: if it’s all your head, does that mean you only think you
feel better? Adv Mind Body Med 2000; 16: 7–11.
13. Ader R. Conditioned immunomodulation: research needs and directions. Brain Behav
Immun 2002; 17: S51–7. Ader R, Cohen N. Behaviorally conditioned
immunosuppression and murine systemic lupus erythematosus. Science 1982; 215:
1534–6.
14. Ader R, Felten DL, Cohen N, editors. Psychoneuroimmunology. San Diego:
Academic Press; 2001.
15. Amanzio M, Benedetti F. Neuropharmacological dissection of placebo analgesia:
expectation-activated opioid systems versus conditioningactivated specific
subsystems. J Neurosci 1999; 19: 484–94.
16. Amanzio M, Pollo A, Maggi G, Benedetti F. Response variability to analgesics: a role
for non-specific activation of endogenous opioids. Pain 2001; 90: 205–15.
17. American Psychological Association. Ethical principles of psychologists and code of
conduct. Am Psychol 2002; 57: 1060–73.
18. Anda R, Williamson D, Jones D, Moacera C, Eaker E, Glassman A, et al. Depressed
affect, hopelessness, and the risk of ischemic heart disease in a cohort of U.S. adults.
Epidemiology 1993; 4: 285–94.

REFERENCES 2022
30
19. Bandura A. Self-efficacy: the exercise of control. New York: W. H. Freeman and
Company; 1997.
20. Barsky AJ, Saintfort R, Rogers MP, Borus JF. Nonspecific medication side effects
and the nocebo phenomenon. JAMA 2002; 287: 622.
21. Bausell RB, Lao L, Bergman S, Lee WL, Berman BM. Is acupuncture analgesia an
expectancy effect? Preliminary evidence based on participants’ perceived assignments
in two placebo-controlled trials. Eval Health Prof 2005; 28: 9–26.
22. Bazil CW, Kothari M, Luciano D, Moroney J, Song S, Vasquez B, et al. Provocation
of non-epileptic seizures by suggestion in a general seizure population. Epilepsia
1994; 35: 768–70.
23. Benedetti F. The opposite effects of the opiate antagonist naloxone and the
cholecystokinin antagonist proglumide on placebo analgesia. Pain 1996; 64: 535–43.
24. Benedetti F, Amanzio M, Casadio C, Oliaro A, Maggi G. Blockade of nocebo
hyperalgesia by the cholecystokinin antagonist proglumide. Pain 1997; 71: 135–40.
25. Benedetti F, Arduino C, Costa S, Vighetti S, Tarenzi L, Rainero I, et al. Loss of
expectation-related mechanisms in Alzheimer’s disease makes analgesic therapies less
effective. Pain 2006; 121: 133–44.
26. Benedetti F, Colloco L, Torre E, Lanotte M, Melcarne A, Pesare M, et al. Placebo-
responsive Parkinson patients show decreased activity in single neurons of
subthalamic nucleus. Nat Neurosci 2004; 7: 587–8.
27. Benedetti F, Mayberg HS, Wager TD, Stohler CS, Zubieta J-K. Neurobiological
mechanisms of the placebo effect. J Neurosci 2005; 25: 10390–402.
28. Benedetti F, Pollo A, Lopiano L, Lanotte M, Vighetti S, Rainero I. Conscious
expectation and unconscious conditioning in analgesic, motor, and hormonal
placebo/nocebo responses. J Neurosci 2003; 23: 4315–23.
29. Bergmann J-F, Chassany O, Gandiol J, Deblois P, Kanis JA, Segrestaa J-M, et al. A
randomised clinical trial of the effect of informed consent on the analgesic activity of
placebo and naproxen in cancer pain. Clin Trials Metaanal 1994; 29: 41–7.
30. Bingel U, Lorenz J, Schoell E, Weiller C, Buchel C. Mechanisms of placebo
analgesia: rACC recruitment of a subcortical antinocideptive network. Pain 2006;
120: 8–15.
31. Bok S. Ethical issues in use of placebo in medical practice and clinical trials. In:
Guess HA, Kleinman A, Kusek JW, Engel LW, editors. The science of the placebo.
London: Br Med J Books; 2002. p. 53–74.
32. Bouchet C, Guillemin F, Briancon S. Nonspecific effects in longitudinal studies:
impact on quality of life measures. J Clin Epidemiol 1996; 49: 15–20.
33. Branthwaite A, Cooper P. Analgesic effects of branding in treatment of headaches. Br
Med J 1981; 282: 1576–8. Brody HM. The placebo response. J Fam Pract 2000; 49:
649–54.
34. Buckalew L. An analysis of experimental components in a placebo effect. Psychol
Rec 1972; 22:113–9.
35. Stoessl AJ. Expectation and dopamine release: mechanism of the placebo effect in
Parkinson’s disease. Science 2001; 293: 1164–6.
36. Di Blasi Z, Harkness E, Ernst E, Georgiou A, Kleijnen J. Influence of context effects
on health outcomes: a systematic review. Lancet 2001; 357: 757
37. Di Blasi Z, Harkness E, Ernst E, Georgiou A, Kleijnen J. Influence of
context effects on health outcomes: a systematic review. Lancet 2001;
357: 757–62.
38. Evans FJ. Expectancy, therapeutic instructions, and the placebo response. In: White L,

REFERENCES 2022
31
Tursky B, Schwartz GE, editors. Placebo: theory, research, and meachnisms. New
York: The Guilford Press; 1985. p. 215–28.
39. Fedele L, Marchini M, Acaia B, Garagiola U, Tiengo M. Dynamics and significance
of placebo response in primary dysmenorrhea. Pain 1989; 36: 43–7.
40. Flegal KE, Kishiyama S, Zajdel D, Haas M, Oken BS. Adherence to yoga and
exercise interventions in a 6-month clinical trial. BMC Complement Altern Med
2007; 7: 37.
41. Freed CR, Greene PE, Breeze RE, Tsai W-Y, DuMouchel W, Kao R, et al.
Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N
Engl J Med 2001; 344: 710–9.
42. Freeman TB, Vawter DE, Leaverton PE, Godbold JH, Hauser RA, Goetz CG, et al.
Use of placebo surgery in controlled trials of a cellular-based therapy for Parkinson’s
disease. N Engl J Med 1999; 341: 988–92.
43. Freund J, Krupp G, Goodenough D, Preston LW. The doctor-patient relationship and
drug effect. Clin Pharmacol Ther 1972; 13: 172–80.
44. Fricchione G, Stefano GB. Placebo neural systems: nitric oxide, morphine and the
dopamine brain reward and motivation circuitries. Med Sci Monit 2005; 11: MS54–
65.
45. Geers AL, Helfer SG, Kosbab K, Weiland PE, Landry SJ. Reconsidering the role of
personality in placebo effects: dispositional optimism, situational expectations, and
the placebo response. J Psychosom Res 2005; 58: 121–7.
46. Geers AL, Koshab K, Helfer SG, Weiland PE, Wellman JA. Further evidence for
individual differences in placebo responding: an interactionist perspective. J
Psychosom Res 2007; 62: 563–70.
47. iang DW, Goodman AD, Schiffer RB, Mattson DH, Petrie M, Cohen N, et al.
Conditioning of cyclophosphamide-induced leukopenia in humans. J Neuropsychiatry
1996; 8: 194–201.
48. Goetz CG, Leurgan S, Raman R, Group PS. Placebo-associated improvements in
motor function: comparison of subjective and objective sections of the UPDRS in
early Parkinson’s disease. Mov Disord 2002; 17: 283–8.
49. Goetz CG, Leurgan S, Raman R, Stebbins G. Objective changes in motor function
during placebo treatment in PD. Neurology 2000; 54: 710–9.
50. Gracely RH, Dubner R, Wolskee PJ, Deeter WR. Placebo and naloxone can alter
postsurgical pain by separate mechanisms. Nature 1983; 306: 264–5.
51. Gracely RH, Dubner R, Deeter WR, Wolskee PJ. Clinicians’ expectation influence
placebo analgesia. Lancet 1985; 1: 43.
52. Gryll SL, Karahn M. Situational factors contributing to the placebo effect.
Psychophamacology 1978; 57: 253–61.
53. Guess HA, Kleinman A, Kusek JW, Engel LW, editors. The science of placebo.
London: BMJ Books; 2002. Hahn RA. The nocebo phemomenon: concept, evidence,
and implications for public health. Prev Med 1997; 26: 607–11.
54. Hashish I, Hai HK, Harvey W, Feinmann C, Harris M. Reduction of postoperative
pain and swelling by ultrasound treatment: a placebo effect. Pain 1988; 33: 303–11.
55. Holroyd KA, Penzien DB, Hursey KG, Tobin DL, Rogers L, Holm JE, et al. Change
mechanisms in EMG biofeedback training: cognitive changes underlying
improvements in tension headache. J Consult Clin Psychol 1984; 52: 1039–53.
56. Horng S, Miller FG. Is placebo surgery unethical. N Engl J Med 2002; 347: 137–9.
57. Horwitz RI, Viscoli CM, Berkman L, Donaldson RM, Horwitz S, Murray CJ, et al.
Treatment adherence and risk of death after a myocardial infarction. Lancet 1990;

REFERENCES 2022
32
336: 542–5.
58. Hrobjartsson A, Gotzsche PC. Is the placebo powerless? An analysis of clinical trials
comparing placebo with no treatment. N Engl J Med 2001; 344: 1594–620.
59. Hyland ME, Whalley B, Geraghty AWA. Dispositional predictors of placebo
responding: a motivational interpretation of flower essence and gratitude therapy. J
Psychosom Res 2007; 62: 331–40.
60. Ilnyckyj A, Shanahan F, Anton PA, Cheang M, Bernstein CN. Quantification of the
placebo response in ulcerative colitis. Gastroenterology 1997; 112: 1854–8.
61. Irizarry KJL, Licinio J. An explanation for the placebo effect? Science 2005; 307:
1411–2.
62. Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM, et al.
Intramuscular interferon beta-1a for disease progression in relapsing multiple
sclerosis. Ann Neurol 1996; 39: 285–94.
63. Johansen O, Brox J, Flaten MA. Placebo and nocebo responses, cortisol, and
circulating beta-endorphin. Psychosom Med 2003; 65: 786–90.
64. Jones MW, Blume WT, Guberman A, Lee MA, Pillay N, Weaver DE, et al.
Remacemide hydrochloride as an add-on therapy in epilepsy: a randomized, placebo-
controlled trial of three dose levels (300, 600 and 800 mg/day) in a B.I.D. regimen.
Seizure 2002; 11: 104–13.
65. Levine JD, Gordon NC, Fields HL. The mechanism of placebo analgesia.
Lancet 1978; 2: 654–7.
66. Martikainen IK, Hagelberg N, Mansikka H, Hietala J, Nagren K,
Scheinin H. Association of striatal dopamine D2/D3 receptor binding
potential with pain but not tactile sensitivity or placebo analgesia.
Neurosci Lett 2005; 376: 149–53
67. Pollo A, Amanzio M, Arslanian A, Casadio C, Maggi G, Benedetti F. Response
expectancies in placebo analgesia and their clinical relevance. Pain 2001; 93: 77–84.
68. Pollo A, Torre E, Lopiano L, Rizzone M, Lanotte M, Cavanna A, et al. Expectation
modulates the response to subthalamic nucleus stimulation in Parkinsonian patients.
Neuroreport 2002; 13: 1383–6.
69. Pollo A, Vighetti S, Rainero I, Benedetti F. Placebo analgesia and the heart. Pain
2003; 102: 125–33.
70. Petrovic P, Dietrich T, Fransson P, Andersson J, Carlsson K, Ingvar M.
Placebo in emotional processing—induced expectations of anxiety relief
activate a generalized modulatory network. Neuron 2005; 46: 957.
71. Petrovic P, Kalso E, Petersson KM, Ingvar M. Placebo and opioid
analgesia - imaging a shared neuronal network. Science 2002; 295:
1737–40.
72. Porter DR, Capell HA. The ‘Natural’ history of active rheumatoid arthritis over 3-6
Months — an analysis of patients enrolled into trials of potential disease-modifying
anti-rheumatic drugs, and treated with placebo. Br J Rheumatol 1993; 32: 463–6.
73. Price DD, Finniss DG, Benedetti F. A comprehensive review of the placebo effect:
recent advances and current thought. Ann Rev Psychol 2008; 59 2: 1–226.
74. Phillips PEM, Stuber GD, Helen MAV, Wightman RM, Carelli RM.
Subsecond dopamine release promotes cocaine seeking. Nature 2003;
75. Price DD, Milling LS, Kirsch I, Duff A, Montgomery GH, Nicholls SS. An analysis
of factors that contribute to the magnitude of placebo analgesia in an experimental
paradigm. Pain 1999; 83: 147–56.

REFERENCES 2022
33
76. Quitkin FM, McGrath PJ, Rabkin JG, Stewart JW, Harrison W, Ross DC, et al.
Different types of placebo response in patients receiving antidepressants. Am J
Psychiatry 1991; 148: 197–203.
77. Raz A. Hypnobo: perspectives on hypnosis and placebo. Am J Clin Hypn 2007; 50:
29–36.
78. Ribeiro SC, Kennedy SE, Smith YR, Stohler CS, Zubieta J-K. Interface of physical
and emotional stress regulation through the endogenous opioid system and [mu]-
opioid receptors. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29: 1264–80.
79. Ribeiro SCM, Tandon R, Grunhaus L, Greden JF. The DST as a predictor of outcome
in depression: a meta-analysis. Am J Psychiatry 1993; 150: 1618–29.
80. Rochon PA, Binns MA, Litner JA, Litner GM, Fischbach MS, Eisenberg D, et al. Are
randomized control trial outcomes influenced by the inclusion of a placebo group? a
systematic review of nonsteroidal antiinflammatory drug trials for arthritis treatment.
J Clin Epidemiol 1999; 52: 113–22.
81. Rogers SL, Friedhoff LT, Group at DS. The efficacy and safety of donepezil in
patients with Alzheimer’s disease: results of a US multicenter, randomized, double-
blind, placebo-controlled trial. Dementia 1996; 7: 293–303.
82. Rohsenow DJ, Marlatt GA. The balanced placebo design: methodological
considerations. Addict Behav 1981; 6: 107–22.
83. Ross S, Krugman AD, Lyerly SB, Clyde DJ. Drugs and placebos: a model design.
Psychol Rep 1962; 10: 383–92.
84. Schapira K, McClelland HA, Griffiths NR, Newell DJ. Study on the effects of tablet
colour in the treatment of anxiety states. Br Med J 1970; 1: 446–9.
85. Schultz W. Behavioral theories and the neurophysiology of reward. Ann Rev Psychol
2006; 57: 87–115.
86. Scott DJ, Stohler CS, Egnatuk CM, Want H, Koeppe RA, Zubieta JK.
Individual differences in reward responding explain placebo-induced
expectations and effects. Neuron 2007; 55: 325–36.
87. Schwedt TJ, Hentz JG, Dodick DW. Factors associated with the prophylactic effect of
placebo injections in subjects enrolled in a study of botulinum toxin for migraine.
Cephalalgia 2007; 27: 528–34.
88. Scott DJ, Stohler CS, Egnatuk CM, Want H, Koeppe RA, Zubieta JK. Individual
differences in reward responding explain placebo-induced expectations and effects.
Neuron 2007; 55: 325–36.
89. Shapiro DA. Comparative crediblity of treatment rationales: three tests of expectancy
theory. Br J Clin Psychol 1981; 20: 111–22.
90. Shetty N, Friedman JH, Kieburtz K, Marshall FJ, Oakes D. The placebo response in
Parkinson’s disease. Clin Neuropharmacol 1999; 22: 207–12.
91. Siegel S. Explanatory mechanisms for placebo effects: Pavlovian conditioning. In:
Guess HA, Kleinman A, Kusek JW, Engel LW, editors. The science of the placebo.
London: BMJ Books; 2002.
92. Sievenpiper JL, Eztagha A, Dascalu A, Vuksan V. When a placebo is not a
‘placebo’L a placebo effect on postprandial glycaemia. Br J Clin Pharmacol 2007; 64:
546–9.
93. Simpson SH, Eurich DT, Majumdar SR, Padwal RS, Tsuyuki RT, Varney J, et al. A
meta-analysis of the association between adherence to drug therapy and mortality. Br
Med J 2006; 333: 15–20.
94. Skovlund E. Should we tell trial patients that they might receive placebo? Lancet
1991; 337: 1041.

REFERENCES 2022
34
95. Thompson JJ, Ritenbaugh C, and Nichter M., Reconsidering the Placebo Response
from a Broad Anthropological Perspective. Cult Med Psychiatry. 2009;33: 112–152
Benedetti F. Placebo Effects. Understanding the mechanisms in health and disease.
Oxford University Press., New York, N.Y. (2009).
96. Hróbjartsson A.and Gøtzsche Is the Placebo Powerless? — An Analysis of Clinical
Trials Comparing Placebo with No Treatment PC N Engl J Med 2001; 344:1594-
1602.
97. De Pascalis V., Chiaradia C and Carotenuto E. The contribution of suggestibility and
expection to placebo analgesia phenomenon in an experimental setting. Pain. 2002;
96; 393-402.
98. Lasagna L. Decision processes in establishing the effi cacy and safety of psychotropic
agents. In: Prien RF, Robinson DS, editors. Clinical evaluation of psychotropic drugs:
principles and guidelines. New York (NY): Raven Press; 1994. p 13–28.
99. Waber RL. Shiv B, Carmon Z, and Ariely D. Commercial features of placebo and
therapeutic efficacy. JAMA 2008;299:1016-7.
100. Haake M, Muller HH, Schade-Brittinger C, et al. German Acupuncture Trials
(GERAC) for chronic low back pain: randomized, multicenter, blinded, parallel-group
trial with 3 groups. Arch Intern Med. 2007;167:1892–1898
101. Finniss DG, Kaptchuk, and Benedetti, F. Placebo effects: Biological, Clinical
and Ethical Advances. Lancet. 2010:375:686-695.
102. Kaptchuk TJ. The placebo effect in alternative medicine: Can the
performance of a healing ritual have clinical significance? Annals of Internal
Medicine. 2002;136:817–825
103. Kaptchuk TJ, Kelley JM, Tversky A and Kahneman D. Judgment under
Uncertainty: Heuristics and Biases Science, New Series, Vol. 185 (1974), pp. 1124-
1131.
104. Kleinman A, Guess HA and Wilendtz IS. The Science of the Placebo Effect:
Toward an Interdisciplinary Research Agenda. (2002) BMJ Books, London. pp. 1-32.
105. Dimond EG, Kittle CF, and Crockett JE., Comparison of internal mammary
artery ligation and sham operation for angina pectoris, Am. Journal of Cardiology,
5;1960: p. 483-486.
106. Glassman A, O’Connor C, Califf R, et al. Sertraline treatment of major
depression in patients with acute MI or unstable angina. J.A.M.A.288;701. 2002.
107. Epidemic hysteria: A review of the published literature. Epidemiol. Rev.
1997;19:233-243.
108. Schou M. Lithium. In: Healy D, editor. The psychopharmacologists. Vol 2.
London (GB): Chapman and Hall; 1998. p 259–284.
109. Challis GB, Stam HJ. A longitudinal study of the development of antici-
patory nausea and vomiting in cancer chemotherapy patients: the role of
absorption and autonomic perception. Health Psychol 1992; 11: 181–9.
110. Wager TD, Scott DJ, Zubieta JK. Placebo effects on human m—opioid
activity during pain. PNAS 2007; 104: 11056–61.
Walach H.
111. Zubieta J-K, Bueller JA, Jackson LR, Scott DJ, Xu Y, Koeppe RA, et al.
Placebo effects mediated by endogenous opioid activity on mu opioid
receptors. J Neurosci 2005; 25: 7754–62.

REFERENCES 2022
35
112. Wager TD, Scott DJ, Zubieta JK. Placebo effects on human m—opioid
activity during pain. PNAS 2007; 104: 11056–61
113. Giang DW, Goodman AD, Schiffer RB, Mattson DH, Petrie M, Cohen N,
et al. Conditioning of cyclophosphamide-induced leukopenia in
humans. J Neuropsychiatry 1996; 8: 194–201
114. Lieberman MD, Jarcho JM, Berman S, Naliboff BD, Suyenobu BY,
Mandelkern M, et al. The neural correlates of placebo effects: a
disruption account. Neuroimage 2004; 22: 447–55.
115. Koyama T, McHaffie JG, Laurienti PJ, Coghill RC. The subjective
experience of pain: Where expectations become reality. Proc Natl
Acad Sci 2005; 102: 12950–5
116. Zubieta J-K, Bueller JA, Jackson LR, Scott DJ, Xu Y, Koeppe RA, et al.
Placebo effects mediated by endogenous opioid activity on mu opioid
receptors. J Neurosci 2005; 25: 7754–62.
117. Kong J, Gollub RL, Rosman IS, Webb JM, Vangel MG, Kirsch I, et al.
Brain activity associated with expectancy-enhanced placebo analgesia as
measured by functional magnetic resonance imaging. J Neurosci 2006;
26: 381–8.
118. Pariente J, White P, Frackowiak RSJ, Lewith G. Expectancy and belief
modulate the neuronal substrates of pain treated by acupuncture.
NeuroImage 2005; 25: 1161–7.
119. Lucki I. The spectrum of behaviors influenced by serotonin. Biol Psychol
1998; 44: 151–62.
120. Mayberg HS, Silva JA, Brannan SK, Tekell JL, Mahurin RK, McGinnis S,
et al. The functional neuroanatomy of the placebo effect. Am J
Psychiatry 2002; 159: 728–37.
121. Mayberg HS, Silva JA, Brannan SK, Tekell JL, Mahurin RK, McGinnis S,
et al. The functional neuroanatomy of the placebo effect. Am J
Psychiatry 2002; 159: 728–37.
122. Stefano GB, Fricchione GL, Slingsby BT, Benson H. The placebo effect and
relaxation response: neural processes and their coupling to constitutive
nitric oxide. Brain Res Brain Res Rev 2001; 35: 1–19.
123. de la Fuente-Fernandez R, Ruth TJ, Sossi V, Schulzer M, Calne DB,
Stoessl AJ. Expectation and dopamine release: mechanism of the placebo
effect in Parkinson’s disease. Science 2001; 293: 1164–6

REFERENCES 2022
36

Placebo Effects in Clinical Trials and Conditions

Recommended

Recommended

More Related Content

Similar to Placebo Effects in Clinical Trials and Conditions

Similar to Placebo Effects in Clinical Trials and Conditions (16)

Recently uploaded

Recently uploaded (20)

Placebo Effects in Clinical Trials and Conditions