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Effects of Personal Placebo Response Information on Future Placebo Response

Permanent Link: http://ufdc.ufl.edu/UFE0015747/00001

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Title: Effects of Personal Placebo Response Information on Future Placebo Response
Physical Description: 1 online resource (49 p.)
Language: english
Creator: Chung, Soyeon Karen
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2007

Subjects

Subjects / Keywords: attitudes, conditioning, expectation, mood, pain, placebo, suggestion
Clinical and Health Psychology -- Dissertations, Academic -- UF
Genre: Psychology thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: The ethics of placebo use has been debated since discovery of the phenomena. However, there has yet to be a study that examines the aftereffect of individuals discovering that they experienced a placebo response on their future ability to experience a placebo response. Seventy-seven participants, 41 female and 36 male undergraduate students from the University of Florida were recruited via flyers and the college undergraduate subject pool and divided into three conditions: placebo informed, placebo uninformed, and repeated baseline. We used a double-placebo design with verbal placebo suggestion and conditioning to induce a placebo response and to examine the effect of providing information about a participant s personal placebo response on their future placebo response. We discovered that there was no difference in future pain responding between participants who were told that they experienced a placebo response versus those who were not. Interestingly, the placebo effect persisted when a second placebo cream was applied even after participants were told that the first cream used in the study was a placebo. In addition, this study corroborated that revelation of an individual s placebo response does not appear to cause adverse effects on mood. Similar to mood, attitudes about the likelihood of using medical and non-medical treatments for pain, likelihood of participating in future studies, likeability of experimenters and trust of experimenters remained unaffected. Examining the concepts of expectation for pain and the desire for pain relief, we found that desire was a more consistent predictor than expectation in predicting a placebo response. Furthermore, characteristics such as somatic focus may be related to a participant s ability to experience a placebo response, but we found no evidence of any differences in placebo responding between the sexes. These results suggest that placebo use in experimental settings does not have detrimental effects.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Soyeon Karen Chung.
Thesis: Thesis (Ph.D.)--University of Florida, 2007.
Local: Adviser: Robinson, Michael E.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2010-08-31

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Source Institution: UFRGP
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Classification: lcc - LD1780 2007
System ID: UFE0015747:00001

Permanent Link: http://ufdc.ufl.edu/UFE0015747/00001

Material Information

Title: Effects of Personal Placebo Response Information on Future Placebo Response
Physical Description: 1 online resource (49 p.)
Language: english
Creator: Chung, Soyeon Karen
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2007

Subjects

Subjects / Keywords: attitudes, conditioning, expectation, mood, pain, placebo, suggestion
Clinical and Health Psychology -- Dissertations, Academic -- UF
Genre: Psychology thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: The ethics of placebo use has been debated since discovery of the phenomena. However, there has yet to be a study that examines the aftereffect of individuals discovering that they experienced a placebo response on their future ability to experience a placebo response. Seventy-seven participants, 41 female and 36 male undergraduate students from the University of Florida were recruited via flyers and the college undergraduate subject pool and divided into three conditions: placebo informed, placebo uninformed, and repeated baseline. We used a double-placebo design with verbal placebo suggestion and conditioning to induce a placebo response and to examine the effect of providing information about a participant s personal placebo response on their future placebo response. We discovered that there was no difference in future pain responding between participants who were told that they experienced a placebo response versus those who were not. Interestingly, the placebo effect persisted when a second placebo cream was applied even after participants were told that the first cream used in the study was a placebo. In addition, this study corroborated that revelation of an individual s placebo response does not appear to cause adverse effects on mood. Similar to mood, attitudes about the likelihood of using medical and non-medical treatments for pain, likelihood of participating in future studies, likeability of experimenters and trust of experimenters remained unaffected. Examining the concepts of expectation for pain and the desire for pain relief, we found that desire was a more consistent predictor than expectation in predicting a placebo response. Furthermore, characteristics such as somatic focus may be related to a participant s ability to experience a placebo response, but we found no evidence of any differences in placebo responding between the sexes. These results suggest that placebo use in experimental settings does not have detrimental effects.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Soyeon Karen Chung.
Thesis: Thesis (Ph.D.)--University of Florida, 2007.
Local: Adviser: Robinson, Michael E.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2010-08-31

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2007
System ID: UFE0015747:00001


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EFFECTS OF PERSONAL PLACEBO RESPONSE INFORMATION ON FUTURE
PLACEBO RESPONSE




















By

SOYEON KAREN CHIUNG


A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE
UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE
REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY

UNIVERSITY OF FLORIDA


2007

































Copyright 2007 Soyeon Karen Chung
















ACKNOWLEDGMENTS

I want to thank my advisor, Dr. Michael E. Robinson, for his support and guidance

throughout this proj ect. Also, I want to acknowledge those associated with the Center for

Pain Research for their input and assistance.





















TABLE OF CONTENTS


page

ACKNOWLEDGMENTS .............. ...............iii....


LIST OF TABLES .............. ...............vi....


LIST OF FIGURES ................. ...............vii...............


ABSTAT............... ..................vi


CHAPTER


1 INT RODUCT ION ................. ...............1.......... ......


D ef inition............... .. .............

Discovery of the Placebo ................ ............... ........ ......... ........ ...2
It' s Not Nothing ................. ...............3.......... .....
The Placebo Effect ................. ...............4............ ....
M echanism s .............. ...............6.....
Conditioning .............. ...............7.....

Expectancy ................. ............. ...............8.......
Ethics: Experimental Setting .............. ...............8.....
Clinical Use of Placebo ................. ...............11.......... ....

Proposed Study ................. ...............13.......... ......

2 MATERIALS AND METHOD............... ...............14.


Participants .............. ...............14....
Apparatus .............. ... ........... .........1
Medoc Thermal Sensory Analyzer ................. ...............14................
Mechanical Visual Analog Scale (VAS) ................ ..............................14
Placebo Cream............... ...............15.
Measures .............. .........................1

Demographics Questionnaire .............. ...............15....
Illness Attitude Scale (IAS) ................. ...... .......... .. ...............15....
Pennebacker Inventory of Limbic Languidity (PILL)............._ ........._.._.....16
Visual Analogue Scales of Mood (VAS Mood) .............. ....................1
Procedures ........._..._... ...............17.._.._.. ......

Stage 1: Baseline .............. .... ... ...............1
Stage 2: Conditioning and Suggestion ........._..._... ........._.... ...... 18_._.....













Stage 3: First Placebo ........................... ........19
Stage 4: Second Placebo............... ...............20


3 RESULTS .............. ...............21....


Verification of the Placebo Effect ................. ........................ ..............21

Pain Ratings .............. ...............22....
Mood ................. ...............24.................
Attitudes............... ...............2

Expectation ................. ...............26.................
Desire for Pain Relief................ ...............27

Expectation and Desire Interaction ................. ...............29................
Somatization ........._.__........_. ...............29....
Sex Differences............... ..............3


4 DI SCUS SSION ........._.__....... .__. ...............3 1...


LIST OF REFERENCES .............. ...............36....


BIOGRAPHICAL SKETCH .............. ...............40....


















LIST OF TABLES

Table pg

2-1 An overview of the study design. ................ ........................ ..............17

3-1 Mood mixed-model ANOVA results. ............. ...............24.....

3-2 Attitude mixed-model ANOVA results ................. ...............25...............

















LIST OF FIGURES

Fiu~re pg

3-1 Verification of the placebo effect. ..........._.....__ ...............22.

3-2 Pain ratings at baseline, time 1 and time 2 for the placebo informed and
uniform ed groups ................. ...............23.................

3-3 Expectation for pain ratings at baseline, pre-first placebo and pre-second
placebo for the placebo informed and uninformed groups ................. ................ .27

3-4 Desire for pain relief at pre-conditioning and pre-second placebo for the placebo
informed and uninformed groups. ............. ...............28.....
















Abstract of Dissertation Presented to the Graduate School
of the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Doctor of Philosophy

EFFECTS OF PERSONAL PLACEBO RESPONSE INFORMATION ON FUTURE
PLACEBO RESPONSE

By

Soyeon Karen Chung

August 2007

Chair: Michael E. Robinson
Major: Psychology

The ethics of placebo use has been debated since discovery of the phenomena.

However, there has yet to be a study that examines the aftereffect of individuals

discovering that they experienced a placebo response on their future ability to experience

a placebo response. Seventy-seven participants, 41 female and 36 male undergraduate

students from the University of Florida were recruited via flyers and the college

undergraduate subject pool and divided into three conditions: placebo informed, placebo

uninformed, and repeated baseline. We used a double-placebo design with verbal placebo

suggestion and conditioning to induce a placebo response and to examine the effect of

providing information about a participant' s personal placebo response on their future

placebo response. We discovered that there was no difference in future pain responding

between participants who were told that they experienced a placebo response versus those

who were not. Interestingly, the placebo effect persisted when a second placebo cream

was applied even after participants were told that the first cream used in the study was a










placebo. In addition, this study corroborated that revelation of an individual's placebo

response does not appear to cause adverse effects on mood. Similar to mood, attitudes

about the likelihood of using medical and non-medical treatments for pain, likelihood of

participating in future studies, likeability of experimenters and trust of experimenters

remained unaffected. Examining the concepts of expectation for pain and the desire for

pain relief, we found that desire was a more consistent predictor than expectation in

predicting a placebo response. Furthermore, characteristics such as somatic focus may be

related to a participant's ability to experience a placebo response, but we found no

evidence of any differences in placebo responding between the sexes. These results

suggest that placebo use in experimental settings does not have detrimental effects.















CHAPTER 1
INTRODUCTION

Significant progress has been made in placebo research and this progress is most

evident in pain research. Hoffman, Harrington & Fields (2005) indicated three possible

reasons for this:

(1) clinically, the placebo-induced pain reduction is probably the best verified
instance of this general response; (2) methodologically, the most elegant
experimental work on the placebo response has used pain as its paradigm; and (3)
conceptually, we have more insight into the brain mechanisms underlying placebo
analgesia than we have for any other placebo response.

Definition

There are several terms commonly used in placebo research that are important to

define and distinguish. A placebo is an intervention designed to simulate medical therapy,

but not believed to be a specific therapy for the target condition (Turner, Deyo, Loeser,

Von Korff, & Fordyce, 1994). However, the terms placebo effect and placebo response

have been frequently used interchangeably. The placebo effect refers to any average

difference between the condition of a group of subj ects that has received a placebo

treatment, assuming that no change would have been observed in the absence of the

placebo administration (Hoffman et al., 2005). In other words, it is the mean placebo

response. In contrast, the placebo response refers to the change in an individual caused by

a placebo manipulation (Hoffman et al., 2005). This is an important distinction because

our focus is the psychology of the placebo response rather than the placebo effect. These

definitions will be used for the remainder of the paper.









Discovery of the Placebo

The discovery of the placebo has a serendipitous history. In the 19th century, a

leading European neurologist, Jean Martin Charcot became interested in a disorder called

hysteria. Symptoms of this mysterious disorder included convulsions, paralysis, tunnel

vision, color blindness, patches of anesthesia, incessant coughing, tics, and feelings of

choking. While physicians were baffled by this disorder, Charcot took an analytic

approach revealing underlying patterns with four completely predictable stages of the

disease. It was later revealed that the "universal" physiology and mechanism of this

disease was entirely local and only occurred within Charcot's studio. Charcot had been

deceived by the subjective experiences of his patients, interpreting them as objective

displays of universal significance (Harrington, 2000).

The idea that hysteria was a "made-up" entity was exposed when Hippolyte, a rival

of Charcot, showed that he could reproduce, change and extinguish all of the symptoms

of hysteria. He claimed that all of these symptoms were a kind of sham: nothing more

than effects of a physiological process called suggestion. This finding led to the

conclusion that bodily symptoms caused by suggestion are a psychological lie; that those

who respond to these types of treatments were not suffering from a real disease at all. In

the 1930s and 1940s, the perception of the placebo effect began to change with the

discovery of sulfa drugs. The placebo effect began to be perceived as noise, a serious

hindrance to medicine's progress (Harrington, 2000).

In 1955, Henry Beecher wrote a seminal article about the history of research on the

placebo effect titled, "The Powerful Placebo" (Beecher, 1955). As the title suggested, the

paper wanted to demonstrate that the placebo effect was powerful and pervasive. Beecher

claimed that approximately 1/3 of patients across a review of 15 clinical trials










experienced a placebo response. Beecher also claimed that the placebo response could

produce obj ectively measurable changes in a patient' s physiology, changes that rivaled

the effects of the active agent against which the placebo is being compared. Beecher

argued that a randomized placebo controlled trial methodology was necessary to protect

the active treatment data from the placebo effect.

Subsequently, it became clear that patient expectation or suggestibility was not the

only possible confound for researchers. Additional problems included researcher bias,

measurement error, statistical regression to the mean, and spontaneous remission. The

placebo control group simply became a catch-all for these all of these confounds.

It's Not Nothing

Since the discovery of the placebo effect, placebos have been used as the control

arm in randomized placebo control trials. Placebos were perceived as nuisances in the

quest to find the actual effect of the "active" treatment. However, what has been ignored

until recently is the fact that placebos in itself can affect significant change, sometimes in

magnitudes similar to the "active" treatment against which it is being compared.

Recent imaging studies have documented specific brain regions to be associated

with a placebo response. A study (Lieberman, Jarcho, Berman, Naliboff, Suyenobu,

Mandelkern, & Mayer, 2004) using Positron Emission tomography (PET) with patients

with Irritable Bowel Syndrome (IBS) both before and after a 3-week placebo regimen

found that increases in ventrolateral prefrontal cortex (RVLPFC) activity from pre-

placebo to post-placebo predicted self-reported symptom improvement. Another study

(Wager, Rilling, Smith, Sokolik, Casey, Davidson, Kosslyn, Rose, & Cohen, 2004)

examined placebo- inducted changes during anticipation and experience of pain using

functional magnetic resonance imaging (fMRI). The investigators found that placebo










analgesia was related to decreased brain activity in pain-sensitive brain regions including

the thalamus, insula, and anterior cingulate cortex. During anticipation of pain, placebo

analgesia was associated with increased activity in the prefrontal cortex. These studies

provide not only important insights into the neural mechanisms of placebo analgesia, but

also evidence that placebos actually alter the experience of pain.

The placebo response is an extremely complex phenomenon. For example, a

placebo analgesic effect can be localized. In a study (Benedetti, Arduino, & Amanzio,

1999), when a placebo analgesic was applied to one index finger and pain stimulation

was applied to both index fingers, the placebo response was localized to the finger on

which the placebo had been applied. Also, participants receiving placebos can experience

improvements in addition to undesirable sid e effects known as nocebos (Hahn, 1997).

Placebos appear to show a dose-response relationship of active agents, for instance, more

frequent placebo administration was related to a larger placebo response (De Craen,

Moerman, Heisterkamp, Tytgat, Tijssen, & Kleijnen, 1999). The same study found that

placebo inj sections produce stronger effects than placebo capsules and pills (De Craen et

al., 1999). These studies collectively demonstrate that placebos produce physiologic as

well as psychological changes.

The Placebo Effect

Since Beecher (1955) reported that 35.2% of Participants were placebo responders,

it has been assumed that there is a fixed- fraction of placebo responders. However, his

examination of 11 studies found large variations in the average number of placebo

responders. This idea of placebo-responders were assumed based on a comparison of

group differences; however, the same differences could be a result of two scenarios: (1)

all individuals in the placebo group exhibiting a moderate response or, (2) a relatively









small subset of individuals exhibiting a large response (Hoffman et al., 2005). Therefore,

it has been suggested that it is safer to assume that the fraction varies from 0 to 100%

(Benedetti & Amanzio, 1997). Also, it appears that a given subject does not consistently

show a placebo response in different situations (Liberman, 1964). Rather, placebo

reactivity can be conceptualized as a potential tendency that can be activated under the

right situation rather than as trait that only certain people possess (Liberman, 1964). After

a survey of placebo literature, Wickramasekera (1985) concluded that (1) only a subset of

patients show a significant therapeutic response to placebo substances and procedures in

any given study, (2) we cannot identify these participants beforehand, (3) the same subset

may not respond in subsequent administrations, (4) the right conditions for a response

remains unknown.

Although medicine has not always been interested in the placebo effect itself, it has

managed to gather a lot of potentially valuable information through 50 years of clinical

trials. However, much of the data are confounded by factors other than the placebo effect

because of the lack of natural history conditions in most of these studies. The natural

histories of pain and the psychological circumstances und er which placebo treatments are

administered vary widely across different studies. A recent meta-analysis of placebo-

controlled clinical trials attempted to assess the magnitude of the placebo effect despite

these confounds (Hrobjartsson & Gotzsche, 2001). A total of 114 studies were examined

and Hrobj artsson and Gotzsche (2001) were able to estimate the magnitude of the

placebo effect. They concluded that these effects are less widespread and weaker than

previously believed. Also, they only found a significant effect when studies with

continuous data were examined versus those with dichotomous data. However, these









results are a result of combining studies of 40 different conditions such as hypertension,

alcohol abuse, anxiety, asthma, and martial discord. This assumes that placebos are

effective across all of these different disorders, an assumption that is not held by placebo

researchers (Stewart-Williams & Podd, 2004).

There is a major limitation with concluding that the magnitude of the placebo effect

is small from the overall results of the Hrobjartsson and Gotzche (2001), meta-analysis.

In the meta-analysis, only the condition of pain had a large enough sample for separate

analysis. In this condition, the researchers found a small but significant placebo effect.

However, there were two major types of studies included in this study: those that were

clinical and testing an active drug treatment and those studying actual placebo analgesic

mechanisms. The mean effect size was 0.95 (Cohen's d, a large effect) in the 14 studies

of placebo mechanisms where strong suggestions for pain relief were typically given

(Vase, Riley, & Price, 2002). Also, since Hrobjartsson and Gotzsche's paper, several

well-controlled experimental studies about the placebo effect have been published.

Stewart-Williams and Podd (2004) reviewed 16 studies and found that 14 demonstrated

effect sizes equal or greater than 0.50 standard deviations, a medium effect size.

The Vase et al. (2002) meta-analysis demonstrated the importance of placebo

mechanisms in the magnitude of placebo analgesia. While studies inducing placebo

analgesia with conditioning or suggestion alone demonstrated effect sizes of 0.83 and

0.85 (Cohen's d), respectively, the magnitude for studies using a combination of

conditional and suggestion was 1.45, almost double that of either method alone.

Mechanisms

There are multiple theories regarding the mechanism of placebo. The anxiety

theory hypothesizes that the placebo response is due to a reduction of anxiety, which in









turn is associated with a decrease in pain perception. However, this theory does not

clarify whether this reduction in anxiety is the cause or consequence of the placebo

response (Benedetti & Amanzio, 1997). Two major theories of the placebo response are

the conditioning and cognitive or expectancy theories.

Conditioning

The conditioning theory suggests that the placebo response represents a form a

classical conditioning. According to this theory, by pairing a neutral stimulus with a

stimulus (US) that elicits an unconditioned response (UR), the neutral stimulus becomes

a conditioned stimulus (CS) that can also elicit a response similar or related to the UR

called the conditioned response (CR). Therefore, stimuli such as a pill or a white lab coat

(CS) that may be initially neutral with repeated association with an active drug or

procedure (US) that elicits a specific response (UR) could elicit a response similar or

related to the active drug or procedure in the absence of this active drug or procedure

(CR).

Much of the research in support of the classical conditioning theory has been done

on nonhuman animals such as dogs, rats and mice. However, a series of influential

studies by Voudouris et al. (1985; 1989; 1990) showed that the placebo response can

indeed be conditioned in humans. In their study, after an initial testing session, his

participants were divided into two groups and a neutral cream was applied to the skin of

both of these groups (Voudouris et al., 1985). However, in one group, the level of

nociceptive stimulation was decreased with the administration of the placebo cream while

the stimulation was increased in the second group. A final pain testing suggested that

placebo responses could be conditioned in the laboratory in both positive and negative

directions.










Expectancy

The expectancy theory is the second maj or theory. According to this theory, a

placebo produces an effect because the recipient expects it to (Stewart-Williams & Podd,

2004). In fact, classical conditioning itself may lead to the acquisition of expectancies

(Price, 1999). However, expectation can also reflect knowledge about the active agent,

the circumstances around administration of the agent, and the condition the agent is

treating (Price, 1999). This implies that expectancies can be formed before an initial

exposure, contrary to the conditioning theory where an initial association needs to be

formed with the active agent.

The expectancy theory has a number of interesting implications. For example, drug

advertising may lead to more powerful placebo effects. Another implication is that a drug

simply treating the symptoms could treat the underlying disease by affecting expectations

that the treatment is working. Listing the possible side effects of a drug may increase the

likelihood that patients will experience these effects. Finally, those with hypochondriacal

tendencies are at increased risk of developing the physiological or psychological health

problems they worry about (Stewart-Williams & Podd, 2004).

Ethics: Experimental Setting

The ethics of placebo use has always been a controversial topic since discovery of

the phenomena. The World Medical Association rekindled the debate with the release of

a revision of the Declaration of Helsinki in October 2000. Section 29 states

The benefits, risks, burdens and effectiveness of a new method should be tested
against those of the best current prophylactic, diagnostic, and therapeutic methods.
This does not exclude the use of placebo, or no treatment, in studies where no
proven prophylactic, diagnostic or therapeutic method exists. (Association, 2004)









This section was particularly seen for its potential to cause substantial difficulties for

future development of medical products if it is literally interpreted and universally

implemented (Lewis, Jonsson, Kreutz, Sampaio, & van Zwieten-Boot, 2002).

Section 29 was written for the highly admirable purpose of ensuring that patients

are not exploited when they take part in clinical trials. This possibility is of particular

concern for individuals from less-developed countries who may be involved in research

to benefit individuals in more developed countries (Lewis et al., 2002). However, the

wording of Section 29 implies ruling out some crucial uses of placebo-controlled trials in

areas of medicine where proven prophylactic, diagnostic or therapeutic methods already

exist, malong no exceptions for possible benefits, adequate patient consent, avoidance of

irreversible harm and other precautions against ethically unacceptable consequences

(Lewis et al., 2002).

Since then, the Declaration of Helsinki has been clarified with a revision in 2004.

The clarification states,

a placebo-controlled trial may be ethically acceptable, even if proven therapy is
available, under the following circumstances: where for compelling and
scientifically sound methodological reasons its use is necessary to determine the
efficacy or safety of a prophylactic, diagnostic or therapeutic method; or where a
prophylactic, diagnostic or therapeutic method is being investigated for a minor
condition and the patients who receive placebo will not be subj ect to any additional
risk of serious or irreversible harm. (Association, 2004)

This recent clarification has also been criticized, particularly for the use of the word 'or'

linking the two situations. This could be interpreted as scientifically compelling reasons

could be used to justify increased risk of serious harm through use of placebo; therefore,

perhaps the connector should be 'and' not 'or' (Carlson, Boyd, & Webb, 2004). Also, the

use of the word, 'best current' has been questioned since the 'best current' may not be

available in a local context (Carlson et al., 2004). In addition, the 'best current' treatment









for some conditions remains controversial without consensus among professionals.

Moreover, while it is clear that for some serious conditions where there is often one

opportunity for a cure where placebo-controls need to be ruled out, there are other

conditions where providing rescue or escape medications are acceptable with adequate

patient awareness and consent (Carlson et al., 2004).

Methodologically, the use of placebos is crucial. Researchers, particularly with

respect to pain treatment endeavor to determine the efficacy of a specific treatment and

why patients improve with treatment (Turner et al., 1994). The randomized controlled

trial is the closest that clinical research can get to the experimental situation (Stang,

Hense, Jockel, Turner, & Tramer, 2005). The common argument against the use of

placebo is that it is unnecessary, that new treatments should be tested against existing

treatments (Stang et al., 2005). However, the reality is that "proven effective therapy" is

often assumed and fails to show superiority to placebo (Stang et al., 2005). Without a

placebo arm, it would not be possible to make the crucial distinction that two drugs are

equally ineffective rather than equally effective.

The Vioxx Gastrointestinal Outcomes Research (VIGOR) provides a concrete

example of another potential pitfall of not having a placebo control arm in a clinical

study. The VIGOR trial showed a five-fold difference in the incidence of myocardial

infarction in the Vioxx (rofecoxib) group compared with the naproxen group (Stang et

al., 2005). Unfortunately, without a placebo group, it remained unclear whether there was

an increased risk of myocardial infarction with Vioxx or a decreased risk with naproxen

(Stang et al., 2005). Four years later, after tens of millions of patients received Vioxx,

Merck withdrew the drug from the market because of an increased cardiovascular risk










(Stang et al., 2005). The Declaration of Helsinki (2004) states, "Medical research is only

justified if there is reasonable likelihood that the populations in which the research is

carried out stand to benefit from the results of the research." Stang et al. (2005) asserts,

"In this case, by trying very hard to be ethical and adhering too rigidly to the anti-placebo

dogma, one can end up being unethical."

It is clear that the use of placebo is a hotly contested topic. While there is much

debate regarding the ethics of using placebos, it is clear that placebos serve an important

function in research and the lack of a placebo control group can have detrimental effects

as demonstrated in the Vioxx study. However, much of this debate revolves around the

assumption that the placebo effect is somehow not real; that a placebo itself cannot effect

true change. There is growing evidence this is not the case. As mentioned earlier, there is

mounting evidence from imaging studies that placebos produce real physiologic as well

as psychological changes, sometimes similar to that of active treatments. The question

then remains, are placebos used in clinical settings and can or should placebos be used in

clinical settings?

Clinical Use of Placebo

In 2000, the Sunday New York Times Magazine publicized in a cover article that

"the powerful placebo" has come of age and suggested that medicine should make

regular use of it (Hoffman et al., 2005). Despite an upsurge of new research into placebo

mechanisms and the use of placebos in clinical trials, much remains unknown, especially

regarding use of the placebo in the clinical setting. However, a few researchers have

attempted to explore this topic.

A team of French researchers (Berthelot, Maugars, Abgrall, & Prost, 2001)

interviewed 300 rheumatology inpatients and 100 nurses about their beliefs about the









placebo effect. While all nurses interviewed reported knowing about the placebo effect,

only 59% of patients reported knowing about the placebo effect. Regarding the

characteristic of placebo responders, all nurses surveyed and 91% of patients believed the

placebo effect was dependent on patient personality, while only 63% of nurses and 38%

of patients attributed the effect to the personality of the physician. Eighty-three percent of

patients and 62% of nurses believed that those who respond well to placebos are

psychologically fragile. When asked about the use of placebos in clinical settings, 45% of

patients and 66% of nurses reported that physicians should use placebos to treat their

patients. Twenty seven percent of patients believed the physician should tell their patients

while only 3% of nurses thought the same. Twenty eight percent of patients and 45% of

nurses reported that they would agree to take a placebo. It is clear from these results that

there is a wide range of knowledge and beliefs about the placebo effect with a lot of

ambivalence regarding the topic among patients and nurses (Berthelot et al., 2001).

Focusing more on behaviors rather than beliefs, Nitzan and Lichtenberg (2004)

surveyed 89 nurses and physicians from different hospitals, departments and clinics

around Israel about the use of placebos in their medical practice. The results were

surprising. The authors had assumed that the use of placebo was not widespread and

would not exceed 10%. However, they found that 60% admitted using a placebo (53% of

doctors and 71% of nurses). No effects of sex or age were revealed. Thirty seven percent

of those surveyed reported using a placebo as often as once a month or more. Of those

who used a placebo, 94% reported that placebos were generally (33% of respondents) to

occasionally (61% of respondents) effective. Also, 68% of those who used a placebo

reported telling patients that they were receiving a real medicine, 17% reported saying









nothing at all, and 11% reported telling the patients that they are receiving a non-specific

medicine. Only 5% responded that the use of placebos should be categorically prohibited

while 75% attributed the effect to purely psychological mechanisms. The authors point

out that the retrospective nature of the study may bias frequency estimations; however,

the use of placebos or not in a clinical setting is not likely to be forgotten, suggesting that

placebos are indeed widely used in clinical practice.

Proposed Study

While the literature on the clinical use of placebos remains limited, it appears that

healthcare professionals may routinely use placebos in medical settings. If this is the

case, what are the implications of administering placebos to patients? How would people

respond if they realized that they experienced a placebo response?

It is possible that knowledge of personally experiencing a placebo response will

detrimentally affect the future likelihood of experiencing a placebo response. However, it

is also possible that knowledge of personally experiencing a placebo response may

enhance the future likelihood of experiencing a placebo response. The primary goal of

this study is to test these competing hypotheses. Also, the role of expectation for pain and

desire for pain relief will be examined in their ability to predict placebo responses. Next,

the effect of knowledge of a personal placebo response on likelihood of participating in

future studies and trust and likeability ratings of experimenters will be assessed. Lastly,

we will investigate the relationship between somatization and placebo response.















CHAPTER 2
MATERIALS AND METHOD

Participants

Seventy-seven participants, 41 female and 36 male undergraduate students from the

University of Florida, were recruited via flyers and the college undergraduate subj ect

pool. Before starting, all participants completed a consent form, which explained the

nature of the noxious stimulation. Those with heart conditions, hypertension, diabetes

mellitus, asthma, seizures, frostbite, past trauma to hands, lupus erythematosus, arthritis

or those on pain medication were excluded from the study. Participants were told that

they could withdraw from the experiment at any time.

Apparatus

Medoc Thermal Sensory Analyzer

All thermal stimuli were delivered using a computer-controlled Medoc Thermal

Sensory Analyzer (TSA-2001, Ramat Yishai, Israel), which is a peltier-element-based

stimulator. The stimuli were a range of temperatures from an adapting temperature of

330C up to 51oC. Stimuli were applied in a counterbalanced order to the forearm by a

contact thermode and were 3 seconds in duration. Multiples sites located on the forearms

of both arms were employed. Stimuli presentations were timed such that no site was

stimulated with less than a 3- minute interval to avoid sensitization of the site.

Mechanical Visual Analog Scale (VAS)

Participants rated stimuli using a mechanical VAS anchored at the left end by "no

pain" the right end by "the most intense pain imaginable." This method of pain










assessment has been shown to yield ratio scale measurement of clinical pain, which is

both internally consistent and provides independent sensory intensity and affective

dimensions of experimentally induced pain.

Placebo Cream

The placebo analgesic was in the form of a cream. A simple cold cream was mixed

with linalol/oil of thyme in a ratio of 8: 1, which gave the cream a distinct smell. The

cream was removed with cotton. The control cream was an 8:1 mixture of cold cream and

water.

Measures

Demographics Questionnaire

The demographics questionnaire provided information concerning the participants'

sex, age, education, race, income, marital status, work status, occupation, height, weight,

and pain conditions.

Illness Attitude Scale (IAS)

The IAS (Kellner, Abbott, Winslow, & Pathak, 1987) is a self-report measure

designed to measure psychopathology associated with hypochondriasis. The IAS consists

of 9 a priori subscales: Worry about Illness, Concerns about Pain, Health Habits,

Hypochondriacal Beliefs, Thanatophobia, Disease Phobia, Bodily Preoccupations,

Treatment Experience, and Effects of Symptoms. There have been multiple attempts at

analyzing the factor structure of the IAS using principal components analysis (Ferguson

& Daniel, 1995) (Stewart & Watt, 2000) (Hadjistavropoulos & Asmundson, 1998).

Hadjistavropoulos et al. (1999) conducted a exploratory and confirmatory factor analysis

and found considerable support for four distinct factors (1) Fear of illness, disease, pain

and death, (2) symptom effects, (3) treatment experience, and (4) disease conviction. The









four factor structure was corroborated by Stewart et al. (2000) with a few changes and the

factors were renamed fears, behavior, beliefs, and effects.

Pennebacker Inventory of Limbic Languidity (PILL)

The PILL is a self-report measure of the occurrence and frequency of common

physical symptoms and sensations. It consists of 54 items, such as coughing, sneezing,

racing heart, and headache. Response categories are: have never or almost never

experienced the symptom, less than 3 or 4 times per year, every month or so, every week

or so, and more than once every week, which are indicated by a five-point Likert scale.

This measure asks for generally experienced symptoms over an unspecified time period

in the past and assesses a general tendency to experience and report symptoms rather than

the actual, everyday symptom experience (Gij sbers van Wijk, van Vliet, & Kolk, 1996).

Thus, this trait-like symptom scale is used to assess somatization or a general tendency

for reporting physical symptoms (Pennebaker, Hughes, & O'Heeron, 1987). When used

with healthy participants, a high score is indicative of somatization. Internal consistency

is high (Cronbach' s alpha=0.91) (Gij sbers van Wijk et al., 1996). The PILL has sufficient

test-retest reliability (0.83) and was found to correlate moderately with comparable

symptom scales (Pennebaker, Gonder-Frederick, Stewart, Elfman, & Skelton, 1982).

Visual Analogue Scales of Mood (VAS Mood)

Mood was assessed with a mechanical VAS. The negative feelings associated with

pain experience assessed were depression, anxiety, frustration, fear, and anger, with end

points designated as "none" and as "the most severe imaginable". Visual Analogue

Scales (VAS) of pain have been demonstrated to be reliable, internally consistent

measures of experimental pain sensation intensity (Price, Bush, Long, & Harkins, 1994).










Procedures

All participants participated in four pain testing stages consecutively. Participants

were divided into three groups: placebo informed, placebo uninformed and repeated

baseline conditions. Table 2- 1 provides a brief overview of the difference in procedures

between the three groups. The repeated baseline group was informed that they would be

tested using a control cream that does not contain any active agents. On the other hand,

both the placebo uninformed and informed groups were told that we are testing the

effects of an ointment on pain and given the suggestion of an active agent. Finally, the

placebo informed group was told after the first placebo testing stage that the cream used

was a placebo while the placebo uninformed group was not told that the first cream used

was a placebo. The following paragraphs provide a more detailed description of each

stage.

Table 2-1. An over ew of the study design.
Placebo Uninformed Placebo Informed ReetdBaseline
Initial Information Told we are testing the effects of a cream on Told we will not be
pain testing cream
because they are in
the control condition
Questionnaire Same for all groups (counterbalanced)
Calibration Trials Same for all grus(testing tempeatures determined)
Baseline Same 4 trials for all groups
Conditioning 8 trials, 4 at placebo temp w/ cream, 4 at Also 8 trials, but got
baseline temp placebo temp on all
areas
First Placebo Same 4 trials at Baseline Temp
Information/ Graph Shown and Graph Shown and Graph shown and
Graph Presentation told that the cream told that they told that it represents
worked as expected received a placebo their pain ratings at 2
and the difference time points
in pain ratings
demonstrates a
placebo response
Second Placebo Same 4 trials at the baseline temperature
Questionnaire Same for all grus (counterbalanced)












Stage 1: Baseline

During the first stage, each subject began with the following instructions:

After filling out several questionnaires about yourself, your attitudes and your
mood, you will be asked to participate in four sensory-testing sessions
consecutively using a heat thermode where you will receive several brief heat
pulses to different areas on your forearms. These pulses will range from
undetectable to painful. After the first three sessions, you will be provided with
information about your responses during the previous trials. After the information
is provided, you will then be asked to participate in the last sensory testing session.
After the last session, you will be asked to complete several additional
questionnaires.

Half of the participants were randomly assigned to complete a packet of questionnaires

including a demographics questionnaire (which will ask for age, sex, education, marital

status, ethnicity, occupation/area of study, socioeconomic status), IAS and PILL while

the other half were asked to complete the questionnaire at the end of the study. Also,

VAS-Mood, likeability of experimenters and trust of experimenters were assessed in all

participants before beginning the pain trials.

Next, calibration trials were conducted to control for individual differences in pain

perception. An ascending series of trials starting from 430C increasing by steps of loC

were completed. The participants rated the pain intensity immediately on a VAS

following each trial. On a 0-10 scale, the temperatures at which the patient rated their

pain intensity between 0 and 2 (placebo) and between 4-6 (control) were noted. During

the first stage after the calibration trials, each subj ect completed 4 pain-trials at the

control stimulus intensity to determine their baseline pain ratings.

Stage 2: Conditioning and Suggestion

In stage 2, the subject in the placebo informed and uninformed conditions were

provided with instructions regarding the nature of the experiment. They were told, "The










agent you have just been given is known to significantly reduce pain in some patients".

They were also informed that the level of stimulation during this session would remain

constant. On counterbalanced selected locations on the arm, each participant received 8

total pain-trials, 4 with the placebo cream at the placebo temperature and 4 at the control

temperatures (as determined during the calibration trials) without the placebo cream.

Eight trials were used because repeated pairings are necessary for conditioning to occur.

The intensity of the stimulus was surreptitiously lowered for the placebo cream to

produce the conditioning effect. Participants assigned to the repeated baseline condition

were told that they would not receive an active agent during their participation. They

were given 8 total pain-trials at the placebo temperature to prevent conditioning.

Expected levels of pain intensity, measured on the same scale that was used to rate

experimental pain, was assessed from all groups before this session and pain intensity

ratings were assessed after each pain trial.

Stage 3: First Placebo

Participants in the placebo informed andc uninformed groups were given 4 trials

with the placebo cream. Pain intensity ratings were assessed after each pain trial. At the

end of this stage, bar graphs of the pain responses were presented to the subject. In this

graph, two bars represented the average pain ratings reported with the placebo cream and

average ratings without.

Those in the placebo informed group were told that they received a placebo cream

and that the reduction in pain ratings with the placebo reflects their placebo response.

Those in the placebo uninformed group were told that, as expected, the cream was

successful in reducing their pain levels (or unsuccessful if a significant change was not









observed). Those assigned to the repeated baseline condition were also provided with a

graph of their pain ratings during the baseline and the first testing stage.

Stage 4: Second Placebo

Those in the placebo informed group were correctly told that they had received a

placebo cream and would now receive the actual cream the study is testing. However,

they again received the placebo cream. Those in the placebo uninformed group were told

that the cream is being tested again, and again received the placebo cream. Those

assigned to the repeated baseline condition were told that they would be tested again with

the control cream. All groups again participated in 4 trials. Pain intensity ratings were

assessed after each pain trial. Mood, trust of experimenters, and likeability of

experimenters were assessed from all groups. At the end of this stage, the actual purpose

of the experiment was explained to the participants in a debriefing.















CHAPTER 3
RESULTS

Verification of the Placebo Effect

The pain ratings from the repeated baseline group were compared to the pain

ratings from the placebo informed and uninformed groups to verify that reductions in

pain from the baseline to the first and second placebo testing were the result of the

placebo manipulation and not simply habituation with time or repeated testing. To assess

this possibility, the pain ratings from the placebo uninformed and informed groups were

collapsed and compared with the pain ratings from the repeated baseline group.

A mixed model repeated measures ANOVA, with time as a within subject factor

(3) and group as a between subject factor (2) was performed. Results indicated a

significant main effect for group (F(1,75)= 565.957, p<0.001), and for time

(F(2,150)=20.042, p<0.001), and a significant time (baseline, first testing, second testing)

by group (placebo informed plus uninformed and repeated baseline) interaction (F(2,

1 50)=5.3 79, p=0.006). Decomposition of the interaction revealed that the main effect for

time was not significant for the repeated baseline group (F(2,32)=2.512, p>0.05, partial

eta squared=0.136) whereas it was significant for the collapsed placebo informed and

uninformed groups (F(2,118)=47.417, p<0.001, partial eta squared=0.446), confirming

that the change in pain ratings were, for the most part, the result of our manipulation. The

effect size (Cohen's d) for the change in pain ratings from the baseline to the first placebo

was 0.99 for the collapsed placebo informed and uninformed group whereas it was 0.29

for the repeated baseline group. (Figure 3-1)





















6 M PlaceboGrorups










Baseline Time 1 Timne 2
Time



Figure 3-1. Verifieation of the placebo effect.

The level of a participant' s placebo response was calculated by subtracting their

pain ratings at the first placebo testing from their pain ratings at baseline. Only those who

demonstrated a placebo response (i.e., difference scores > 0) were included in the

following analyses. Fifty participants out of the total 60 tested in the placebo informed

and uninformed conditions fit this requirement.

Pain Ratings

We wanted to determine whether there was a difference in the placebo effect

between the placebo informed and uninformed groups at the first placebo (after

conditioning) and second placebo testing (after placebo response information

presentation). A repeated measures mixed-model ANOVA revealed a non-signifieant

group (placebo informed and uninformed) by time (baseline, first placebo, and second










placebo) interaction (F(2,96)=0.218, p>0.05). Test of within-subj ects effects revealed a

significant main effect across the three time points (F(2,96)=99.699, p<0.001). The pain

ratings from baseline (M=5.253, SD=1.283) to first placebo (M=3.289, SD=1.297)

decreased significantly (F(1,48) =135.136, p<0.001) whereas the ratings between first

placebo and second placebo (M=3.600, SD=1.457) significantly increased

(F(1,48)=7.643, p=0.008). The test of between-subject effects showed that there was no

significant overall difference between the two information groups (F(1,48)=0.528,

p>0.05). (Figure 3-2)


j


Baseline


Tl
Time


Figure 3-2. Pain ratings at baseline, time 1 and time 2 for the placebo informed and
uninformed groups.


~ Blaccbalnform~ed

Flsctb~ I]nlnrcrrm~J


T2









Mood

A series of mixed- model ANOVAs was conducted to examine the time (pre and

post) by group (placebo informed and uninformed) interaction and main effects for group

and time for mood. No significant interactions were found for depression, anxiety,

frustration, anger, or fear. A test of within-subj ects effects revealed no significant

changes for time in depression and anger from pre to post. However significant

improvements (main effects for time) were found for anxiety, frustration, and fear. In

addition, the main effects for group (placebo informed and uninformed) were not

significant for depression (F(1,48)=0.052, p>0.05), anxiety (F(1,48)=0.415, p>0.05),

frustration (F(1,48)=0.955, p>0.05), anger (F(1,48)=0.596, p>0.05), and fear

(F(1,48)=0.799, p>0.05). These results show there were significant general improvements

over time for anxiety, frustration and fear, but there were no significant group differences

for any of the mood variables. (Table 3-1)

Table 3-1. Mood mixed-model ANOVA results.
Mood Time by Pre-post change Pre Post Pre-post
condition (within change
interaction subj ects) (Cohen's d)
Depression F(1,48)=0.761 F(1,48)=0.322 M=0.733 M=0.690 0.027
p>0.05 p>0.05 SD=1 .63 0 SD=1 .5 59
Anxi ety F(1,48)=0.50 1 F(1,48)=10.701 M=2.078 M=1.514 0.265
p>0.05 p=0.002* SD=2.293 SD=1.952
Frustration F(1,48)=0.076 F(1, 48)=6.693 M=1.696 M=1.114 0.269
p>0.05 P=0.013* SD=2.389 SD=1.917
Anger F(1,48)=0.006 F(1,48)=.896 M=0.783 M=0.639 0.077
p>0.05 p>0.05 SD=2.006 SD=1.732
Fear F(1,48)=1.667 F(1,48)= 8.194 M=0.997 M=0.538 0.274
p>0.05 p=0.006* SD=1.863 SD=1.463


Attitudes

A series of mixed- model ANOVAs were conducted to examine the time (pre and

post) by group (placebo informed and uninformed) interaction and main effects for group









and time for the different attitude variables (the participants' likelihood of using medical

treatments to treat pain, likelihood of using non-medical treatments to treat pain,

likelihood of future participation in studies in general, likelihood of future participation in

studies conducted in our lab, likeability of experimenters in general, likeability of

experimenters in our lab, trust of experimenters in general, and trust of experimenters in

our lab). No significant time by group interactions were found for any of the attitude

variables. Moreover, a test of within-subj ects effects revealed no significant main effects

for time. Similarly, a test of between-subjects effects found no main effects for group in

the participants' likelihood of using medical treatments to treat pain (F(1,48)=1.004,

p>0.05), likelihood of using non-medical treatments to treat (F(1,48)=1.758, p>0.05),

likelihood of future participation in studies in general (F(1,48)=0.539, p>0.05), likelihood

of future participation in studies conducted in our lab (F(1,48)=1.342, p>0.05), likeability

of experimenters in general (F(1,48)=1.345, p>0.05), likeability of experimenters in our

lab (F(1,48)=2.704, p>0.05), trust of experimenters in general (F(1,48)=1093, p>0.05),

and trust of experimenters in our lab (F(1,48)=3.427, p=0.07). (Table 3-2)

Table 3-2. Attitude mixed-model ANOVA results.
Variable Time by Pre-post change Pre Post
condition (within
interacti on subj ects)
participants' likelihood of F(1,48)=0.423 F(1, 48)=0.929 M=3.907 M=4. 196
using medical treatments p>0.05 p>0.05 SD=2.954 SD=2.826
to treat pain
likelihood of using non- F(1,48)=1.357 F(1,48)=3.251 M=2. 110 M=2.528
medical treatments to treat p>0.05 p>0.05 SD=2.881 SD=3.096
pain
likelihood of future F(1,48)=1.067 F(1,48)=0.371 M=6.450 M=6.3 12
participation in studies in p>0.05 p>0.05 SD=2.594 SD=2.588
general
likelihood of future F(1,48)-0.155 F(1,48)=1.897 M=5.641 M=6.086
participation in studies p>0.05 p>0.05 SD=2.985 SD=2.922
conducted in our lab









likeability of F(1,48)=0.403 F(1,48)=0.882 M=6.747 M=6.926
experimenters in general p>0.05 p>0.05 SD=2.226 SD=2.393
likeability of F(1,48)=0.003 F(1,48)=0.456 M=7.915 M=7.721
experimenters in our lab p>0.05 p>0.05 SD=1.889 SD=2.047
trust of experimenters in F(1,48)=0.016 F(1,48)=.827 M=6.555 M=6.367
general p>0.05 p>0.05 SD=2.400 SD=2.477
trust of experimenters in F(1,48)=0.914 F(1,48)=2.213 M=7.752 M=7.472
our lab p>0.05 p>0.05 SD=1.941 SD=2. 018


Expectation

Expected pain levels were rated before the baseline, first test, and second test. A

repeated measures mixed-model ANOVA revealed a non-significant group (placebo

informed and uninformed) by time (baseline, before first placebo, and before second

placebo) interaction (F(2,96)=2.273, p>0.05). The main effect for group was also not

significant (F(1,48)=1.148, p>0.05). However, the main effect for time showed

significant change over time (F(2,96)=88.626, p<0.001). Expectation for pain decreased

significantly from baseline (M=4.866, SD=1.082) to the first placebo (M=2.376,

SD=1.326; F(1,49)=144.855, p<0.001) and decreased significantly from baseline to the

second placebo (M=2.804, SD=1.328; F(1,49)=136.710, p<0.001), but significantly

increased from the first placebo to the second placebo (F(1,49)=5.974, p=0.018). (Figure

3-3)

Simple linear regressions were employed to determine whether changes in expected

pain levels from baseline to the first placebo test and from baseline to the second placebo

test predicted the first or second placebo responses (baseline minus first placebo pain

testing ratings) and second (baseline minus second placebo pain testing ratings) placebo

response. Change in expected pain intensity from baseline to the first test (baseline

expectation minus pre-first test expectation) did not significantly predict the first placebo

response (F(1,48)=2.659, p>0.05, r2=0.052) or the second placebo response















































Figure 3-3. Expectation for pain ratings at baseline, pre-first placebo and pre-second
placebo for the placebo informed and uninformed groups.

Desire for Pain Relief

Desire for pain relief was assessed at two time points. The first was just before the

conditioning trials and the second was just after showing pre to post first placebo pain

ratings to the participants and just prior to administering the second placebo. A mixed-

model ANOVA revealed a non-significant group (placebo informed and uninformed) by

time (before conditioning, and before second placebo) interaction (F(1,47)=1.074,


(F=(1,48)=2.732, p>0.05, r2=0.026). However, change in expectation from baseline to the

second test (baseline expectation minus pre-second test expectation) did significantly

predict the second placebo response (F(1,48)=6.098, p=0.017, std. beta=0. 161, r2=0. 113),

but not the first placebo response (F=(1,48), F=3.305, p>0.05, r2=0.045).


-






Baseline Pare-1st Placebo Pre-2nd Placebot
Timet


SPlacebo Informed

t.._. Plalcebo Unlnformed










p>0.05). Additionally, the main effect for group was also not significant (F(1,47)=0.634,

p>0.05). However, there was a significant main effect for time (F(1,47)=7.652, p=0.008)

from pre-conditioning (M=5.9776, SD=2.670) to pre-second testing (M=5.259,

SD=2.989). (Figure 3-4)

Simple linear regressions were employed to determine whether the change in desire

predicted the first (baseline minus first placebo pain testing ratings) and second (baseline

minus second placebo pain testing ratings) placebo responses. The change in desire

significantly predicted the first (F(1,47)=6.791, p=0.012, std. beta=0.355, r2=0.126) and

second (F(1,47)=9.168, p=0.004, std. beta=0.404, r2=0.163) placebo response.


10




7 -

B: 6 M laceba Informed










Pre-Con~ditioning Pre--2nd Placebo
Tirn~e




Figure 3-4. Desire for pain relief at pre-conditioning and pre-second placebo for the
placebo informed and uninformed groups.










Expectation and Desire Interaction

To predict the first placebo effect, the change in expectation and desire from pre-

conditioning to just prior to the 2nd placebo were entered together in the first step of a

hierarchical regression. In the first model, both changes in expected pain intensities

(t=2.233, std. beta=0.260, p=0.030) and desire (t=3.436, std. beta=0.400, p=0.001)

significantly predicted the first placebo effect both independently and together

(F(2,56)=17.826, p<.001, r2=0.264). When the expectation and desire interaction (i.e.,

product) was added in the final model of the hierarchical regression, the interaction was

not significant (t=-0.365, std. beta= -0.045, p>0.05); however, the complete model

(F(3,55)=11.965, p=0.001, r2=0.265) and both expectation (t=2.238, std. beta=0.263,

p=0.029) and desire (t=3.358, std. beta=0.414, p=0.001) remained significant.

Predicting the second placebo effect, again the change in expectation and desire

from pre-conditioning to the 2nd placebo were entered together in the first step of a

hierarchical regression. In the first model, both changes in expectation (t=2.847, std.

beta=0.320, p=0.006) and desire (t=3.598, std. beta=0.405, p=0.001) significantly

predicted the first placebo effect both independently and together (F(2,56)=17.212,

p<0.001, r2=0.312). When the expectation and desire interaction was added in the final

model of the hierarchical regression, the interaction was not significant (t=-0.609, std.

beta=-0.072, p>0.05); however, the complete model (F(3,55)=11.645, p<0.001, r2=0.316)

and both expectation (t=2.871, std. beta=0.326, p=0.006) and desire (t=3.593, std.

beta=0.427, p=0.001) remained significant.

Somatization

Two measures of somatization were administered, the PILL and the IAS. The total

scores of the measures were found to be significantly correlated (r-0.392, p=0.007) with









each other. The PILL (F(1,46)=4.215, p=0.046) was predictive of a participant' s first

placebo response explaining 8.4% of the variance. However, the PILL was not predictive

of a participant' s second placebo response (F(1,46)=3.671, p>0.05) when entered in a

regression.

The IAS total score was not predictive of a participant' s first (F(1,48)=0.758,

p>0.05) or second (F(1,48)=0.161, p>0.05) placebo response. Given the multifactorial

nature of the IAS, the 4 factors proposed by Stewart et al. (2000) were independently

entered in a regression. The factors fear (F(1,48)=0.708, p>0.05), behavior

(F(1,48)=0.284, p>0.05), beliefs (F(1,48)=1.480, p>0.05) and effects (F(1,48)=1.119,

p>0.05) did not significantly predict a participant's first placebo response. In addition,

fear (F(1,48)=1.119), p>0.05), behavior (F=1,48)=3 .328, p>0.05), beliefs (F(1,48)=0.766,

p>0.05) and effects (F(1,48)=0.444, p>0.05) did not significantly predict a participant' s

second placebo response.

Sex Differences

A 2x2 ANOVA was used to analyze whether there were any significant differences

between men and women in their ability to get a first or second placebo response. The

interaction between sex and information condition (F(1,46)=0. 119, p>0.05) in the

participant' s ability to get a first placebo response was not significant. Additionally, there

was neither a main effect for sex (F(1,46)=0.779, p>0.05) nor information group

(F(1,46)=0.411, p>0.05). Similarly, the interaction between sex and information

condition in the participant's ability to get a second placebo response was also non-

significant (F(1,46)=0. 134, p>0.05). Also, the main effects for sex (F(1,46)=1.499,

p>0.05) and information condition (F(1,46)=0.428, p>0.05) were both not significant.















CHAPTER 4
DISCUS SION

The ethics of placebo use has been debated since discovery of the phenomena.

Under the heading, "No place for placebos when treating pain," Dr. Sullivan (2004)

wrote, "this deception of the patient is damaging and unjustified." Alternatively, Dr. Oh

(1994) concludes, "in appropriate patients, doctors might consider giving a placebo when

active treatment is both costly and likely to confer only marginal or transient benefit."

While neither extreme may be the answer, this debate has persisted without a good

understanding of the result of placebo use. There has yet to be a study that examines the

aftereffect of individuals discovering that they experienced a placebo response on their

future ability to experience a placebo response. The main goal of this study was to

explore the effect of such information on pain response.

We discovered that there was no difference in future pain responding between

participants who were told that they experienced a placebo response versus those who

were not. Interestingly, the placebo effect persisted when a second placebo cream was

applied even after participants were told that the first cream used in the study was a

placebo. Although the strength of that second placebo was slightly reduced,

approximately 84% of the original placebo effect remained. Next, we wanted to explore

the effect of feedback of personal placebo information on mood.

A previous pilot study (Chung, Price, Verne, Perlstein, Craggs, & Robinson, 2006)

found no detrimental effects when information was revealed to patients with irritable

bowel syndrome about their pain reduction from a placebo. We replicated this finding in









a more general population. This study corroborated that revelation of an individual's

placebo response does not appear to cause adverse effects on mood. While we found no

change in depression and anger; curiously, we found that participants' anxiety, frustration

and fear improved at the end of the study regardless of the information provided during

the study. Since there were no differences between the two information groups, it is

possible the improvement is a result of repeated testing or related to the participants'

reaction to simply completing the study. If the improvements were related to procedures

or information provided in the study, the exact nature and mechanism remains unknown.

Nevertheless, the lack of worsening mood is notable.

Similar to mood, attitudes about the likelihood of using medical and non-medical

treatments for pain, likelihood of participating in future studies, likeability of

experimenters and trust of experimenters were assessed both before and after the study.

Despite the level of deception involved in participating in the placebo information

condition, there were no differences between the placebo informed and uninformed

groups in their attitudes. This suggests that participants may not change their attitudes

about pain treatment, research participation or feelings toward experimenters after

participating in a study involving placebo use with experimental pain. Moreover,

attitudes seem unaffected by learning that the pain reduction reflected a placebo response.

Given that previous mood, attitudes, and pain responding do not appear to be

affected by placebo information, what role does expectation and desire for pain relief

have on the placebo effect in the context of providing personal placebo information?

Similar to the findings regarding pain ratings, there were no differences between the two

information groups in their expected pain intensities. The change in expected pain









intensities from baseline to the first test was not related to the first or second placebo

response. However, the change in expectation from baseline to the second test was

significantly predictive of the second placebo response, but not the first placebo response.

Examining the concept of desire, similar to expectation, there were no differences

between the two groups in their desire for pain relief. However, the change in desire for

pain relief from before the conditioning session did significantly predict a participant' s

first and second placebo response. In addition, the interaction between desire and

expectation did not significantly predict the first or second placebo effect.

Previous studies have suggested that desire for pain relief may be more of a factor

in clinical pain where pain is threatening or has uncertain duration. Furthermore, Price et

al. (Price, Milling, Kirsch, Duff, Montgomery, & Nicholls, 1999) found that expectation

for pain but not desire was associated with the magnitude of placebo analgesia. However,

although our study was conducted in an experimental setting where the participants were

informed about the number of pain testing stages (potentially increasing predictability),

desire was a more consistent predictor of the placebo response than expectation. It will be

important to further explore the relationship between expectation, desire and pain

responding in future studies.

Next, we examined the role of personal characteristics, somatization and sex, in

participants' placebo responses and maintaining those the response after feedback about

their placebo responses. Two measures of somatization, the PILL and the IAS were used

to examine this relationship. While the IAS was not significantly predictive of placebo

responding at any level, the PILL did predict participants' first placebo responses, but not

the second placebo responses. We can speculate why the two measures may have










produced different results. The IAS is a face valid measure that asks about worries,

behaviors and beliefs about illnesses. On the other hand, the PILL is a symptom checklist

that asks participants about their experience with various symptoms. While it is assumed

that the PILL measures an element of somatic focus, exactly what the questionnaire

measures remains unknown. The PILL may be measuring something more than

somatization (such as anxiety) that enhanced its sensitivity to predict placebo responders.

Further studies are needed to explore the relationship between PILL and the ability to

experience a placebo response.

Finally, we examined sex differences in the ability to experience a placebo

response. We found no differences between men and women's first or the second placebo

response. These results suggest that characteristics such as somatic focus may be related

to a participant' s placebo response, but we found no evidence of any differences in

placebo responding or the effect of placebo response information between the sexes.

Conclusions and Future Directions. The lack of differences in pain responding

and in worsening mood has noteworthy implications for future placebo studies. These

results suggest that placebo use in experimental settings may not result in detrimental

effects. While our study demonstrated that a double placebo design is feasible to examine

the role of a placebo use on a second placebo administration, we do not know if our

findings will generalize to clinical setting. Future studies should examine the effect of

placebo use with clinical populations. Furthermore, we found that the placebo effect

significantly decreased during the second placebo administration regardless of the

assigned information condition. The reason for this is unclear. One possibility is that any

information decreases the placebo effect. It is also possible that with time, the placebo









effect will be reduced. If so, it would be important to explore the rate of decay and the

variables related to this decay. Such information may assist in the development of

protocols that maximizes the magnitude and longevity of placebo effects.
















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BIOGRAPHICAL SKETCH

S. Karen Chung graduated from the University of California, Los Angeles, in June

2002 with a Bachelor of Science degree in psychobiology. In May 2004, she received a

master' s degree in psychology at the Department of Clinical and Health Psychology at

the University of Florida. Her clinical and research interests are in the area of clinical and

health psychology and include psychosocial and cognitive influences on responses to

pain and illness





PAGE 1

EFFECTS OF PERSONAL PLACEBO RESPONSE INFORMATION ON FUTURE PLACEBO RESPONSE By SOYEON KAREN CHUNG A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2007

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Copyright 2007 Soyeon Karen Chung

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iii ACKNOWLEDGMENTS I want to thank my advisor, Dr. Michael E. Robinson, for his support and guidance throughout this project. Also, I want to acknowledge those associated with the Center for Pain Research for their input and assistance.

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iv TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. iii LIST OF TABLES ................................ ................................ ................................ .............. vi LIST OF FIGURES ................................ ................................ ................................ ........... vii ABSTRACT ................................ ................................ ................................ ...................... viii CHAPTER 1 INTRODUCTION ................................ ................................ ................................ ........ 1 Definition ................................ ................................ ................................ ...................... 1 Discovery of the Placebo ................................ ................................ .............................. 2 Its Not Nothing ................................ ................................ ................................ ............ 3 The Placebo Effect ................................ ................................ ................................ ........ 4 Mechanisms ................................ ................................ ................................ .................. 6 Conditioning ................................ ................................ ................................ ................. 7 Expectancy ................................ ................................ ................................ .................... 8 Ethics: Experimental Setting ................................ ................................ ........................ 8 Clinical Use of Placebo ................................ ................................ .............................. 11 Proposed Study ................................ ................................ ................................ ........... 13 2 MATERIALS AND METHOD ................................ ................................ .................. 14 Participants ................................ ................................ ................................ ................. 14 Apparatus ................................ ................................ ................................ .................... 14 Medoc Thermal Sensory Analyzer ................................ ................................ ...... 14 Mechanical Visual Analog Scale (VAS) ................................ ............................. 14 Placebo Cream ................................ ................................ ................................ ..... 15 Measures ................................ ................................ ................................ ..................... 15 Demographics Questionnaire ................................ ................................ .............. 15 Illness Attitude Scale (IAS) ................................ ................................ ................. 15 Pennebacker Inventory of Limbic Languidity (PILL) ................................ ......... 16 Visual Analogue Scales of Mood (VAS Mood) ................................ ............... 16 Procedures ................................ ................................ ................................ ................... 17 Stage 1: Baseline ................................ ................................ ................................ 18 Stage 2: Conditioning and Suggestion ................................ ................................ 18

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v Stage 3: First Placebo ................................ ................................ .......................... 19 Stage 4: Second Placebo ................................ ................................ ...................... 20 3 RESULTS ................................ ................................ ................................ ................... 21 Verification of the Placebo Effect ................................ ................................ .............. 21 Pain Ratings ................................ ................................ ................................ ................ 22 Mood ................................ ................................ ................................ ........................... 24 Attitudes ................................ ................................ ................................ ...................... 24 Expectation ................................ ................................ ................................ ................. 26 Desire for Pain Relief ................................ ................................ ................................ 27 Expectation and Desire Interaction ................................ ................................ ............. 29 Somatization ................................ ................................ ................................ ............... 29 Sex Differences ................................ ................................ ................................ ........... 30 4 DISCUSSION ................................ ................................ ................................ ............. 31 LIST OF REFERENCES ................................ ................................ ................................ ... 36 BIOGRAPHICAL SKETCH ................................ ................................ ............................. 40

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vi LIST OF TABLES Table page 2 1 An overview of the study design. ................................ ................................ ............. 17 3 1 Mood mixed model ANOVA results. ................................ ................................ ...... 24 3 2 Attitude mixed model ANOVA results. ................................ ................................ ... 25

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vii LIST OF FIGURES Figure page 3 1 Verification of the placebo effect. ................................ ................................ ............ 22 3 2 Pain ratings at baseline, time 1 and time 2 for the placebo informed and uninformed groups. ................................ ................................ ................................ ... 23 3 3 Expectation for pain ratings at baseline, pre first placebo and pre seco nd placebo for the placebo informed and uninformed groups. ................................ ...... 27 3 4 Desire for pain relief at pre conditioning and pre second placebo for the placebo informed and uninformed groups. ................................ ................................ ............ 28

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viii Abstract of Dissertation Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy EFFECTS OF PERSONAL PLACEBO RESPONSE INFORMATION ON FUTURE PLACEBO RE SPONSE By Soyeon Karen Chung August 2007 Chair: Michael E. Robinson Major: Psychology The ethics of placebo use has been debated since discovery of the phenomena. However, there has yet to be a study that examines the aftereffect of individuals discovering that they experienced a placebo response on their future ability to experience a placebo response. Seventy seven participants, 41 female and 36 male undergraduate students from the University of Florida were recruited via flyers and the college undergraduate subject pool and divided into three conditions: placebo informed, placebo uninformed, and repeated baseline. We used a double placebo design with verbal placebo suggestion and conditioning to induce a placebo response and to examine the effect of providing information about a participants personal placebo response on their future placebo response. We discovered that there was no difference in future pain responding between participants who were told that they experienced a pl acebo response versus those who were not. Interestingly, the placebo effect persisted when a second placebo cream was applied even after participants were told that the first cream used in the study was a

PAGE 9

ix placebo. In addition, this study corroborated that revelation of an individuals placebo response does not appear to cause adverse effects on mood. Similar to mood, attitudes about the likelihood of using medical and non medical treatments for pain, likelihood of participating in future studies, likeabilit y of experimenters and trust of experimenters remained unaffected. Examining the concepts of expectation for pain and the desire for pain relief, we found that desire was a more consistent predictor than expectation in predicting a placebo response. Furthe rmore, characteristics such as somatic focus may be related to a participants ability to experience a placebo response, but we found no evidence of any differences in placebo responding between the sexes. These results suggest that placebo use in experime ntal settings does not have detrimental effects.

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1 CHAPTER 1 INTRODUCTION Significant progress has been made in placebo research and this progress is most evident in pain research. Hoffman, Harrington & Fields (2005) indicated three possible reasons for this : (1) clinically, the pla cebo induced pain reduction is probably the best verified instance of this general response; (2) methodologically, the most elegant experimental work on the placebo response has used pain as its paradigm; and (3) conceptually, we have more insight into the brain mechanisms underlying placebo analgesia than we have for any other placebo response. Definition There are several terms commonly used in placebo research that are important to define and distinguish. A placebo is an intervention designed to simulate medical therapy, but not believed to be a specific therapy for the target condition (Turner, Deyo, Loeser, Von Korff, & Fordyce, 1994) However, the terms placebo effect and placebo response have been frequently used interchangeably. The placebo effect refers to any average difference between the condition of a group of subjects that has received a placebo treatment, as suming that no change would have been observed in the absence of the placebo administration (Hoffman et al., 2005) In other words, it is the mean placebo response. In contrast, the placebo response refers to the change in an individual caused by a placebo manipulation (Hoffman et al., 2005) This is an important distinction because our focus is the psychology of the placebo response rather than the placebo effect. These definitions will be used for the remainder of the paper.

PAGE 11

2 Discovery of th e Placebo The discovery of the placebo has a serendipitous history. In the 19 th century, a leading European neurologist, Jean Martin Charcot became interested in a disorder called hysteria. Symptoms of this mysterious disorder included convulsions, paraly sis, tunnel vision, color blindness, patches of anesthesia, incessant coughing, tics, and feelings of choking. While physicians were baffled by this disorder, Charcot took an analytic approach revealing underlying patterns with four completely predictable stages of the disease. It was later revealed that the universal physiology and mechanism of this disease was entirely local and only occurred within Charcots studio. Charcot had been deceived by the subjective experiences of his patients, interpreting t hem as objective displays of universal significance (Harrington, 2000) The idea that hysteria was a made up entity was exposed when Hippolyte, a rival of Charcot, showed that he could reproduce, change and extinguish all of the symptoms of hysteria. He c laimed that all of these symptoms were a kind of sham: nothing more than effects of a physiological process called suggestion. This finding led to the conclusion that bodily symptoms caused by suggestion are a psychological lie; that those who respond to t hese types of treatments were not suffering from a real disease at all. In the 1930s and 1940s, the perception of the placebo effect began to change with the discovery of sulfa drugs. The placebo effect began to be perceived as noise, a serious hindrance t o medicines progress (Harrington, 2000) In 1955 Henry Beecher wrote a seminal article about the history of research on the placebo effect titled, The Powerful Pla cebo (Beecher, 1955) As the title suggested, the paper wanted to demonstrate that the placebo effect was powerful and pervasive. Beecher claimed that approximately 1/3 of patients across a review of 15 clinical trials

PAGE 12

3 experienced a placebo response. Beecher also claimed that the placebo response could produce objectively measurable changes in a patients physiology, changes that rivaled the effects of the active agent against which the placebo is being compared. Beecher argued that a randomized placebo controlled trial methodology was necessary to protect the active treatment data from the placebo effect. Subsequently, it became clear that patient expectation or suggestibility was not the only poss ible confound for researchers. Additional problems included researcher bias, measurement error, statistical regression to the mean, and spontaneous remission. The placebo control group simply became a catch all for these all of these confounds. Its Not N othing Since the discovery of the placebo effect, placebos have been used as the control arm in randomized placebo control trials. Placebos were perceived as nuisances in the quest to find the actual effect of the active treatment. However, what has been ignored until recently is the fact that placebos in itself can affect significant change, sometimes in magnitudes similar to the active treatment against which it is being compared. Recent imaging studies have documented specific brain regions to be as sociated with a placebo response. A study (Lieberman, Jarcho, Berman, Naliboff, Suyenobu, Mandelkern, & Mayer, 2004) using Positron Emission tomography (PET) with patients with Irritable Bowel Syndrome (IBS) both before and after a 3 week placebo regimen found that increases in ventrolateral prefrontal cortex (RVLPFC) activity from pre placebo to post placebo predicted self reported symptom improvement. Another study (Wager, Rilling, Smith, Sokolik, Casey, Davidson, Kosslyn, Rose, & Cohen, 2004) examined placebo inducted changes durin g anticipation and experience of pain using functional magnetic resonance imaging (fMRI). The investigators found that placebo

PAGE 13

4 analgesia was related to decreased brain activity in pain sensitive brain regions including the thalamus, insula, and anterior ci ngulate cortex. During anticipation of pain, placebo analgesia was associated with increased activity in the prefrontal cortex. These studies provide not only important insights into the neural mechanisms of placebo analgesia, but also evidence that placeb os actually alter the experience of pain. The placebo response is an extremely complex phenomenon. For example, a placebo analgesic effect can be localized. In a study (Benedetti, Arduino, & Amanzio, 1999) when a placebo analgesic was applied to o ne index finger and pain stimulation was applied to both index fingers, the placebo response was localized to the finger on which the placebo had been applied. Also, participants receiving placebos can experience improvements in addition to undesirable sid e effects known as nocebos (Hahn, 1997) Placebos appear to show a dose response relationship of active agents, for instance, more frequent placebo administrat ion was related to a larger placebo response ( De Craen, Moerman, Heisterkamp, Tytgat, Tijssen, & Kleijnen, 1999) The same study found that placebo injections produce stronger effects than placebo capsules and pills (De Craen et al., 1999) These studies collectively demonstrate that placebos produce physiologic as well as psychological change s. The Placebo Effect Since Beecher (1955) reported that 35.2% of Participants were placebo responders, it has been assumed that there is a fixed fraction of placebo responders. Ho wever, his examination of 11 studies found large variations in the average number of placebo responders. This idea of placebo responders were assumed based on a comparison of group differences; however, the same differences could be a result of two scenari os: (1) all individuals in the placebo group exhibiting a moderate response or, (2) a relatively

PAGE 14

5 small subset of individuals exhibiting a large response (Hoffman et al., 2005) Therefore, it has been suggested that it is safer to assume that the fra ction varies from 0 to 100% (Benedetti & Amanzi o, 1997) Also, it appears that a given subject does not consistently show a placebo response in different situations (Liberman, 1964) Rather, placebo reactivity can be conceptualized as a potential tendency that can be activated under the right situation rather than as trait that only certain people possess (Liberman, 1964) After a survey of placebo literature, Wickramasekera (1985) concluded that (1) only a subset of patients show a significant therapeutic response to placebo substances and procedures in any given study, (2) we cannot identify these participants beforehand, (3) the same subset ma y not respond in subsequent administrations, (4) the right conditions for a response remains unknown. Although medicine has not always been interested in the placebo effect itself, it has managed to gather a lot of potentially valuable information through 50 years of clinical trials. However, much of the data are confounded by factors other than the placebo effect because of the lack of natural history conditions in most of these studies. The natural histories of pain and the psychological circumstances und er which placebo treatments are administered vary widely across different studies. A recent meta analysis of placebo controlled clinical trials attempted to assess the magnitude of the placebo effect despite these confounds (Hrobjartsson & Gotzsche, 2001) A total of 114 studies were examined and Hrobjartsson and Gotzsche (2001) were able to estimate the magnitude of the placebo effect. They concluded that these effects are less widespread and weaker than previously believed. Also, they only found a significant effect when studies wit h continuous data were examined versus those with dichotomous data. However, these

PAGE 15

6 results are a result of combining studies of 40 different conditions such as hypertension, alcohol abuse, anxiety, asthma, and martial discord. This assumes that placebos ar e effective across all of these different disorders, an assumption that is not held by placebo researchers (Stewart Williams & Podd, 2004) There is a major limitation with concluding that the magnitude of the placebo effect is small from the overall results of the Hrobja rtsson and Gotzche (2001) meta analysis. In the meta analysis, only the condition of pain had a large enough sample for separate anal ysis. In this condition, the researchers found a small but significant placebo effect. However, there were two major types of studies included in this study: those that were clinical and testing an active drug treatment and those studying actual placebo a nalgesic mechanisms. The mean effect size was 0.95 (Cohens d, a large effect) in the 14 studies of placebo mechanisms where strong suggestions for pain relief were typically given (Vase, Riley, & Price, 2002) Also, since Hrobjartsson and Gotzsches paper, several well controlled experimental studies about the placebo effect have been published. Stewart Williams and Podd (200 4) reviewed 16 studies and found that 14 demonstrated effect sizes equal or greater than 0.50 standard deviations, a medium effect size. The Vase et al. (2002) meta analysis demonstrated the importance of placebo mechanisms in the magnitude of placebo analgesia. While studies inducing placebo analgesia with conditioning or suggestion alone demonstrated eff ect sizes of 0.83 and 0.85 (Cohens d), respectively, the magnitude for studies using a combination of conditional and suggestion was 1.45, almost double that of either method alone. Mechanisms There are multiple theories regarding the mechanism of placeb o. The anxiety theory hypothesizes that the placebo response is due to a reduction of anxiety, which in

PAGE 16

7 turn is associated with a decrease in pain perception. However, this theory does not clarify whether this reduction in anxiety is the cause or consequen ce of the placebo response (Benedetti & Amanzio 1997) Two major theories of the placebo response are the conditioning and cognitive or expectancy theories. Conditioning The conditioning theory suggests that the placebo response represents a form a classical conditioning. According to this theory, b y pairing a neutral stimulus with a stimulus (US) that elicits an unconditioned response (UR), the neutral stimulus becomes a conditioned stimulus (CS) that can also elicit a response similar or related to the UR called the conditioned response (CR). There fore, stimuli such as a pill or a white lab coat (CS) that may be initially neutral with repeated association with an active drug or procedure (US) that elicits a specific response (UR) could elicit a response similar or related to the active drug or proce dure in the absence of this active drug or procedure (CR). Much of the research in support of the classical conditioning theory has been done on nonhuman animals such as dogs, rats and mice. However, a series of influential studies by Voudouris et al. (1985; 1989; 1990) showed that the placebo response can indeed be conditioned in humans. In their study, after an initial testing session, his participants were divided into two groups and a neutral c ream was applied to the skin of both of these groups (Voudouris et al., 1985) However, in one group, the level of no ciceptive stimulation was decreased with the administration of the placebo cream while the stimulation was increased in the second group. A final pain testing suggested that placebo responses could be conditioned in the laboratory in both positive and nega tive directions.

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8 Expectancy The expectancy theory is the second major theory. According to this theory, a placebo produces an effect because the recipient expects it to (Stewart Williams & Podd, 2004) In fact, classical conditioning itself may lead to the acquisition of expectancies (Price, 1999) However, expectati on can also reflect knowledge about the active agent, the circumstances around administration of the agent, and the condition the agent is treating (Price, 1999) This implies that expectancies can be formed before an initial exposure, contrary to the conditioning theory where an initial association n eeds to be formed with the active agent. The expectancy theory has a number of interesting implications. For example, drug advertising may lead to more powerful placebo effects. Another implication is that a drug simply treating the symptoms could treat th e underlying disease by affecting expectations that the treatment is working. Listing the possible side effects of a drug may increase the likelihood that patients will experience these effects. Finally, those with hypochondriacal tendencies are at increas ed risk of developing the physiological or psychological health problems they worry about (Stewart Williams & Podd, 2004) Ethics: Experimental Setting The ethics of placebo use has always been a controversial topic since discovery of the phenomena. The World Medical Associ ation rekindled the debate with the release of a revision of the Declaration of Helsinki in October 2000. Section 29 states The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, dia gnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists (Association, 2004)

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9 This section was particularly seen for its potential to cause substantial difficulties for fut ure development of medical products if it is literally interpreted and universally implemented (Lewis, Jonsson, Kreutz, Sampaio, & van Zwieten Boot, 2002) Section 29 was written for the highly admirable purpose of ensuring that patients ar e not exploited when they take part in clinical trials. This possibility is of particular concern for individuals from less developed countries who may be involved in research to benefit individuals in more developed countries (Lewis et al., 2002) However, the wording of Section 29 implies ruling out some crucial uses of placebo controlled trials in areas of medicine where proven prophylactic, diagnostic or therapeutic methods already exist, making no exceptions for possible benefits, adequa te patient consent, avoidance of irreversible harm and other precautions against ethically unacceptable consequences (Lewis et al., 2002) Since then, the Declaration of Helsinki has been clarified with a revision in 2004. The clarificatio n states a placebo controlled trial may be ethically acceptable, even if proven therapy is available, under the following circumstances: where for compelling and scientifically sound methodological reasons its use is necessary to determine the efficacy or safety of a prophylactic, diagnostic or therapeutic method; or where a prophylactic, diagnostic or therapeutic method is being investigated for a minor condition and the patients who receive placebo will not be subject to any additional risk of serious or irreversible harm (Association, 200 4) This recent clarification has also been criticized, particularly for the use of the word or linking the two situations. This could be interpreted as scientifically compelling reasons could be used to justify increased risk of serious harm through u se of placebo; therefore, perhaps the connector should be and not or (Carlson, Boyd, & Webb, 2004) Also, the use of the word, best current has been questioned since the best current may not be available in a local context (Carlson et al., 2004 ) In addition, the best current treatment

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10 for some conditions remains controversial without consensus among professionals. Moreover, while it is clear that for some serious conditions where there is often one opportunity for a cure where placebo contro ls need to be ruled out, there are other conditions where providing rescue or escape medications are acceptable with adequate patient awareness and consent (Carlson et al., 2004) Methodologically, the use of placebos is crucial. Researchers, particula rly with respect to pain treatment endeavor to determine the efficacy of a specific treatment and why patients improve with treatment (Turner et al., 1994) The randomized controlled trial is the closest that clinical research can get to the experimental situation (Stang, Hense, Jockel, Turner, & Tramer, 2005) The common argument against the use of placebo is that it is unnecessary, that new treatments should be tested against existing treatments (Stang et al., 2005) However, the real ity is that proven effective therapy is often assumed and fails to show superiority to placebo (Stang et al., 2005) Without a placebo arm, it would not be possible to make the crucial distinction that two drugs are equally ineffective rather than equally effective. The Vioxx Gastrointestinal Outcomes Research (VIGOR) provides a concrete example of another potential pitfall of not having a placebo control arm in a clinical study. The VIGOR trial showed a five fold difference in the incidence of myocardial infarction in the Vioxx (rofecoxib) group compared with t he naproxen group (Stang et al., 2005) Unfortunately, with out a placebo group, it remained unclear whether there was an increased risk of myocardial infarction with Vioxx or a decreased risk with naproxen (Stang et al., 2005) Four years later, after tens of millions of patients received Vioxx, Merck withdrew the drug from the market because of an increased cardiovascula r risk

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11 (Stang et al., 2005) The Declaration of Helsinki (2004) states, Medi cal research is only justified if there is reasonable likelihood that the populations in which the research is carried out stand to benefit from the results of the research. Stang et al. (2005) asserts, In this case, by trying very hard to be ethical and adhering too rigidly to the anti placebo d ogma, one can end up being unethical. It is clear that the use of placebo is a hotly contested topic. While there is much debate regarding the ethics of using placebos, it is clear that placebos serve an important function in research and the lack of a pl acebo control group can have detrimental effects as demonstrated in the Vioxx study. However, much of this debate revolves around the assumption that the placebo effect is somehow not real; that a placebo itself cannot effect true change. There is growing evidence this is not the case. As mentioned earlier, there is mounting evidence from imaging studies that placebos produce real physiologic as well as psychological changes, sometimes similar to that of active treatments. The question then remains, are pla cebos used in clinical settings and can or should placebos be used in clinical settings? Clinical Use of Placebo In 2000, the Sunday New York Times Magazine publicized in a cover article that the powerful placebo has come of age and suggested that medic ine should make regular use of it (Hoffman et al., 2005) Despite an upsurge of new research into placebo mechanisms and the use of placebos in clinical trials, much remains unknown, especially regarding use of the placebo in the clinical setting. H owever, a few researchers have attempted to explore this topic. A team of French researchers (Berthelot, Maugars, Abgrall, & Prost, 2001) interviewed 300 rheumatology inpatients and 100 nurses about t heir beliefs about the

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12 placebo effect. While all nurses interviewed reported knowing about the placebo effect, only 59% of patients reported knowing about the placebo effect. Regarding the characteristic of placebo responders, all nurses surveyed and 91% o f patients believed the placebo effect was dependent on patient personality, while only 63% of nurses and 38% of patients attributed the effect to the personality of the physician. Eighty three percent of patients and 62% of nurses believed that those who respond well to placebos are psychologically fragile. When asked about the use of placebos in clinical settings, 45% of patients and 66% of nurses reported that physicians should use placebos to treat their patients. Twenty seven percent of patients believ ed the physician should tell their patients while only 3% of nurses thought the same. Twenty eight percent of patients and 45% of nurses reported that they would agree to take a placebo. It is clear from these results that there is a wide range of knowledg e and beliefs about the placebo effect with a lot of ambivalence regarding the topic among patients and nurses (Berthelot et al., 2001) Focusing more on behaviors rather than beliefs, Nitzan and Licht enberg (2004) surveyed 89 nurses and physicians from different hospitals, departments and clinics around Israel about the use of placebos in their medical practice. The results were surprising. The authors had assu med that the use of placebo was not widespread and would not exceed 10%. However, they found that 60% admitted using a placebo (53% of doctors and 71% of nurses). No effects of sex or age were revealed. Thirty seven percent of those surveyed reported using a placebo as often as once a month or more. Of those who used a placebo, 94% reported that placebos were generally (33% of respondents) to occasionally (61% of respondents) effective. Also, 68% of those who used a placebo reported telling patients that th ey were receiving a real medicine, 17% reported saying

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13 nothing at all, and 11% reported telling the patients that they are receiving a non specific medicine. Only 5% responded that the use of placebos should be categorically prohibited while 75% attributed the effect to purely psychological mechanisms. The authors point out that the retrospective nature of the study may bias frequency estimations; however, the use of placebos or not in a clinical setting is not likely to be forgotten, suggesting that placeb os are indeed widely used in clinical practice. Proposed Study While the literature on the clinical use of placebos remains limited, it appears that healthcare professionals may routinely use placebos in medical settings. If this is the case, what are the implications of administering placebos to patients? How would people respond if they realized that they experienced a placebo response? It is possible that knowledge of personally experiencing a placebo response will detrimentally affect the future likel ihood of experiencing a placebo response. However, it is also possible that knowledge of personally experiencing a placebo response may enhance the future likelihood of experiencing a placebo response. The primary goal of this study is to test these compet ing hypotheses. Also, the role of expectation for pain and desire for pain relief will be examined in their ability to predict placebo responses. Next, the effect of knowledge of a personal placebo response on likelihood of participating in future studies and trust and likeability ratings of experimenters will be assessed. Lastly, we will investigate the relationship between somatization and placebo response.

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14 CHAPTER 2 MATERIALS AND METHOD Participants Seventy seven participants, 41 female and 36 male undergraduate students from the University of Florida, were recruited via flyers and the college undergraduate subject pool. Before starting, all participants com pleted a consent form, which explained the nature of the noxious stimulation. Those with heart conditions, hypertension, diabetes mellitus, asthma, seizures, frostbite, past trauma to hands, lupus erythematosus, arthritis or those on pain medication were e xcluded from the study. Participants were told that they could withdraw from the experiment at any time. Apparatus Medoc Thermal Sensory Analyzer All thermal stimuli were delivered using a computer controlled Medoc Thermal Sensory Analyzer (TSA 2001, Ramat Yishai, Israel), which is a peltier element based stimulator. The stimuli were a range of temperatures from an adapting temperature of 33 o C up to 51 o C. Stimuli were applied in a counterbalanced order to the forearm by a contact thermode and were 3 seconds in duration. Multiples sites located on the forearms of both arms were employed. Stimuli presentations were timed such that no site was stimulated with less than a 3 minute interval to avoid sensitization of the site. Mechanical Visual Analog Scale (VA S) Participants rated stimuli using a mechanical VAS anchored at the left end by no pain the right end by the most intense pain imaginable. This method of pain

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15 assessment has been shown to yield ratio scale measurement of clinical pain, which is both internally consistent and provides independent sensory intensity and affective dimensions of experimentally induced pain. Placebo Cream The placebo analgesic was in the form of a cream. A simple cold cream was mixed with linalol/oil of thyme in a ratio o f 8:1, which gave the cream a distinct smell. The cream was removed with cotton. The control cream was an 8:1 mixture of cold cream and water. Measures Demographics Questionnaire The demographics questionnaire provided information concerning the participa nts' sex, age, education, race, income, marital status, work status, occupation, height, weight, and pain conditions. Illness Attitude Scale (IAS) The IAS (Kellner, Abbott, Winslow, & Pathak, 1987) is a self report measure designed to measure psychopathology associated with hypochondriasis. The IAS consists of 9 a pr iori subscales: Worry about Illness, Concerns about Pain, Health Habits, Hypochondriacal Beliefs, Thanatophobia, Disease Phobia, Bodily Preoccupations, Treatment Experience, and Effects of Symptoms. There have been multiple attempts at analyzing the factor structure of the IAS using principal components analysis (Ferguson & Daniel, 1995) (Stewart & Watt, 2000) (Hadjistavropoulos & Asmundson, 1998) Hadjistavropoulos et al. (1999) conducted a exploratory and co nfirmatory factor analysis and found considerable support for four distinct factors (1) Fear of illness, disease, pain and death, (2) symptom effects, (3) treatment experience, and (4) disease conviction. The

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16 four factor structure was corroborated by Stewa rt et al. (2000) with a few changes and the factors were renamed fears, behavior, beliefs, and effects. Pennebacker Inventory of Limbic Languidity (PILL) The PILL is a self report measure of the occurrence and frequency of common physical symptoms and sensations. It consists of 54 items, such as coughing sneezing, racing heart, and headache. Response categories are: have never or almost never experienced the symptom, less than 3 or 4 times per year, every month or so, every week or so, and more than once every week, which are indicated by a five point Li kert scale. This measure asks for generally experienced symptoms over an unspecified time period in the past and assesses a general tendency to experience and report symptoms rather than the actual, everyday symptom experience (Gijsbers van Wijk, van Vliet, & Kolk, 1996) Thus, this trait like symptom scale is used to assess somatizat ion or a general tendency for reporting physical symptoms (Pennebaker, Hughes, & O'Heeron, 1987) When used with healthy participants, a high score is indicative of somatization. Internal consistency is high (Cronbachs alpha=0.91) (Gijsbers van Wijk et al., 1996) The PILL has sufficient test retest reliability (0.83) and was found to correlate moderately with comparable symptom scales (Pennebaker, Gonder Frederick, Stewart, Elfman, & Skelton, 1982) Visual Analogue Scales of Mood (VAS Mood) Mood was assessed with a mechanical VAS. The negative feelings associated with pain experience assessed were depression, anxiety, frustration, fear, and anger, with end points designated as none and as the most severe imaginable. Visual Analogue Scales (VAS) of pain have been demonstrated to be reliable, internally consistent measures of experimental pain sensation intensity (P rice, Bush, Long, & Harkins, 1994)

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17 Procedures All participants participated in four pain testing stages consecutively. Participants were divided into three groups: placebo informed, placebo uninformed and repe ated baseline conditions. Table 2 1 provid es a brief overview of the difference in procedures between the three groups. The repeated baseline group was informed that they would be tested using a control cream that does not contain any active agents. On the other hand, both the placebo uninformed a nd informed groups were told that we are testing the effects of an ointment on pain and given the suggestion of an active agent. Finally, the placebo informed group was told after the first placebo testing stage that the cream used was a placebo while the placebo uninformed group was not told that the first cream used was a placebo. The following paragraphs provide a more detailed description of each stage. Table 2 1. An overview of the study design Placebo Uninformed Placebo Informed Repeated Baseline Initial Information Told we are testing the e ffects of a cream on pain Told we will not be testing cream because they are in the control condition Questionnaire Same for all groups (counterbalanced) Calibration Trials Same for all groups ( t esting temperatures determined) Baseline Same 4 trials for all groups Conditioning 8 trials, 4 at placebo temp w/ cream, 4 at baseline temp Also 8 trials, but got placebo temp on all areas First Placebo Same 4 trials at Baseline Temp Information/ Graph Presentation Graph Shown and told that the cream worked as expected Graph Shown and told that they received a placebo and the difference in pain ratings demonstrates a placebo response Graph shown and told that it represents their pain ratings at 2 time points Second Placebo Same 4 trials at the baseline tempera ture Questionnaire Same for all groups (counterbalanced)

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18 Stage 1: Baseline During the first stage, each subject began with the following instructions: Af ter filling out several questionnaires about yourself, your attitudes and your mood, you will be asked to participate in four sensory testing sessions consecutively using a heat thermode where you will receive several brief heat pulses to different areas o n your forearms. These pulses will range from undetectable to painful. After the first three sessions, you will be provided with information about your responses during the previous trials. After the information is provided, you will then be asked to parti cipate in the last sensory testing session. After the last session, you will be asked to complete several additional questionnaires. Half of the participants were randomly assigned to complete a packet of questionnaires including a demographics questionnai re (which will ask for age, sex, education, marital status, ethnicity, occupation/area of study, socioeconomic status), IAS and PILL while the other half were asked to complete the questionnaire at the end of the study. Also, VAS Mood, likeability of exper imenters and trust of experimenters were assessed in all participants before beginning the pain trials. Next, calibration trials were conducted to control for individual differences in pain perception. An ascending series of trials starting from 43C incr easing by steps of 1C were completed. The participants rated the pain intensity immediately on a VAS following each trial. On a 0 10 scale, the temperatures at which the patient rated their pain intensity between 0 and 2 (placebo) and between 4 6 (control ) were noted. During the first stage after the calibration trials, each subject completed 4 pain trials at the control stimulus intensity to determine their baseline pain ratings. Stage 2: Conditioning and Suggestion In stage 2, the subject in the placebo informed and uninformed conditions were provided with instructions regarding the nature of the experiment. They were told, The

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19 agent you have just been given is known to significantly reduce pain in some patients". They were also informed that the level o f stimulation during this session would remain constant. On counterbalanced selected locations on the arm, each participant received 8 total pain trials, 4 with the placebo cream at the placebo temperature and 4 at the control temperatures (as determined d uring the calibration trials) without the placebo cream. Eight trials were used because repeated pairings are necessary for conditioning to occur. The intensity of the stimulus was surreptitiously lowered for the placebo cream to produce the conditioning e ffect. Participants assigned to the repeated baseline condition were told that they would not receive an active agent during their participation. They were given 8 total pain trials at the placebo temperature to prevent conditioning. Expected levels of pai n intensity, measured on the same scale that was used to rate experimental pain, was assessed from all groups before this session and pain intensity ratings were assessed after each pain trial. Stage 3: First Placebo Participants in the placebo informed an d uninformed groups were given 4 trials with the placebo cream. Pain intensity ratings were assessed after each pain trial. At the end of this stage, bar graphs of the pain responses were presented to the subject. In this graph, two bars represented the av erage pain ratings reported with the placebo cream and average ratings without. Those in the placebo informed group were told that they received a placebo cream and that the reduction in pain ratings with the placebo reflects their placebo response. Those in the placebo uninformed group were told that, as expected, the cream was successful in reducing their pain levels (or unsuccessful if a significant change was not

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20 observed). Those assigned to the repeated baseline condition were also provided with a gra ph of their pain ratings during the baseline and the first testing stage. Stage 4: Second Placebo Those in the placebo informed group were correctly told that they had received a placebo cream and would now receive the actual cream the study is testing. However, they again received the placebo cream. Those in the placebo uninformed group were told that the cream is being tested again, and again received the placebo cream. Those assigned to the repeated baseline condition were told that they would be test ed again with the control cream. All groups again participated in 4 trials. Pain intensity ratings were assessed after each pain trial. Mood, trust of experimenters, and likeability of experimenters were assessed from all groups. At the end of this stage, the actual purpose of the experiment was explained to the participants in a debriefing.

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21 CHAPTER 3 RESULTS Verification of the Placebo Effect The pain ratings from the repeated baseline group were compared to the pain ratings from the placebo informed and uninformed groups to verify that reductions in pain from the baseline to the first and se cond placebo testing were the result of the placebo manipulation and not simply habituation with time or repeated testing. To assess this possibility, the pain ratings from the placebo uninformed and informed groups were collapsed and compared with the pai n ratings from the repeated baseline group. A mixed model repeated measures ANOVA, with time as a within subject factor (3) and group as a between subject factor (2) was performed. Results indicated a significant main effect for group (F(1,75)= 565.957, p<0.001), and for time (F(2,150)=20.042, p<0.001), and a significant time (baseline, first testing, second testing) by group (placebo informed plus uninformed and repeated baseline) interaction (F(2, 150)=5.379, p=0.006). Decomposition of the interaction r evealed that the main effect for time was not significant for the repeated baseline group (F(2,32)=2.512, p>0.05, partial eta squared=0.136) whereas it was significant for the collapsed placebo informed and uninformed groups (F(2,118)=47.417, p<0.001, part ial eta squared=0.446), confirming that the change in pain ratings were, for the most part, the result of our manipulation. The effect size (Cohens d) for the change in pain ratings from the baseline to the first placebo was 0.99 for the collapsed placebo informed and uninformed group whereas it was 0.29 for the repeated baseline group. (Figure 3 1)

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22 Figure 3 1. Verification of the placebo effect. The level of a participants placebo response was calculated by subtracting their pain ratings at the first placebo testing from their pain ratings at baseline. Only those who demonstrated a placebo response (i.e., difference scores > 0) were included in the following analyses. Fifty participants out of the total 60 tested in the placebo informed and uninformed conditions fit this requirement. Pain Ratings We wanted to determine whether there was a difference in the placebo effect between the placebo informed and uninformed groups at the first placebo (after conditioning) and second placebo testing (after placebo response information presentation). A repeated measures mixed model ANOVA revealed a non significant group (placebo informed and uninformed) by time (baseline, first placebo, and second

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23 placebo) interaction (F(2,96)=0.218, p>0.05). Test of within subjects effects revealed a significant main effect across the three time points (F(2,96)=99.699, p<0.001). The pain ratings from baseline (M=5.253, SD=1.283) to first placebo (M=3.289, SD=1.297) decreased significantly (F(1,48) =135.136, p<0.001) whereas the rati ngs between first placebo and second placebo (M=3.600, SD=1.457) significantly increased (F(1,48)=7.643, p=0.008). The test of between subject effects showed that there was no significant overall difference between the two information groups (F(1,48)=0.528 p>0.05). (Figure 3 2) Figure 3 2. Pain ratings at baseline, time 1 and time 2 for the placebo informed and uninformed groups.

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24 Mood A series of mixed model ANOVAs was conducted to examine the time (pre and post) by group (placebo informed and uninformed ) interaction and main effects for group and time for mood. No significant interactions were found for depression, anxiety, frustration, anger, or fear. A test of within subjects effects revealed no significant changes for time in depression and anger from pre to post. However significant improvements (main effects for time) were found for anxiety, frustration, and fear. In addition, the main effects for group (placebo informed and uninformed) were not significant for depression (F(1,48)=0.052, p>0.05), anx iety (F(1,48)=0.415, p>0.05), frustration (F(1,48)=0.955, p>0.05), anger (F(1,48)=0.596, p>0.05), and fear (F(1,48)=0.799, p>0.05). These results show there were significant general improvements over time for anxiety, frustration and fear, but there were n o significant group differences for any of the mood variables. (Table 3 1) Table 3 1. Mood mixed model ANOVA results. Mood Time by condition interaction Pre post change (within subjects) Pre Post Pre post change (Cohens d) Depression F(1,48)=0.761 p>0.0 5 F(1,48)=0.322 p>0.05 M=0.733 SD=1.630 M=0.690 SD=1.559 0.027 Anxiety F(1,48)=0.501 p>0.05 F(1,48)=10.701 p=0.002* M=2.078 SD=2.293 M=1.514 SD=1.952 0.265 Frustration F(1,48)=0.076 p>0.05 F(1, 48)=6.693 P=0.013* M=1.696 SD=2.389 M=1.114 SD=1.917 0.26 9 Anger F(1,48)=0.006 p>0.05 F(1,48)=.896 p>0.05 M=0.783 SD=2.006 M=0.639 SD=1.732 0.077 Fear F(1,48)=1.667 p>0.05 F(1,48)= 8.194 p=0.006* M=0.997 SD=1.863 M=0.538 SD=1.463 0.274 Attitudes A series of mixed model ANOVAs were conducted to examine the ti me (pre and post) by group (placebo informed and uninformed) interaction and main effects for group

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25 and time for the different attitude variables (the participants likelihood of using medical treatments to treat pain, likelihood of using non medical treat ments to treat pain, likelihood of future participation in studies in general, likelihood of future participation in studies conducted in our lab, likeability of experimenters in general, likeability of experimenters in our lab, trust of experimenters in g eneral, and trust of experimenters in our lab). No significant time by group interactions were found for any of the attitude variables. Moreover, a test of within subjects effects revealed no significant main effects for time. Similarly, a test of between subjects effects found no main effects for group in the participants likelihood of using medical treatments to treat pain (F(1,48)=1.004, p>0.05), likelihood of using non medical treatments to treat (F(1,48)=1.758, p>0.05), likelihood of future participat ion in studies in general (F(1,48)=0.539, p>0.05), likelihood of future participation in studies conducted in our lab (F(1,48)=1.342, p>0.05), likeability of experimenters in general (F(1,48)=1.345, p>0.05), likeability of experimenters in our lab (F(1,48) =2.704, p>0.05), trust of experimenters in general (F(1,48)=1093, p>0.05), and trust of experimenters in our lab (F(1,48)=3.427, p=0.07). (Table 3 2) Table 3 2. Attitude mixed model ANOVA results. Variable Time by condition interaction Pre post change (w ithin subjects) Pre Post participants likelihood of using medical treatments to treat pain F(1,48)=0.423 p>0.05 F(1, 48)=0.929 p>0.05 M=3.907 SD=2.954 M=4.196 SD=2.826 likelihood of using non medical treatments to treat pain F(1,48)=1.357 p>0.05 F(1,4 8)=3.251 p>0.05 M=2.110 SD=2.881 M=2.528 SD=3.096 likelihood of future participation in studies in general F(1,48)=1.067 p>0.05 F(1,48)=0.371 p>0.05 M=6.450 SD=2.594 M=6.312 SD=2.588 likelihood of future participation in studies conducted in our lab F(1,48) 0.155 p>0.05 F(1,48)=1.897 p>0.05 M=5.641 SD=2.985 M=6.086 SD=2.922

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26 likeability of experimenters in general F(1,48)=0.403 p>0.05 F(1,48)=0.882 p>0.05 M=6.747 SD=2.226 M=6.926 SD=2.393 likeability of experimenters in our lab F(1,48)=0.003 p>0.05 F (1,48)=0.456 p>0.05 M=7.915 SD=1.889 M=7.721 SD=2.047 trust of experimenters in general F(1,48)=0.016 p>0.05 F(1,48)=.827 p>0.05 M=6.555 SD=2.400 M=6.367 SD=2.477 trust of experimenters in our lab F(1,48)=0.914 p>0.05 F(1,48)=2.213 p>0.05 M=7.752 SD=1. 941 M=7.472 SD=2.018 Expectation Expected pain levels were rated before the baseline, first test, and second test. A repeated measures mixed model ANOVA revealed a non significant group (placebo informed and uninformed) by time (baseline, before first pl acebo, and before second placebo) interaction (F(2,96)=2.273, p>0.05). The main effect for group was also not significant (F(1,48)=1.148, p>0.05). However, the main effect for time showed significant change over time (F(2,96)=88.626, p<0.001). Expectation for pain decreased significantly from baseline (M=4.866, SD=1.082) to the first placebo (M=2.376, SD=1.326; F(1,49)=144.855, p<0.001) and decreased significantly from baseline to the second placebo (M=2.804, SD=1.328; F(1,49)=136.710, p<0.001), but signifi cantly increased from the first placebo to the second placebo (F(1,49)=5.974, p=0.018). (Figure 3 3) Simple linear regressions were employed to determine whether changes in expected pain levels from baseline to the first placebo test and from baseline to t he second placebo test predicted the first or second placebo responses (baseline minus first placebo pain testing ratings) and second (baseline minus second placebo pain testing ratings) placebo response. Change in expected pain intensity from baseline to the first test (baseline expectation minus pre first test expectation) did not significantly predict the first placebo response (F(1,48)=2.659, p>0.05, r=0.052) or the second placebo response

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27 (F=(1,48)=2.732, p>0.05, r=0.026). However, change in expectat ion from baseline to the second test (baseline expectation minus pre second test expectation) did significantly predict the second placebo response (F(1,48)=6.098, p=0.017, std. beta=0.161, r=0.113), but not the first placebo response (F=(1,48), F=3.305, p>0.05, r=0.045). Figure 3 3. Expectation for pain ratings at baseline, pre first placebo and pre second placebo for the placebo informed and uninformed groups. Desire for Pain Relief Desire for pain relief was assessed at two time points. The first wa s just before the conditioning trials and the second was just after showing pre to post first placebo pain ratings to the participants and just prior to administering the second placebo. A mixed model ANOVA revealed a non significant group (placebo informe d and uninformed) by time (before conditioning, and before second placebo) interaction (F(1,47)=1.074,

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28 p>0.05). Additionally, the main effect for group was also not significant (F(1,47)=0.634, p>0.05). However, there was a significant main effect for time (F(1,47)=7.652, p=0.008) from pre conditioning (M=5.9776, SD=2.670) to pre second testing (M=5.259, SD=2.989). (Figure 3 4) Simple linear regressions were employed to determine whether the change in desire predicted the first (baseline minus first placebo pain testing ratings) and second (baseline minus second placebo pain testing ratings) placebo responses. The change in desire significantly predicted the first (F(1,47)=6.791, p=0.012, std. beta=0.355, r=0.126) and second (F(1,47)=9.168, p=0.004, std. bet a=0.404, r=0.163) placebo response. Figure 3 4. Desire for pain relief at pre conditioning and pre second placebo for the placebo informed and uninformed groups.

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29 Expectation and Desire Interaction To predict the first placebo effect, the change in expe ctation and desire from pre conditioning to just prior to the 2 nd placebo were entered together in the first step of a hierarchical regression. In the first model, both changes in expected pain intensities (t=2.233, std. beta=0.260, p=0.030) and desire (t= 3.436, std. beta=0.400, p=0.001) significantly predicted the first placebo effect both independently and together (F(2,56)=17.826, p<.001, r=0.264). When the expectation and desire interaction (i.e., product) was added in the final model of the hierarchic al regression, the interaction was not significant (t= 0.365, std. beta= 0.045, p>0.05); however, the complete model (F(3,55)=11.965, p=0.001, r=0.265) and both expectation (t=2.238, std. beta=0.263, p=0.029) and desire (t=3.358, std. beta=0.414, p=0.001 ) remained significant. Predicting the second placebo effect, again the change in expectation and desire from pre conditioning to the 2 nd placebo were entered together in the first step of a hierarchical regression. In the first model, both changes in expe ctation (t=2.847, std. beta=0.320, p=0.006) and desire (t=3.598, std. beta=0.405, p=0.001) significantly predicted the first placebo effect both independently and together (F(2,56)=17.212, p<0.001, r=0.312). When the expectation and desire interaction was added in the final model of the hierarchical regression, the interaction was not significant (t= 0.609, std. beta= 0.072, p>0.05); however, the complete model (F(3,55)=11.645, p<0.001, r=0.316) and both expectation (t=2.871, std. beta=0.326, p=0.006) and desire (t=3.593, std. beta=0.427, p=0.001) remained significant. Somatization Two measures of somatization were administered, the PILL and the IAS. The total scores of the measures were found to be significantly correlated (r=0.392, p=0.007) with

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30 each ot her. The PILL (F(1,46)=4.215, p=0.046) was predictive of a participants first placebo response explaining 8.4% of the variance. However, the PILL was not predictive of a participants second placebo response (F(1,46)=3.671, p>0.05) when entered in a regre ssion. The IAS total score was not predictive of a participants first (F(1,48)=0.758, p>0.05) or second (F(1,48)=0.161, p>0.05) placebo response. Given the multifactorial nature of the IAS, the 4 factors proposed by Stewart et al. (2000) were independently entered in a regression. The factors fear (F(1,48 )=0.708, p>0.05), behavior (F(1,48)=0.284, p>0.05), beliefs (F(1,48)=1.480, p>0.05) and effects (F(1,48)=1.119, p>0.05) did not significantly predict a participants first placebo response. In addition, fear (F(1,48)=1.119), p>0.05), behavior (F=1,48)=3.32 8, p>0.05), beliefs (F(1,48)=0.766, p>0.05) and effects (F(1,48)=0.444, p>0.05) did not significantly predict a participants second placebo response. Sex Differences A 2x2 ANOVA was used to analyze whether there were any significant differences between me n and women in their ability to get a first or second placebo response. The interaction between sex and information condition (F(1,46)=0.119, p>0.05) in the participants ability to get a first placebo response was not significant. Additionally, there was neither a main effect for sex (F(1,46)=0.779, p>0.05) nor information group (F(1,46)=0.411, p>0.05). Similarly, the interaction between sex and information condition in the participants ability to get a second placebo response was also non significant (F( 1,46)=0.134, p>0.05). Also, the main effects for sex (F(1,46)=1.499, p>0.05) and information condition (F(1,46)=0.428, p>0.05) were both not significant.

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31 CHAPTER 4 DISCUSSION The ethics of placebo use has been debated since discovery of the phenomena. Under the heading, No place for placebos when treating pain, Dr. Sullivan (2004) wrote, this deception of the patient is damaging and unjustified. Alternatively, Dr. Oh (1994) concludes, in appropriate patients, doctors migh t consider giving a placebo when active treatment is both costly and likely to confer only marginal or transient benefit. While neither extreme may be the answer, this debate has persisted without a good understanding of the result of placebo use. There h as yet to be a study that examines the aftereffect of individuals discovering that they experienced a placebo response on their future ability to experience a placebo response. The main goal of this study was to explore the effect of such information on pa in response. We discovered that there was no difference in future pain responding between participants who were told that they experienced a placebo response versus those who were not. Interestingly, the placebo effect persisted when a second placebo crea m was applied even after participants were told that the first cream used in the study was a placebo. Although the strength of that second placebo was slightly reduced, approximately 84% of the original placebo effect remained. Next, we wanted to explore t he effect of feedback of personal placebo information on mood. A previous pilot study (Chung, Price, Verne, Perlstein, Craggs, & Robinson, 2006) found no detrimental effects when information was revealed to patients with irritable bowel syndrome about their pain reduction from a placebo. We replicated this finding in

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32 a more general population. This study corroborated that revelatio n of an individuals placebo response does not appear to cause adverse effects on mood. While we found no change in depression and anger; curiously, we found that participants anxiety, frustration and fear improved at the end of the study regardless of th e information provided during the study. Since there were no differences between the two information groups, it is possible the improvement is a result of repeated testing or related to the participants reaction to simply completing the study. If the impr ovements were related to procedures or information provided in the study, the exact nature and mechanism remains unknown. Nevertheless, the lack of worsening mood is notable. Similar to mood, attitudes about the likelihood of using medical and non medical treatments for pain, likelihood of participating in future studies, likeability of experimenters and trust of experimenters were assessed both before and after the study. Despite the level of deception involved in participating in the placebo information c ondition, there were no differences between the placebo informed and uninformed groups in their attitudes. This suggests that participants may not change their attitudes about pain treatment, research participation or feelings toward experimenters after pa rticipating in a study involving placebo use with experimental pain. Moreover, attitudes seem unaffected by learning that the pain reduction reflected a placebo response. Given that previous mood, attitudes, and pain responding do not appear to be affected by placebo information, what role does expectation and desire for pain relief have on the placebo effect in the context of providing personal placebo information? Similar to the findings regarding pain ratings, there were no differences between the two in formation groups in their expected pain intensities. The change in expected pain

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33 intensities from baseline to the first test was not related to the first or second placebo response. However, the change in expectation from baseline to the second test was si gnificantly predictive of the second placebo response, but not the first placebo response. Examining the concept of desire, similar to expectation, there were no differences between the two groups in their desire for pain relief. However, the change in de sire for pain relief from before the conditioning session did significantly predict a participants first and second placebo response. In addition, the interaction between desire and expectation did not significantly predict the first or second placebo eff ect. Previous studies have suggested that desire for pain relief may be more of a factor in clinical pain where pain is threatening or has uncertain duration. Furthermore, Price et al. (Price, Milling, Kirsch, Duff, Montgomery, & Nicholls, 1999) found that expectation for pain but not desire was associated with the magnitude of placebo analgesia. However, although our study was conducted in an experimental setting where the participants were informed about the number of pain testing stages (potentially increasing predictability), d esire was a more consistent predictor of the placebo response than expectation. It will be important to further explore the relationship between expectation, desire and pain responding in future studies. Next, we examined the role of personal characteristi cs, somatization and sex, in participants placebo responses and maintaining those the response after feedback about their placebo responses. Two measures of somatization, the PILL and the IAS were used to examine this relationship. While the IAS was not s ignificantly predictive of placebo responding at any level, the PILL did predict participants first placebo responses, but not the second placebo responses. We can speculate why the two measures may have

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34 produced different results. The IAS is a face valid measure that asks about worries, behaviors and beliefs about illnesses. On the other hand, the PILL is a symptom checklist that asks participants about their experience with various symptoms. While it is assumed that the PILL measures an element of somati c focus, exactly what the questionnaire measures remains unknown. The PILL may be measuring something more than somatization (such as anxiety) that enhanced its sensitivity to predict placebo responders. Further studies are needed to explore the relationsh ip between PILL and the ability to experience a placebo response. Finally, we examined sex differences in the ability to experience a placebo response. We found no differences between men and womens first or the second placebo response. These results sug gest that characteristics such as somatic focus may be related to a participants placebo response, but we found no evidence of any differences in placebo responding or the effect of placebo response information between the sexes. Conclusions and Future Di rections. The lack of differences in pain responding and in worsening mood has noteworthy implications for future placebo studies. These results suggest that placebo use in experimental settings may not result in detrimental effects. While our study demons trated that a double placebo design is feasible to examine the role of a placebo use on a second placebo administration, we do not know if our findings will generalize to clinical setting. Future studies should examine the effect of placebo use with clinic al populations. Furthermore, we found that the placebo effect significantly decreased during the second placebo administration regardless of the assigned information condition. The reason for this is unclear. One possibility is that any information decreas es the placebo effect. It is also possible that with time, the placebo

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35 effect will be reduced. If so, it would be important to explore the rate of decay and the variables related to this decay. Such information may assist in the development of protocols th at maximizes the magnitude and longevity of placebo effects.

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36 LIST OF REFERENCES Association, W. M. (2004). World Medical Association declaration of Helsinki: Ethical priciples for medical research involving human subjects Retrieved June 4, 2005, from http://www.wma.net/e/policy/b3.html Beecher, H. K. (1955). The powerful placebo. Journal of American Medical Association, 159 (17), 1602 1606. Benedetti, F., & Amanzio, M. (1997). The neurobiology of placebo analgesia: from endogenous opioids to cholecystokinin. Progress in Neurobiology, 51 109 125. Benedetti, F., Arduino, C., & Amanzio, M. (1999). Somatotopic activation of opioid systems by target directed expectations of analgesia. Journal of Neuroscience, 19 (9), 3639 3648. Berthelot, J. M., Maugars, Y., Abgrall, M., & Prost, A. (2001). Interindividual variations in beliefs about the placebo effect: a study in 300 rheumatology inpatients and 100 nurses. Joint Bone Spine, 68 (1), 65 70. Carlson, R. V., Boyd, K. M., & Webb, D. J. (2004). The rev ision of the Declaration of Helsinki: Past, present and future. British Journal of Clinical Pharmacology, 57 (6), 695 713. Chung, S. K., Price, D. D., Verne, G. N., Perlstein, W., Craggs, J., & Robinson, M. E. (2006). Post placebo effects in IBS pateints: Does knowledge of a personal past placebo response affect mood and/or attitudes about pain? The Journal of Pain, 7 (4 2), S76. De Craen, A. J., Moerman, D. E., Heisterkamp, S. H., Tytgat, G. N., Tijssen, J. G., & Kleijnen, J. (1999). Placebo effect in the treatment of duodenal ulcer. British Journal of Clinical Pharmacology, 48 (6), 853 860. Ferguson, E., & Daniel, E. (1995). The Illness Attitudes Scale (IAS): a psychometric evaluation on a nonclinical population. Personality and Individual Differences, 18 463 469. Gijsbers van Wijk, C. M., van Vliet, K. P., & Kolk, A. M. (1996). Gender perspectives and quality of care: towards appropriate and adequate health care for women. Soc ial Sci ence and Med icine 43 (5), 707 720.

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37 Hadjistavropoulos, H. D., & Asmundson, G. J. (1998). Factor analytic investigation of the Illness Attitudes Scale in a chronic pain sample. Behavior Research and Therapy, 36 (12), 1185 1195. Hadjistavropoulos, H. D., Frombach, I. K., & Asmundson, G. J. (1999). Exploratory and confirmatory factor analytic in vestigations of the Illness Attitudes Scale in a nonclinical sample. Behaviour Research and Therapy, 37 (7), 671 684. Hahn, R. A. (1997). The nocebo phenomenon: concept, evidence, and implications for public health. Preventive Medicine, 26 (5 Pt 1), 607 611 Harrington, A. (2000, November). "Seeing" the placebo effect: Historical legacies and present opportunities. Paper presented at the science of placebo: towards an interdisciplinary research agenda, Bethesda. Hoffman, G. A., Harrington, A., & Fields H. L. (2005). Pain and the placebo: what we have learned. Perspectives in Biology and Medicine, 48 (2), 248 265. Hrobjartsson, A., & Gotzsche, P. C. (2001). Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. New England Journal of Medicine, 344 (21), 1594 1602. Kellner, R., Abbott, P., Winslow, W. W., & Pathak, D. (1987). Fears, beliefs, and attitudes in DSM III hypochondriasis. J ournal of Nerv ous and Ment al Di s ease 175 (1), 20 25. Lewis, J. A., Jonsson, B., Kreutz, G., Sampaio, C., & van Zwieten Boot, B. (2002). Placebo controlled trials and the Declaration of Helsinki. Lancet, 359 (9314), 1337 1340. Liberman, R. (1964). An e xperimental s tudy of the p lacebo r esponse under t hree d ifferent s ituations of p ain. Journal of Psychiatric Res earch, 33 233 246. Lieberman, M. D., Jarcho, J. M., Berman, S., Naliboff, B. D., Suyenobu, B. Y., Mandelkern, M., et al. (2004). The neural correlates of placebo effects: a disruption account. Neuroimage, 22 (1), 447 455. Nitzan, U., & Lichtenberg, P. (2 004). Questionnaire survey on use of placebo. British Medical Journal, 329 (7472), 944 946. Oh, V. M. S. (1994). The placebo effect: can we use it better? British Medical Journal (309), 69 70. Pennebaker, J. W., Gonder Frederick, L., Stewart, H., Elfman, L ., & Skelton, J. A. (1982). Physical symptoms associated with blood pressure. Psychophysiology, 19 (2), 201 210.

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38 Pennebaker, J. W., Hughes, C. F., & O'Heeron, R. C. (1987). The psychophysiology of confession: linking inhibitory and psychosomatic processes. J ournal of Pers onality and Soc ial Psychol ogy 52 (4), 781 793. Price, D. D. (1999). Placebo Analgesia. In Psychological mechanisms of pain and analgesia (Vol. 15, pp. 155 181). Seattle: IASP Press. Price, D. D., Bush, F. M., Long, S., & Harkins, S. W. (1994). A comparison of pain measurement characteristics of mechanical visual analogue and simple numerical rating scales. Pain, 56 (2), 217 226. Price, D. D., Milling, L. S., Kirsch, I., Duff, A., Montgomery, G. H., & Nicholls, S. S. (1999). An analysis of factors that contribute to the magnitude of placebo analgesia in an experimental paradigm. Pain, 83 (2), 147 156. Stang, A., Hense, H. W., Jockel, K. H., Turner, E. H., & Tramer, M. R. (2005). Is i t a lways u nethical to u se a p lacebo in a c linical t rial? Plos Medicine, 2 (3), 72. St ewart, S. H., & Watt, M. C. (2000). Illness Attitudes Scale dimensions and their associations with anxiety related constructs in a nonclinical sample. Behav iour Res earch and Ther apy 38 (1), 83 99. Stewart Williams, S., & Podd, J. (2004). The placebo effect: dissolving th e expectancy versus conditioning debate. Psychological Bulletin, 130 (2), 324 340. Sullivan, M., Paice, J. A., & Benedetti, F. (2004). Placebos and treatment of pain. Pain Medicine, 5 (3), 325 328. Turner, J. A., Deyo, R. A., Loeser, J. D., Von Korff, M., & Fordyce, W. E. (1994). The importance of placebo effects in pain treatment and research. Journal of American Medical Association, 271 (20), 1609 1614. Vase, L., Riley, J. L., 3rd, & Price, D. D. (2002). A comparison of placebo effects in clinical analges ic trials versus studies of placebo analgesia. Pain, 99 (3), 443 452. Voudouris, N. J., Peck, C. L., & Coleman, G. (1985). Conditioned placebo responses. Journal of Personality and Social Psychology, 48 (1), 47 53. Voudouris, N. J., Peck, C. L., & Coleman, G. (1989). Conditioned response models of placebo phenomena: further support. Pain, 38 (1), 109 116. Voudouris, N. J., Peck, C. L., & Coleman, G. (1990). The role of conditioning and verbal expectancy in the placebo response. Pain, 43 (1), 121 128.

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39 Wager, T. D., Rilling, J. K., Smith, E. E., Sokolik, A., Casey, K. L., Davidson, R. J., et al. (2004). Placebo induced changes in FMRI in the anticipation and experience of pain. Science, 303 (5661), 1162 1167. Wickramasekera, I. (1985). A conditioned response m odel of the placebo effect: predictions of the model. In L. White, B. Tursky & G. E. Schwartz (Eds.), Placebo: t heory, research and mechanisms (pp. 255 287). New York: Guilford Press.

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40 BIOGRAPHICAL SKETCH S. Karen Chung graduated from the University of California, Los Angeles, in June 2002 with a Bachelor of Science degree in psychobiology. In May 2004, she received a masters degree in psychology at the Department of Clinical and Health Psychology at the University of Florida. Her clinical and research interests are in the area of clinical and health psychology and include psychosocial and cognitive influences on responses to pain and illness


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