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Placebo Acceptability in Patients with Chronic Musculoskeletal Pain

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Title:
Placebo Acceptability in Patients with Chronic Musculoskeletal Pain The Effects of a Mechanism-Based Educational Intervention
Creator:
Kisaalita, Nkaku R
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[Gainesville, Fla.]
Florida
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University of Florida
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english
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Thesis/Dissertation Information

Degree:
Doctorate ( Ph.D.)
Degree Grantor:
University of Florida
Degree Disciplines:
Psychology
Clinical and Health Psychology
Committee Chair:
ROBINSON,MIKE E
Committee Co-Chair:
MCCRAE,CHRISTINA SMITH
Committee Members:
DOTSON,VONETTA M
GEORGE,STEVEN
Graduation Date:
8/9/2014

Subjects

Subjects / Keywords:
Analgesia ( jstor )
Analgesics ( jstor )
Chronic pain ( jstor )
Conceptualization ( jstor )
Opioid analgesics ( jstor )
Pain ( jstor )
Pedagogy ( jstor )
Physicians ( jstor )
Placebo effect ( jstor )
Placebos ( jstor )
Clinical and Health Psychology -- Dissertations, Academic -- UF
acceptability -- educational-intervention -- ethics -- pain -- placebo -- placebo-acceptability -- placebo-analgesia -- placebo-education -- placebo-treatment
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bibliography ( marcgt )
theses ( marcgt )
government publication (state, provincial, terriorial, dependent) ( marcgt )
born-digital ( sobekcm )
Electronic Thesis or Dissertation
Psychology thesis, Ph.D.

Notes

Abstract:
Placebo analgesia effects have been shown to be clinically meaningful, with well-defined psychoneurobiological underpinnings. Evidence suggests that current empirical placebo conceptualizations - those emphasizing known mechanisms and the role of contextual factors in treatment efficacy - have largely failed to disseminate to the lay public. Nevertheless, the high frequency of placebo use among healthcare providers is well documented. The acceptability of interventional placebo use remains a divisive issue among researchers, clinicians, and ethicists, with placebo use opponents often touting the presumed negative consequences of deception as the primary deterrent. This is contrasted by recent evidence suggesting that both deceptive and non-deceptive placebos may be acceptable under certain circumstances. The present investigation sought to expand upon the placebo acceptability literature by examining the following among musculoskeletal pain patients: 1) the effects of deception and treatment efficacy on the presumed negative consequences of placebo use; and 2) the impact of mechanism-based placebo education on aspects of treatment acceptability. Fifty-seven musculoskeletal pain patients completed a web-based survey assessing placebo knowledge, acceptability, and effectiveness, as well as examining healthcare provider attributions (i.e., deceptiveness, trust) and patient mood across different treatment scenarios. Patients completed the survey twice in a pre-post intervention design; between competing the first and second survey, roughly half the sample received a brief placebo educational intervention, with the other half receiving a control educational prompt. The results illustrated that perceptions of placebo acceptability were highly context dependent, as patients found placebo treatments more satisfactory when no other known options were available, when explicitly used, and when used as an adjunct/complementary treatment. The findings demonstrated that brief placebo education greatly improved perceptions of placebo knowledge, effectiveness, and acceptability, even in highly deceptive treatment contexts. These results confirmed that patients did perceive placebo treatments as deceptive when not explicitly stated; while patients also experienced greater negative mood and distrust in these scenarios, these factors were mitigated by beneficial treatment outcomes. Together, these findings underscore the significant role of contextual factors in influencing musculoskeletal patients' appraisals of placebo, and demonstrate the powerful impact of mechanism-based education and treatment efficacy in enhancing placebo acceptability. ( en )
General Note:
In the series University of Florida Digital Collections.
General Note:
Includes vita.
Bibliography:
Includes bibliographical references.
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Description based on online resource; title from PDF title page.
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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.
Thesis:
Thesis (Ph.D.)--University of Florida, 2014.
Local:
Adviser: ROBINSON,MIKE E.
Local:
Co-adviser: MCCRAE,CHRISTINA SMITH.
Electronic Access:
RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2016-08-31
Statement of Responsibility:
by Nkaku R Kisaalita.

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Source Institution:
UFRGP
Rights Management:
Applicable rights reserved.
Embargo Date:
8/31/2016
Classification:
LD1780 2014 ( lcc )

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1 PLACEBO ACCEPTABILITY IN PATIENTS WITH CHRONIC MUSCULOSKELETAL PAIN: THE EFFECTS OF A MECHANISM BASED EDUCATIONAL INTERVENTION By NKAKU ROBERT KISAALITA 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 2014

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2 © 2014 Nkaku Robert Kisaalita

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3 To my father, William, for instilling in me a love of science and helping the underserved, and to my wonderful mother, Rose, who has always inspire d me with her heart, her work ethic, and her unwavering dedication to our family.

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4 ACKNOWLE DGMENTS I am extremely grateful for the support and mentorship of my committee chair, Dr. Michael Robinson, for his constant patience, guidance, and encouragement. I would also like to thank my dissertation committee Dr. Steven George, Dr. Christina McCrae, and Dr. Vonetta Dotson for their constructive feedback and advice throughout this process. I am equally indebted to Drs. Roland Staud and Robert Hurley, as well as the many generous participants that I recruited from their respective clinics. I would like to extend a special thanks to Shankar Manamalkav for his invaluable technical expertise in designing the web based study . Finally, I would like to express my sincerest gratitude to all my colleagues, friends, and family members who have steadfastly supported me throughout this incredible journey; none of this would have been possible without their help.

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 4 LIST OF TABLES ................................ ................................ ................................ ............ 7 LIST OF FIGURES ................................ ................................ ................................ .......... 8 ABSTRACT ................................ ................................ ................................ ................... 10 Chapter 1 INTRODUCTION ................................ ................................ ................................ .... 12 History of Placebo ................................ ................................ ................................ ... 14 Conceptualizing and Defining Placebo ................................ ................................ ... 15 Placebo Mechanisms ................................ ................................ .............................. 16 Psychological Mechanisms ................................ ................................ .............. 18 Neurobiological Mechanisms ................................ ................................ ............ 20 Placebo Acceptability ................................ ................................ .............................. 21 Decept ion ................................ ................................ ................................ ......... 21 Placebo Use among Healthcare Providers ................................ ....................... 23 Research on Placebo Ethics ................................ ................................ ............ 23 Placebo Analgesia Acceptability Studies ................................ .......................... 24 Educational Interventions for Chronic Pain Patients ................................ ............... 26 Study Rationale ................................ ................................ ................................ ...... 27 Study Aims ................................ ................................ ................................ .............. 28 Hypotheses ................................ ................................ ................................ ............. 2 8 2 METHODS ................................ ................................ ................................ .............. 29 Participants ................................ ................................ ................................ ............. 29 Procedure ................................ ................................ ................................ ............... 29 Measures ................................ ................................ ................................ ................ 30 Demographic Questionnaire ................................ ................................ ............. 30 Pa in Assessment Questionnaire ................................ ................................ ...... 30 Placebo Education Intervention and Control Group ................................ ......... 30 Placebo Knowledge Survey: Knowledge, Effectiveness, and Acceptability ...... 31 Treatment Vignettes Survey: Deception, Trust in Physician, and Negative Mood ................................ ................................ ................................ ............. 32 Statistical Analyses ................................ ................................ ................................ . 33 Sample S ize ................................ ................................ ................................ ..... 33 Descriptive Statistics ................................ ................................ ........................ 34 Placebo Knowledge, Conceptualization, and Effectiveness ............................. 34 Placebo Acceptability ................................ ................................ ....................... 34 Deception, Trust in Physician, and Negative Mood ................................ .......... 34

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6 3 RESULTS ................................ ................................ ................................ ............... 36 Participants ................................ ................................ ................................ ............. 36 Demographic Information ................................ ................................ ................. 36 Chro nic Pain Information ................................ ................................ .................. 36 Pretest Survey Results ................................ ................................ ........................... 37 Placebo Acceptability ................................ ................................ ....................... 37 Deception, Trust, and Negative Mood ................................ .............................. 37 Posttest Survey Results ................................ ................................ .......................... 38 Treatment Groups ................................ ................................ ............................ 38 Placebo Knowledge, Conceptualization, and Effectiveness ............................. 38 Placebo Acceptability ................................ ................................ ....................... 39 Deception ................................ ................................ ................................ ......... 39 Trust in Healthcar e Provider ................................ ................................ ............. 39 Negative Mood ................................ ................................ ................................ . 39 4 DISCUSSION ................................ ................................ ................................ ......... 61 LIST OF REFERENCES ................................ ................................ ............................... 70 BIOGRAPHIC AL SKETCH ................................ ................................ ............................ 79

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7 LIST OF TABLES Table page 3 1 Participant demographics and chronic pain characteristics ................................ .... 41 3 2 Pretest placebo knowledge and effectiveness ................................ ....................... 43 3 3 Pretest placebo acceptability ................................ ................................ ................. 44 3 4 Pretest deception (VAS 0 100: not at all deceptive; most deceptive imaginable) ................................ ................................ ................................ ......... 45 3 5 Pretest trust (VAS 0 100: no trust; most trust imaginable) ................................ ... 46 3 6 Pretest negative mood (VAS 0 100: no negative mood; most negative mood imaginable) ................................ ................................ ................................ ......... 47 3 7 Pretest acceptability one factor ANOVA ................................ ................................ 48 3 9 Posttest ratings for total sample, control group, and intervention group ................. 50 3 10 Posttest placebo knowledge, conceptualization, and effectiveness univariate ANOVAs ................................ ................................ ................................ ............. 51 3 11 Posttest placebo acceptability mixed model (6 x 2) ANOVA ................................ 52 3 12 Posttest deception, trust, and negative mood mixed model (2 x 3 x 2) ANOVAs ................................ ................................ ................................ ............. 53

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8 LIST OF FIGURES Figure page 2 1 Flow chart of stud y experimental design ................................ ............................ 35 3 1 Pretest deceptiveness ratings by treatment instructions and treatment outcome. * = significant main effect ( p < .05); error bars are 95% confidence intervals. ................................ ................................ ................................ ............. 54 3 2 Pretest trust in physician ratings by treatment instructions and treatment outcome. * = significant main effect ( p < .05); error bars are 95% confidence intervals. ................................ ................................ ................................ ............. 55 3 3 Pretest negative mood ratings by treatment instructions and treatment outcome. * = significant main effect ( p p < .05); error bars are 95% confidence intervals. ................................ .................... 56 3 4 Posttest deceptiveness ratings by educational interventions, treatment instructions, and treatment outcome. * = significant main effect ( p < .05); error bars are 95% confidence intervals. ................................ ............................ 57 3 5 Posttest trust ratings by educational intervention, treatment instructions, and treatment outcome. * = significant main effect ( p < .05); error bars are 95% confidence intervals. ................................ ................................ ........................... 58 3 6 Posttest negative mood ratings by educational intervention, treatment instructions, and treatment outcome. * = significant main effect ( p < .05); error bars are 95% confidence intervals. ................................ ............................ 59 3 7 The ef fect of the placebo educational intervention on placebo acceptability contexts ratings. * = significant main effect ( p < .05); error bars are 95% confidence intervals. ................................ ................................ ........................... 60

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9 LIST OF ABBREVIATIONS ANOVA Analysis of variance CCK C holecystokinin CR Conditioned response CS Conditioned stimulus EBT Evidence based/established treatments ES Effect size F F statistic IASP International Association for the Study of Pain IBS Irritable bowel syndrome LBP Low back pain M Mean n Sample size 2 Partial eta squared NS Neutral stimulus p The probability, if the test statistic really were distributed as it would be under the null hypothesis, of observing a test statistic [as extreme as, or more extreme than] the one actually observed RA Random assignment RCT Randomized controlled trial SD Standard deviation TMJ Temporomandibular joint disorder Tx Treatment US Unconditioned stimulus UR Unconditioned response VAS Visual analog ue scale

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10 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 PLACEBO ACCEPTABILITY IN PATIENTS WITH CHRONIC MUSCULOSKELET AL PAIN: THE EFFECTS OF A MECHANISM BASED EDUCATIONAL INTERVENTION By Nkaku Robert Kisaalita August 2014 Chair: Michael Robinson Major: Psychology Placebo analgesia effects have been shown to be clinically meaningful, with well defined psychoneurobiological underpinnings. Evidence suggests that current empirical placebo conceptualizations those emphasizing known mechanisms and the role of contextual factors in treatment efficacy have largely failed to disseminate to the lay public. N evertheless, the high frequency of placebo use among healthcare providers is well documented. The acceptability of interventional placebo use remains a divisive issue among researchers, clinicians, and ethicists, with placebo use opponents often touting th e presumed negative consequences of deception as the primary deterrent. This is contrasted by recent evidence suggesting that both deceptive and non deceptive placebos may be acceptable under certain circumstances. The present investigation sought to expan d upon the placebo acceptability literature by examining the following among musculoskeletal pain patients: 1) the effects of deception and treatment efficacy on the presumed negative consequences of placebo use; and 2) the impact of mechanism based placeb o education on aspects of treatment acceptability.

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11 Fifty seven musculoskeletal pain patients completed a web based survey assessing placebo knowledge, acceptability, and effectiveness, as well as examining healthcare provider attributions (i.e., deceptiv eness , trust) and patient mood across different treatment scenarios. Patients completed the survey twice in a pre post intervention design; between competing the first and second survey, roughly half the sample received a brief placebo educational interven tion, with the other half receiving a control educational prompt. The results illustrated that perceptions of placebo acceptability were highly context dependent, as patients found placebo treatments more satisfactory when no other known options were avai lable, when explicitly used, and when used as an adjunct/complementary treatment. The findings demonstrated that brief placebo education greatly improved perceptions of placebo knowledge, effectiveness, and acceptability, even in highly deceptive treatment contexts. These results confirmed that patients did perceive placebo treatments as deceptive when not explicitly stated; w hile patients also experienced greater negative mood and distrust in these scenarios, these factors were mitigated by beneficial trea tment outcomes. Together, these findings underscore the significant role of contextual factors in infl uencing musculoskeletal patient s appraisals of placebo, and demonstrate the powerful impact of mechanism based education and treatment efficacy in enhan cing placebo acceptability.

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12 CHAPTER 1 INTRODUCTION The International Association for the Study of Pain (IASP) defines pain as an sue ( Turk & Me lzack, 2011 ) . As illustrated by the IASP definition, pain is multifaceted, with sensory, cognitive, social and affective factors contributing to and influencing its presentation. The complexity of this experience is reflected in the challenges and costs of adequately managing pain. Although pain is necessary for survival, it also exerts an immense burden on our society, is the number one reason patients seek medical care, and is estimated to costs over 100 billion dollars annually ( Hing, Cherry, & Woodwell, 2006 ; Turk & Melzack, 2011 ) . Research illustrates that a fourth of the US population suffers from chronic and/or recurrent pain, and for nearly half of these individuals, this experience has a moderately or severely debilitatin g impact on their quality of life ( Turk & Robinson, 2011 ) . Musculoskeletal pain, defined as pain affecting the muscles, ligaments and tendons, and bones, is considered the most common causes of pain related disease burden in both developed and undeveloped countries ( Brooks, 2005 ) . Chronic musculoskeletal pain conditions such as low back pain (LBP) and osteoarthritis are a major contributor to disability adjusted life years and associated medical costs ( Brooks, 2006 ) . Osteo arthritis is a significant cause of functional impairments and has been estimated to affect as many as 40% of adults over the age of 65 ( Hitzeman & Athale, 2010 ; Zhang, et al., 2007 ) . LBP is highly prevalent in the United States ,

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13 particularly among the elderly, as an estimated 70 80% of adults will experience significant LBP at some point in their lives ( Andersson, 1999 ; Freburger, et al., 2009 ) . With the high prevalence of musculoskeletal chronic pain conditions in the United States, the use of pharmaco logical pain interventions has seen a dramatic rise as new pain relieving drugs are manufactured at increasing rates ( Parsells Kelly, et al., 2008 ) . In concordance with this trend, there has been a rise in analgesic prescribing practices among healthcare providers, specifically increases i n opioid analgesics for chronic pain ( Gilson, Ryan, Joranson, & Dahl, 2004 ; Katz, et al., 2010 ) . Despite the growing availability of narcotics and other pain relieving medications, chronic pain continues to exert a tremendous burden on society. Whereas the efficacy of opioid analgesics for the treatment of malignant pain and acute pain states is wid ely recognized, the efficacy of long term opioid use for the management of chronic, noncancerous pain remains equivocal ( Chou, 2009 ; Manchikanti, Benyamin, Datta, Vallejo, & Smith, 2010 ; Noble, et al., 2010 ; Trescot, et al., 2008 ) . Empirical evidence has demonstrated that placebo and its related effects can act as active, potent pain relievers. Research has shown that the mechanisms underlying placebo effects are components of virtually all treatments, and thus, likely contribute to the efficacy of all active interventions for pain ( F.G. Miller, Wendler, & Swartzman, 2005 ) . The uses of complementary and alternative treatments for pain, many of which derive their efficacy primarily from placebo factors ( Linde, et al., 2007 ; van Tuld er, Furlan, & Gagnier, 2005 ; White, et al., 2012 ) , have shown dramatic increases in ( Astin, 1998 ; Eisenberg, et al., 1998 ; Eisenberg, et al., 1993 ; Jonas, 1998 ) . Despite scientific evidenc e highlighting both the frequency of use and

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14 efficacy of placebo treatments ( Margrit Fassler, Meissner, Schneider, & Linde, 2010 ; D.D. Price, Finniss, & Benedetti, 2008 ) , direct application of placebo medicine has sparked heated debate and controversy. In order to truly assess the ethics of placebo interventions for chronic pain, it is important to recognize the history that has shaped lay conceptualizations of placebo , understand the psychological and neurobiological mechanisms underlying placebo analgesia, and ultimately, directly investigate the acceptability of placebo analgesic treatments for those suffering from chronic pain. History of Placebo Despite recent adva nces in understanding placebo mechanisms and effects, contemporary use of the word frequently conjures confusion and controversy similar to person future indicative of translating the H ( Aronson, 1999 ) . In the 13 th century, this mistranslation was used by vespers of the mourners of the dead in the hopes of being rewarded by the relatives of the decreased. In this manner, they were referred to as placebos to describe their fake behavior ( Finniss, Kaptchuk, Miller, & Benedetti, 2010 ) . It is unknown exactly when and how the term placebo came to refer to the ( McQuay & Moore, 2005 ) . The u se of placebo comparisons/controls was first introduced in the 16 th century as a means for the Catholic Church to discredit right wing exorcisms. This concept was

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15 later applied to medical experiments in the late 18 th century, at which point the term came t o signify the innocuous use of an inert substance to make a patient feel comfortable ( Finniss, et al., 2010 ) . Prior to World War II, paternalistic ethics were common place in medicine, an ( Kaptchuk, 1998 ) . Generally value of the mind. It was not until after World War II, with the induction of randomized controlled trials, that placebo gained mainstream attention with the publication of Henry Be analysis in 1955 ( Beecher, 1955 ) , which proc laimed that over one third of patients responded positively to placebo treatments. Although Beecher failed to account for several confounding factors in his analysis (e.g., disease natural history, regression to the mean), the impact of his findings contin ue to resonate today. It is thus largely from randomized controlled trial design considered the gold standard for evaluating treatment efficacy that placebo conceptualizations have arisen; namely, that while a placebo is capable of producing a therapeu tic effect, this evaluated. Conceptualizing and Defining Placebo Confusion regarding the definition of a placebo relates to how this term is conceptualized. The protot ypical placebo encounter occurs in a medical environment where a physician gives a patient a pill that, unbeknownst to the patient, is a sugar pill; if that they were administered a pharmacological agent with efficacy for treating their

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16 ailment ( Stewart Williams & Podd, 2004 ) . Within research settings, the response seen in an individual following placebo admin istration is referred to as a placebo response; the response of a population to placebo administration represents the group effect, or placebo effect ( D.D. Price, et al., 2008 ) . In summary, a placebo is commonly referred to as an inert procedure or substance and the placebo response (or effect) is what follows its administration ( Finniss, et al., 2010 ) . This co nceptualization is problematic due its paradoxical logic, as something inert, by definition, cannot exert an effect. To better conceptualize placebo effects in clinical practice and randomized trials, the focus has shifted from the inert contents of the pl acebo to what the intervention is doing to the patient. Thus, the placebo effect is often defined as the psychosocial context of an ( D.D. Price, et al., 2008 ) . In this sense, an attempt has been made to shift the focus of placebo from the contents of treatment to the therapeutic context of the encounter the interaction of situational, patient, and clinician factors. Although se veral authors have in the scientific literature to change at this time ( Finniss, et al., 2010 ) . Further contributing to confusion is the reality that placebo does not reflect a single unitary concept, as studies have shown that there are not one, but many placebo effec ts, with different psychological and neurobiological mechanisms and effects dependent on the context of administration and its intended use. Placebo Mechanisms Much of what we know about placebo comes from the scientific study of placebo for pain relief, as the placebo analgesic response remains one of the best understood

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17 models of placebo ( Colloca, Klinger, Flor, & Bingel, 2013 ; D.D. Price, et al., 2008 ) . Extensive research has illustrated that placebo analgesic effects are real, with fMRI studies illustrating that placebo effects correspond to decreased activity in pain related areas of the brain ( Donald D . Price, Craggs, Nicholas Verne, Perlstein, & Robinson, 2007 ) . Areas of the descending pain modulatory system involved in placebo analgesia include the dorsolateral prefrontal cortex, anterior cingulate cortex, hypothalamus, periaqueductal grey, amygdal a, thalamus, insula, and somatosensory cortex ( Colloca, et al., 2013 ) . Along with cortical and subcortical areas, functional neuroimaging studies have implicated placebo analgesic effects at t he level of the spinal cord the earliest stage of the central nervous system ( Eippert, Finsterbusch, Bingel, & Büchel, 2009 ) . Clinically meaningful placebo analgesic effects have been seen for both experimentally induced pain ( Amanzio & Benedetti, 1999 ; Benedetti, Pollo, & Colloca, 2007 ) and clinical pain ( Levine, Gordon, Smith, & Fields, 1981 ; L. Vase, Petersen, Riley, & Price, 2009 ; Lene Vase, Robinson, Verne, & Price, 2003 , 2005 ) . Although there is variability in placebo effect sizes for pain, placebo mechanisms studies, where placebo factors are systematically controlled to enhance efficacy, have demonstrated experimentally and clinically meaningful e ffect sizes ( L. Vase, et al., 2009 ; Lene Vase, Riley, & Price, 2002 ) . Studies have shown that placebo analgesic effects can be indistinguisha ble from those of active pain relieving agents ( Levine, et al., 1981 ; Lene Vase, et al., 2005 ) . The magnitude of analgesia of known placebo responders can be considerably high ( D.D. Price, et al., 2008 ) , with one study showing that the averag e placebo analgesic response corresponded to a 5 point reduction on 10 point pain numerical rating scale (NRS) ( Benedetti, 1996 ) .

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18 Psy chological Mechanisms There are several well established psychological mechanisms underlying placebo effects for pain, including observational learning ( Colloca & Benedetti, 2009 ) , personality factors ( Jaksi c, Aukst Margetic, & Jakovljevic, 2013 ) , reductions in negative emotion, memory, motivation, and somatic focus ( Finniss, et al., 2010 ; D.D. Price, et al., 2008 ) . Research has shown that the two most promin ent psychological mechanisms are expectancy and classical conditioning ( Enck, Bingel, Schedlowski, & Rief, 2013 ) . Al though historically these approaches have been treated as competing perspectives, new research suggests that both conscious and unconscious learning processes often mediate one another and play important roles in generating placebo analgesic effects. Expec tancy theory refers to the fact that patients who are administered placebos Thus, placebos can be viewed as expectancy manipulations ( Stewart Williams & Podd, 2004 ) . Expectation is often manipulated through use of verbal cues. For example, a Expectation may also be enhanced through use of a conditioning procedure in which participa nts learn to associate a placebo application with decreased pain intensity ( Montgomery & Kirsch, 1997 ) . Expectancy manipulations have been shown to consistently mediate placebo analgesi c responses for reductions of experimental and clinical pain. The impact of expectancy manipulation on the analgesic response has been readily demonstrated in hidden open administrations of opioids; several studies ration of an opioid, by which the patient is aware they are receiving an analgesic treatment, is significantly more effective than

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19 hidden opioid administration, because in the latter the placebo expectancy component is omitted ( Benedetti, Maggi, et al., 2003 ; Colloca, Lopiano, Lanotte, & Benedetti, 2004 ) . The second major psychological mechanism underlying placebo effects is classical conditioning. Historically, this has been characteri zed as follows: when pairing of a neutral stimulus (NS) with a unconditioned stimulus (US) capable of eliciting at unconditioned response (UR), the neutral stimulus in time becomes a conditioned stimulus (CS), whereby it has the ability to illicit a respon se similar to that of the US, subsequently referred to as a conditioned response (CR) ( Stewart Williams & Podd, 2004 ) . Classically conditioned placebo effects can be seen in animals ( A mit & Galina, 1988 ; Watkins, Cobelli, & Mayer, 1981 ) , such that when opioid administration is repeatedly paired with a neutral stimulus, eventually the neutral stimulus alone will elicit an analgesic response ( Bardo & Valone, 1994 ; Bryant, et al., 2009 ; Valone, Randall, Kraemer, & Bardo, 1998 ) . Although the majority of the research supporting classically conditioned placebo effects has occurred within non human animals, it is assumed that the same principles a pply to placebo effects in humans ( Stewart Williams & Podd, 2004 ) . Although there is some evidence that placebo analgesic effects following a classical conditioning paradigm may be primarily media ted by conscious expectation ( Benedetti, Pollo, et al., 2003 ) , these findings do not negat e classical conditioning as a prominent mechanism, particularly when moving beyond outdated conceptualizations of classical conditioning as a simplistic, automatic non cognitive process ( Rescorla, 1988 ) . dependent on the success of the first encounter; in other words, the greater the

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20 expectations, the stronger the placebo effec t, and possibly the more robust the future ( Finniss, et al., 2010 ) . Neurobiological Mechanisms The neurobiology of placebo analgesia is generally divided i nto opioid and non opioid pain modulatory mechanisms. Placebo analgesia has been shown to be completely to partially reversible by the opioid antagonist naloxone, indicating that opioid neurotransmitters play a prominent role in the effect when placebo is induced by open hidden paradigms, classical conditioning, and verbal suggestion ( Amanzio, Pollo, Maggi, & Benedetti, 2001 ; D.D. Price, et al., 2008 ) . Convergent evidence was found by Lipman et al., illustrating that chronic pain patients who were placebo responders had higher concentrations of endorphins in their cerebral spinal fluid than patients who were place bo non responders ( Lipman, et al., 1990 ) . Depending on how a patient is conditioned, a placebo response may not be completely naloxzone reversible, suggesting that other non opioid mechanisms, such a s other neurotransmitters, may also play a role. For example, in one study where placebo analgesia was conditioned by the non opioid ketoralac, the placebo response was insensitive to naloxzone ( Amanzio & Bene detti, 1999 ) . In another study, placebo responses in irritable bowel syndrome (IBS) patients were found to be opioid insensitive, indicating the presence of non opioid pain modulatory system ( Lene Vase, et al., 2005 ) . Recent evidence suggests that other endogenous neuromodulators may play a role in placebo analgesia. Alterations in the dopaminergic system associated with motivation and reward behavior are associated with changes in endogenous opioidergic activity ( Scott Dj, 2008 ; Scott, et al., 2007 ) . There is also evidence that the endogenous cannabinoid system is implicated in non opioid conditioned analgesic responses

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21 ( Benedetti, Amanzio, Ro sato, & Blanchard, 2011 ) . Finally, expectation induced hyperalgeisic responses referred to as the nocebo effect have been shown to be mediated by the peptide hormone cholecystokinin (CCK) ( Benedetti, Amanzio, Casadio, Oliaro, & Maggi, 1997 ; Benedetti, Amanzio, Vighetti, & Asteggiano, 2006 ) . Placebo Acceptability Despite considerable advances in our understanding of the biopsychosocial mechanisms underlying placebo analgesia, debate persists regarding the ethics of interventional placebo use. Whereas the eth ics of placebo use in randomized controlled trials have been well established ( Emanuel & Miller, 2001 ; Kovach, 2002 ; F.G. Miller, 2011 ) , the placebo treatment discussion continues to incite disagreement among ethicists, researchers, and clinicians ( Cahana & Romagnioli, 2007 ) . While placebo use opponents have cited several arguments against their use, including that placebo administration may cause psychological harm and violate the physician patient relationship ( Cupples & Myron, 1985 ) , the crux of the debate centers on decep tion and the assumed negative consequences of deceptive administration ( F.G. Miller, et al., 2005 ) . Deception To date, the majority of the literature on placebo ethics and deception has been based on philosophical tenants, with relatively few data driven investigations. It is likely that, historically, impressions on the negative consequences deception stemmed fro m ( Milgram, 1963 ) . Although undoubtedly a significant addition to the social sciences literature o

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22 finding were exaggerated; in fact there were relatively few long term negative consequences of deception in these experiments ( Herrera, 2001 ) . Perceptions of the negative consequences of deception hinges largely on the philosophical stance one adher es to. If one adopts a moral absolutist stance, whereby the morality of an action is based purely on its adherence to a universal principle, then there may be no circumstances by which deceptive means are deemed acceptable ( Wendler & Miller, 2011 ) . Conversely, if one adopts a consequentialist moral stance, whereby the cost of deception is measured against the consequences and possibly benefits of the act, then it is ethically feasible that there could be circumstanc es by which the use of deception is acceptable ( Wendler & Miller, 2011 ) . Empirical evidence coincides with the latter stance, as research has shown that there are a number of conditions by which the use of deceptio n may be deemed acceptable. Several studies have shown that while research subjects often have complex reasoning behind their moral judgments, they generally find deceptive studies meaningful and within their moral values when the ends of the research is j ustified by the means of deception ( Fisher & Fyrberg, 1994 ; Korn, 1987 ) . The acceptability of deception has also been investigated in clinical settings. In a study by Flemings and colleagues ( Fleming, Ba, Barry, & Fost, 1989 ) , patients in a substance abuse clinic completed an alcohol use questionnaire disguised as a general health questionnaire. When the purpose of the questionnaire was revealed to the patients, nearly two thirds of the participants supported its use and would participate in similar studies in future. Even amongst those who felt that they should be fully informed,

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23 the majority stated that they would be willing to complete the disguised questionnaire in the future. Placebo Use among Healthcare Providers There appears to be a marked discrepancy between the state of placebo ethics and current interventional placebo use. The placebo acceptability debate is further complicated by evidence illustrating that physicians and other healthcare providers prescribe and adm inister placebo treatments ( Margrit Fassler, Gnadinger, Rosemann, & Biller Andorno, 2009 ; M. Fassler, Gnadinger, Rosemann, & Biller Andorno, 2011 ; Hrobjartsson & Norup, 2003 ) . One survey study repor ted that over 50% o f surveyed ( Tilburt, Emanuel, Kaptchuk, Curlin, & Miller, 2008 ) . Another survey found that placebo use was widespread among German general practitioners, with over 75% reporting to have used a placebo treatment within a year of survey completion ( Meissner, Höfner, Fässler, & Linde, 2012 ) . Research on Placebo Ethics Placebo analgesia studies, typically involving a degree of deception in placebo induction, present an ideal model for examining pla cebo ethics and acceptability. One study found that among both IBS patients and non chronic pain patients, the placebo effects caused no negative effects on mood or magnitude of subsequent placebo responses even after the use of placebo was revealed to par ticipants ( S. Karen Ch ung, Donald D. Price, G. Nicholas Verne, & Michael E. Robinson, 2007 ) . Another placebo investigation in healthy controls found no difference in the magnitude of either placebo analgesia or mood between two groups differentiated by whether or not they we re informed of potential deception upon study inclusion ( Martin & Katz, 2010 ) . In another

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24 study, a placebo survey was adm inistered to over 200 general practice patients in New Zealand. Results revealed that most patients were amenable to placebo use despite the use of deceptive means and lack of informed consent ( Chen & Johnson, 2009 ) . There is evidence suggesting that patients may find the explicit use of placebo treatments acceptable. Kaptchuk and colleagues ( Kaptchuk, et al., 2010 ) conducted a three week open labeled randomized control trial of a placebo treatment for patients suffering from IBS. In this study, pati ents were either explicitly told that they would receive a placebo intervention or be randomized to a no treatment control group. The treatment group was people can re 3) positive thinking helps, but is not necessary for the effect; and 4) taking the treatment as prescribed is paramount. The non deceptive placebo was not only acceptable to patient s, but also produced significantly higher global IBS improvement scores at study conclusion, indicating large and clinically meaningful reduction in disease symptom severity. Placebo Analgesia Acceptability Studies Studies from our research group have fur ther clarified the placebo ethics debate. Recently, a web based placebo survey was conducted with a non chronic pain patient sample to assess attitudes regarding the acceptability of interventional placebo use ( Kisaalita, Roditi, & Robinson, 2011 ) . Participants viewed 18 vignettes of a pain patient visiting their physician for pain management. The vignettes systematically varied the progressive pain), the deceptiveness of the placebo instructions (i.e., highly deceptive placebo, moderate deception/enhanced placebo, and non deceptive placebo/random treatment

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25 assignment), and the outcome of the treatment (i.e., pain improved, remained the same, or worsened). After viewing a vignette, participants responded to questions regarding the deceptiveness of the scenario, the impact of placebo use on their relationship with their healt hcare provider, and the effect of the intervention on aspects of patient negative mood. Results illustrated that, while participants overall found placebo interventions deceptive, their perceptions of placebo analgesia treatments were equally dependent on the outcome of the treatment. Furthermore, results suggested that a considerable degree of negative consequences and deceptiveness could be tolerated in ebo. Participants perceived the enhanced placebo instructions, considered by several researchers to be ethically permissible ( Donald D. Price, et a l., 2007 ; D.D. Price, et al., 2008 ) , as highly deceptive, suggesting that lay individual may have a rudimentary understanding of plac ebo mechanisms and effects. Our research team followed up the previously mentioned survey with a broader, more descriptive survey examining placebo conceptualizations, perceived knowledge, acceptably, perceived efficacy of reducing pain, knowledge of anal gesic placebos among different healthcare providers, and the sequelae of placebo analgesia on aspects of patient provider relations and patient mood (Kisaalita & Robinson, 2012). The f indings illustrated that participants conceptualized placebo as primaril sugars pills, saline injections) and were unsure regarding their efficacy for reducing pain. Our findings confirmed that, in concordance with results of other published studies ( Asai, et al., 2004 ; Chen & Johnson, 2009 ) not reflect contemporary conceptualizations of placebo mechanisms. Furthermore, we

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26 found that a beneficial treatment response may mitigate the ne gative consequences of placebo administration, a finding that coincides with our prior research ( Kisaalita, et al., 2011 ) . Educational Interventions for Chronic Pain Patients labeled RCT illustrated how the manner in which a patient is educated about placebo and its related mechanisms may play an important role in both treatment effectiveness and acceptabilit y ( Kaptchuk, et al., 2010 ) . While some level of disease/treatment education is considered beneficial in virtually all pain related physician patient encounters ( Burton, Waddell, Tillotson, & Su mmerton, 1999 ) , empirical evidence of the efficacy of educational interventions for chronic pain is somewhat inconsistent ( Louw, Diener, Butler, & Puentedura, 2011 ) . A meta analysis of individual educational interventions demonstrated that intensive education (e.g., 2.5 hours of oral information) was more effective in reducing short and long term disability for patients wit h sub acute low back pain; however, for chronic pain patients, individual education was generally less effective than more intensive treatment (e.g., chiropractic manipulation) for back specific functions ( Engers Arn o, et al., 2008 ) . It should be noted that many of these interventions were aimed at changing behaviors related to a specific disease state (e.g., education to promote behavioral activation) rather than information about the mechanisms of a certain treat ment. Main and colleagues note that, while realistic limitations exist, patient education as a treatment modality can be effective in reducing pain related disability ( Main & Burton, 2012 ) . They further note that the optimal educational intervention for LBP should be delivered within a biopsychosocial framework with a focus on central pain mechanisms. This claim is supported by a recent

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27 pain, disability, and mood in patients with musculoskeletal pain ( Louw, et al., 2011 ) . There is ample evidence that educational interventions can improve negative pain related beliefs as well. For example , one RCT illustrated that that a psychosocial educational program for LBP had a positive influence on pain beliefs in a primary prevention military setting ( George, et al., 2009 ) . To date, no published study has systematically examined placebo analgesia acceptability in a musculoskele tal pain population, nor has any study explored the effects of an ultra brief online educational intervention (i.e. less than 5 minutes) on patient perceptions of treatment ethics. Study Rationale While considerable advances have been made over the past 10 years in understanding placebo ethics, many crucial questions remain. The purpose of the present study is to address the following questions regarding placebo analgesia acceptability: 1) what do chronic pain patients know about placebo analgesia; 2) doe s knowledge of placebo impact acceptability and perceptions of treatment efficacy; 3) and what role does deception and treatment effectiveness play in perceptions of treatment acceptability? Addressing these questions is imperative for several reasons. Fi rst, the results will present an invaluable addition to the limited literature on placebo analgesia treatment acceptability. To our knowledge, no study has systematically examined placebo analgesia knowledge, acceptability, and perceived efficacy in chroni c pain patients. Although our research group has thoroughly examined placebo analgesia acceptability in healthy controls ( Kisaalita & Robinson, 2012 ; Kisaalita, et al., 2011 ) , it is also important to examine this concept in the targeted clinical population chronic pain patients. Secondly, this study will assess the potential impact of a brief ed ucational

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28 intervention on perceptions of placebo acceptability. As studies have shown that both patients and lay individuals have limited understandings of placebo mechanisms, the present investigation will determine whether an increased understanding of p lacebo the proposed study will investigate the relationship between deception, treatment outcomes, and placebo acceptability. Although it is commonly assumed that dec eption is a prerequisite for placebo effects, recent evidence suggests that non deceptive placebo treatments may be feasible and effective ( Kaptchuk, et al., 2010 ) . Research of an acceptable placebo trea tment, particularly if patients experience a beneficial treatment response ( Kisaalita, et al., 2011 ) . Study Aims The specific aims for the proposal are as follows: 1. To investigate the influence of deception and placebo effectiveness on the negative consequences and acceptability of placebo. 2. To examine whether an educational intervention will influence aspects of placebo acceptability, knowledge, and the negative consequences of placebo. Hypotheses The following hypotheses are based on the above aims: 3. Placebo treatments that are explicit and effective for alleviating pain will be perceived as less deceptive, and patients will experience less negative mood and endorse more trust in their prescribing physicians following treatment administration. 4. Patients receiving the educational intervention will endorse more knowledge of placebo and rate placebo treatments as more acceptable and effective for alleviating pain. Additionally, these patie nts will rate placebo interventions as less deceptive, and will report experiencing less negative mood and greater trust in their physicians following treatment administration.

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29 CHAPTER 2 METHODS Participants Patients suffering from chronic musculoskel etal pain were recruited for this study. Inclusion criteria were as follows: 1) adults age 18 years or older, 2) the ability to read English fluently, 3) the presence of musculoskeletal chronic pain that has lasted at least three months, 4) and internet ac cess to complete the web based study. Exclusion criteria included the following: diagnosis of cancer or any other non musculoskeletal chronic pain etiology (e.g., neuropathic pain). Participants were financially compensated for their participation. Proced ure The web based study was advertised on flyers posted in medical clinics in Shands Hospitals and the surrounding Gainesville Florida community. Interested participants contacted the study coordinator via email or telephone. Study eligibility was confirme d through reading of a screening script. Once enrolled, participants were randomized to either the educational intervention or control group an d provided the study website and a unique username/password to login. Informed consent was obtained electronical ly. After filling out demographic and chronic pain assessment questionnaires, the remainder of the online study constituted a pre post treatment design (Figure 2 1 ). Both groups completed two survey sections twice: the Placebo Knowledge survey and the Trea tment Vignettes survey. Prior to the retest, the treatment group was given the placebo analgesia educational intervention while the control group received information about musculoskeletal pain.

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30 Measures Demographic Questionnaire Demographic information was obtained, including gender, race, marital status, education, and employment. Pain Assessment Questionnaire Patients were asked if they had any of the following diagnoses associated with their chronic pain: fibromyalgia, low ba ck pain, irritable bowel syndrome, osteoarthritis, they believe were associated with their chronic pain. Location of chronic pain was assessed by using a previously devel oped pain site checklist rating the presence or absence of pain in across 17 different bodily regions ( Jensen, Hoffman, & Cardenas, 2005 ) . The majority of these sites could then be collapses on to seven site categories reported the length of time they had been experiencing chronic pain and documented the t reatment modalities they were currently utilizing (i.e., over the counter medication, prescription medication, and complementary and alternative treatments). Placebo Education Intervention and Control Group Half of the patient sample was randomized to rec eive either a placebo analgesia educational intervention or general information about musculoskeletal pain. The educational intervention was a brief, five slide prompt highlighting the following points regarding placebo: 1) efficacy for reducing pain; 2) n eurobiological mechanisms of pain

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31 mechanisms of pain relief (i.e., expectation an d classical conditioning); and 4) data illustrating that healthcare providers often prescribe treatments that rely on placebo mechanisms for efficacy. Each educational point was linked to a relevant empirical citation for additional reference. To highlig ht the psychological mechanisms of classical conditioning, an example of a Pavlovian conditioned hunger response was described and related to a classically conditioned analgesic response. The control condition was comparable in length to the treatment int ervention and included information about the following: 1) the prevalence of pain in the United States; 2) the economic costs of pain; 3) gender and age differences in musculoskeletal pain; and 4) risk factors for the development of musculoskeletal pain. Placebo Knowledge Survey: Knowledge, Effectiveness, and Acceptability The Placebo Knowledge survey represented an abbreviated version of a previously published placebo analgesia web based survey ( Kisaalita & Robinson, 2012 ) . The survey consisted of Visual Analogue Scale (VAS) ratings of the following: 1) conceptualization and perceived knowledge of placebo analgesia, 2) perceived placebo analgesia treatment effectiveness, and 3) placebo analgesia treatment acceptability. Patients were a sked to rate their knowledge of placebo analgesia and how they primary outcome, was evaluated through the following six VAS questions: how acceptable would it be if a physician 1) overtly or 2) covertly administered a placebo treatment for pain; 3) how acceptable woul d it be if a physician used a placebo as an adjunct treatment or treatment enhancer; is it acceptable for a medical practitioner to

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32 treat pain with placebo for a condition for which there 4) are other established treatments or 5) for a condition in which t here are no other established treatments; and Treatment Vignettes Survey: Deception, Trust in Physician, and Negative Mood The negative consequences of placebo treatment administration were investigated in the Treatment Vignettes a revised version of a previously published placebo survey ( Kisaalita, et al., 2011 ) . The survey was comprised of six different hypothetical scenarios , each portraying a clinical encounter in which a patient sees a physician for pain management and subsequently receives a placebo. Our sample of chronic pain individuals was asked to review each hypothetical scenario and to respond as if they were the individual receiving the placebo intervention. After viewing each scenario , our participants responded by rating the deceptiveness of the hypothetical clinical encounter/placebo intervention , their level of trust in the prescribing physician, and the amount of negative mood they woul d experience if they had received the placebo treatment for their pain. Two factors varied per scenario: 1) the health care provider s description of the placebo intervention and 2) the outcome/effectiveness of the treatment. Two distinct treatment descriptions were intended to be experimental manipulations of scenarios, the hypothetical patient in been s , the patient in the scenario was informed that they will receive either

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33 acceptable description of a placebo treatment, more recent evidence has shown that it perceived as hig hly deceptive ( Kisaalita, et al., 2011 ) . There were three levels for treatment effectiveness/outcome: upon completion of the treatment, our sample of chronic pain individuals read that the placebo intervention either worsened, had no e ffect, or improved the pain of the patient depicted in the scenario. Statistical Analyses Sample Size Power analyses were performed to determine the numbe r of participants needed to detect sizable effects using the Placebo Knowledge and Treatment Vignettes measures as primary outcomes. Due to the various analyses conducted for the original publications of these surveys, several methods were used to estimate the necessary sample size. Based upon repeated measures analyses of variance (ANOVA) partial eta squared main effect sizes for deception (.69 and .09) trust in physician (.50 and .46), and negative mood (.43 and .60), and a negative mood interaction effec t size (.08) ( Kisaalita, et al., 2011 ) , it was estimated that a sample size of 42 patients would be sufficient to detect Treatment Vignettes effects at alpha level 0.05 and power 0.80. Based upon repeated measures ANOVA effects sizes for placebo acceptability contexts (.22, .09, .35 and .28) and one d effect sizes (.74, .74 and .68) ( Ki saalita & Robinson, 2012 ) , it was estimated that a sample size of 21 patients would be sufficient to detect Placebo Knowledge effects at alpha level 0.05 and power 0.80. The final sample size is based on the most conservative value needed to optimally p ower the study, plus 20 percent more patients to buffer for

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34 potential participant drop out. Thus, based upon previously published placebo ethics studies, recruitment of 50 pain patients was deemed sufficient to adequately power the study. Descriptive Stat istics Means and standard deviations were calculated for all pretest and posttest VAS outcomes. Frequencies were calculated for all categorical variables. Placebo Knowledge, Conceptualization, and Effectiveness Univariate ANOVAs (with treatment group as signment as the between subjects factor) were conducted for posttest placebo knowledge, conceptualization, and effectiveness ratings. Placebo Acceptability A one factor repeated measures ANOVA was conducted for the six pretest acceptability outcomes. A 6 x 2 (acceptable x educational intervention) mixed model ANOVA was conducted for the six posttest acceptability outcomes. Significant omnibus F tests were followed by simple contrasts or post hoc comparisons for all ANOVA analyses. Deception, Trust in Phys ician, and Negative Mood Three 2 x 3 (treatment instructions x treatment outcome) repeated measures ANOVAs were conducted on prete st deception, trust, and negative mood outcomes. Three 2 x 3 x 2 (treatment instructions x treatment outcome x educational i ntervention) mixed model ANOVAs were conducted to examine the effects of the educational intervention on the three respective posttest survey outcomes.

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35 Figure 2 1. Flow chart of study experimental design D emographic Questionnaire Chronic P ain Questionnaire Randomization Treatment Group (n = 29) Control Group (n = 28 ) Placebo Knowledge Treatment Vignette s Musculoskeletal Pain Information Placebo Knowledge Treatment Vignette s Eligible P atients (n = 57 ) Initial Contact and Screening Placebo Knowledge Treatment Vignette s Placebo Analgesia Education Placebo Knowledge Treatment Vignette s

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36 CHAPTER 3 RESULTS Participants Demographic Information All demographic information can be found in table 3 1. A total of 57 participants with chronic musculoskeletal pain completed the study. The average age was 45.12 and 70% o f the sample was female . The racial/ethnic breakdown of the sample was as follows: 7 5.4% Caucasian; 7% African American/black; 3.5% Indian ; 3.5% Hispanic ; 7% The average annual income for participants was $31 , with income ranging from $0 to $220,000. Over half the sample had either degree . Most participants reported their relationship status as single or married. Chronic Pain Information C hronic pain information can be found in table 3 1. chronic pain for an average of 6.34 years . While completing the survey, the average VAS rating of their current pain was 41.89 ( SD = 25.84) while their average rating of their usual pain was 51.18 ( SD = 23.85). A variety of chronic pain diagnoses were endorsed, with many reporting multiple diagnose s: 63.2% endorsed LBP, 22.8% endorsed Fibromyalgia, 19.3% endorsed osteoarthritis, and 15.8% endorsed IBS. Less Similarly, numerous body regi ons were listed as pain generators, with the majority of patient s endorsing more than one area. The pain regions endorsed most frequently were the lower back ( 63.2% ) and neck ( 49.1% ).

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37 To manage chronic pain, most patients used over the counter treatments Pretest Survey Results Descriptive statistics for pretest ou tcom es are presented in Tables 3 2 , 3 3 , 3 4 , 3 5 , and 3 6 . Placebo Acceptability Significant differences were found between the six placebo acceptability outcomes (Table 3 7 ). Ordered from increasing to decreasing acceptability, they were: 1) acceptability when no other treatments were available; 2) use as a treatment enhancer; 3) diagnostic use for pain; 4) explicit placebo use (i.e., informing patient prior to use); 5) use when other established treatments were available; and 6) deceptive placebo use. Pla cebo use when no other established treatments were available was significantly more acceptable than deceptive placebo ( p < 2 = .38 8 ), explicit placebo ( p < 2 = .1 85 ), and placebo when other established treatments were available ( p p 2 = . 407 ). Similarly, placebo as a treatment enhancer was more acceptable than deceptive placebo ( p 2 = . 264 ), explicit placebo ( p 2 = . 174 ), and placebo used when other established treatments were available ( p < .001, 2 = .27 6 ). Deception, Trust, and Negative Mood Enhanced placebo instructions were rated as most deceptive ( p < . 2 = .544) (Table 3 8 ; Figure 3 1 ), with patients endorsing the most negative mood ( p < .001, 2 = .421) (Table 3 8 ; Figure 3 3 ) and least trust in their health care provider ( p < .001, 2 = .378) (Table 3 8 ; Figure 3 2 ) when receiving this treatment.

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38 While treatment outcome (i.e., whether pain improves, remains the same, or worsens) had no effect on perceptions of placebo deceptiveness ( p = .072), treatment effectiveness had a significant impact on healthcare provider attributions (Table 3 8 ); improved pain outcomes strengthened trust ( p 2 = .123) and greatly decreased negative mood ( p 2 = .396) . There was also a significant in struction by outcome interaction. When randomly assigned, patients reported no difference between pain improved and no change outcomes. However, when receiving the enhanced placebo instruction, patients endorsed greater negative mood when their pain status was unchanged then when it improved. Additionally, when patients received an analgesic treatment response, their mood ratings were the same whether they received a deceptive or non deceptive description. Posttest Survey Results Treatment Groups Twenty e ight patients were randomly assigned to the control group and 29 patients were randomly assigned to the educational intervention group. There were no significant differences in pretest scores between the treatment and control group. Descriptive statistic s for all posttest o utcomes are presented in Table 3 9 . Placebo Knowledge, Conceptualization, and Effectiveness The educational intervention had a significant effect on placebo knowledge and p lacebo efficacy ratings (Table 3 10 ). Patients receiving the educational intervention had higher ratings of placebo knowledge ( p 2 = .245) and conceptualized a p 2 = .207). Those in the intervention group also viewed placebo as a more effective treatment for pain ( p = .0 06 2 = .1 29 ).

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39 Placebo Acceptability Those receiving the educational intervention rated placebo treatments more acceptable across multiple scenarios ( p 2 = .188) (Table 3 1 1 ; Figure 3 7 ). Comparable to pretest outcomes, significant differences in acceptability were also found across the different treatment contexts ( p 2 = .291). Only three pairings were not significa ntly different from one another deceptive placebo compared to when other established treatments were available ( p = .19 2), and the difference between when established treatments were available compared to treatment enhancers ( p = .109) and diagnostic placebo ( p = .309). The interaction between acceptability and educational intervention was also non significant ( p = .158). Deception Enhanced placebo instructions were significantly more deceptive than random assignment institutions ( p 2 = .4 88 ). There was no significant effects for treatment outcome ( p = . 327 ) or the educational intervention ( p = .138) ( Table 3 11; Figure 3 4 ). Trust in Healthcare Provider Trust ratings were significantly higher for random assignment instructions ( p < 2 = .3 23 ) and improved treatment outcomes ( p 2 = .3 20 ) (Table 3 1 2 ; Figure 3 5 ) . There was no significant effect of the educational intervention. Negative M ood The educational intervention had no effect on aspects of negative mood ( p = .3 04 ). Similar to pretest results, negative mood ratings were significantly greater when

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40 patients r eceived enhanced placebo instructions ( p 2 = .32 3 ) and as treatment outcomes worsened ( p 2 = . 399 ) (Table 3 1 2 ; Figure 3 6 ) .

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41 Table 3 1 . Participant d emographics and chronic p ain c haracteristics Demographics/ Characteristic M(SD) n Percentage Participants 57 100% Age (years) 45.12 (19.16) Income ($ thousands ) 31 ( 41) Sex Female 40 70 % Male 17 30 % Ethnicity Caucasian 43 75.4 % African American/black 4 7 % Indian 2 3.5 % Hispanic 2 3.5 % Asian or Pacific Islander 4 7 % Other 2 3.5 % Education No high School Education 1 1.8 % High School Diploma/GED 7 12.3 % Some College Education 20 35.1 % College Degree 12 21.1 % Some Graduate Education 4 7.0 % Graduate School Degree 13 22.8 % Marital Status Single 26 45.6 % Living With Partner 4 7 % Married 24 42.1 % Divorced 2 3.5 % Separated 1 1.8 % 41.89 (25.84) 51.18 (23.85) Years experiencing chronic pain 6.34 (7.34) Participants who uses OTC meds for pain 38 66.7% Participants who use prescription meds for pain 20 35.1% pain 21 36.8% 41.89 (25.84) P ain regions endorsed by participants Lower back 36 63.2 % Neck 28 49.1 % Upper back 24 42.1 % Shoulders 24 42.1 % Legs 24 42.1 % Hips 23 40.4 % Knees 21 36.8% Buttocks 16 28.1% Feet 15 26.3% Ankles 12 21.1 % Wrists 11 19.3% Hands 11 19.3% Head 11 19.3 % Arms 9 15.8 % Elbows 8 14 %

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42 Table 3 1. Continued Demographics/Characteristic M( SD) n Percentage Pain regions endorsed by participants Abdomen or pelvis 8 14% Chest 5 8.8% Hips 5 8.8% Note: VAS, Visual Analogue Scale; M , mean; SD , Standard Deviation, n , sample size; %, percentage.

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43 Table 3 2 . Pretest placebo knowledge and e ffectiveness Factor/Survey Question VAS Anchors (0 100) Abbreviation M (SD) Knowledge producing producing an effect? Completely inert; Completely active Placebo Conceptualization 19.93 (24.73) How much knowledge do you have about placebo for pain relief? No knowledge of pl acebo for pain relief; Most knowledge of placebo for pain relief imaginable Placebo Knowledge 37.19 (33.17) Effectiveness How effective would placebo be for your pain? Completely ineffective; Completely effective Placebo Effectiveness 18.33 (18.82) Note: M , mean; SD , standard deviation .

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44 Table 3 3 . Pretest placebo a cceptability Survey Question VAS Anchors (0 100) Abbreviation M (SD) How acceptable would it be if your physician used a placebo treatment to reduce your pain without telling you? Completely unacceptable; Completely acceptable Deceptive Placebo Acceptability 18.05 (23.79) How acceptable would it be if your physician told you that he/she was going to use a placebo treatment to reduce your pain? Completely unacceptable; Completely acceptable Explicit Placebo Acceptability 29.46 (33.01) How acceptable would it be if your physician told you that he/she was going to use a placebo treatment that may enhance the effectiveness of your usual pain treatm ents? Completely unacceptable; Completely acceptable Treatment Enhancer Placebo Acceptability 41.93 (34.36) How acceptable would it be if your physician treated your pain with placebo when other established treatments were available? Completely unaccepta ble; Completely acceptable Placebo Acceptability when other EBTs are available 20.28 (23.76) How acceptable would it be if your physician treated pain with placebo when NO other established treatments were available? Completely unacceptable; Completely acceptable Placebo Acceptability when NO other EBTs are available 48.21 (39.41) How acceptable would it be if your physician used a placebo to Completely unacceptable; Completely acceptable Diagnostic Placebo Acceptability 36.26 (36.81) Note: M , mean; SD , standard deviation.

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45 Table 3 4 . Pretest d eception (VAS 0 100: n ot at all deceptive ; m ost deceptive imaginable) Treatment Scenarios Question Abbreviation M (SD) Imagine that you are seeing a physician to manage your pain. The doctor provides you with a prescription for your pain, and states that what you have been given has been shown to be a powerful pain reliever in some people. Two weeks after the treatment, you report that your condition has improv ed. You received a placebo. How deceptive would this be? Deceptiveness of enhanced placebo instructions when pain improves 61.70 (32.83) Imagine that you are seeing a physician to manage your pain. The doctor provides you with a prescription for your pain, and states that what you have been given has been shown to be a powerful pain reliever in some people. Two weeks after the treatment, you report that there is no change in your condition. You received a placebo. How deceptive would this be? Deceptive ness of enhanced placebo instructions when pain is unchanged 61.42 (36.91) Imagine that you are seeing a physician to manage your pain. The doctor provides you with a prescription for your pain, and states that what you have been given has been shown to b e a powerful pain reliever in some people. Two weeks after the treatment, you report that your condition has gotten worse. You received a placebo. How deceptive would this be? Deceptiveness of enhanced placebo instructions when pain worsens 71.09 (33.31) Imagine that you are seeing a physician to manage your pain. The doctor tells you that you will randomly receive either a standard drug treatment or a placebo treatment for your pain. Two weeks after the treatment, you report that your condition has improv ed. You received a placebo. How deceptive would this be? Deceptiveness when randomly assigned and pain improved 24.98 (31.96) Imagine that you are seeing a physician to manage your pain. The doctor tells you that you are going to randomly receive either a standard drug treatment or a placebo treatment for your pain. Two weeks after the treatment, you report that there is no change in your condition. You received a placebo. How deceptive would this be? Deceptiveness when randomly assigned and pain is unchan ged 24.30 (31.96) Imagine that you are seeing a physician to manage your pain. The doctor tells you that you will randomly receive either a standard drug treatment or a placebo treatment for your pain. Two weeks after the treatment, you report that your c ondition has gotten worse. You received a placebo. How deceptive would this be? Deceptiveness when randomly assigned and pain worsens 26.19 (26.19) Note: M , mean; SD , standard deviation .

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46 Table 3 5 . Pretest t rust (VAS 0 100: n o trust ; m ost trust imaginable) Treatment Scenarios Question Abbreviation M (SD) Imagine that you are seeing a physician to manage your pain. The doctor provides you with a prescription for your pain, and states that what you have been given has been shown to be a powerful pain reliever in some people. Two weeks after the treatment, you report that your condition has improved. You received a placebo. Rate your level of trust in this physician Trust when enhanced placebo instructions used and pain improves 40.25 (32 .13) Imagine that you are seeing a physician to manage your pain. The doctor provides you with a prescription for your pain, and states that what you have been given has been shown to be a powerful pain reliever in some people. Two weeks after the treatment, you report that there is no change in your condition. You received a placebo. Rate your level of trust in this physician Trust when enhanced placebo instructions used and pain is unchanged 37.42 (33.54) Imagine that you are seeing a physician to manage your pain. The doctor provides you with a prescription for your pain, and states that what you have been given has been shown to be a powerful pain reliever in some people. Two weeks after the treatment, you report that your condition has gotten worse. You received a placebo. Rate your level of trust in this physician Trust when enhanced placebo instructions used and pain worsens 23.84 (24.25) Imagine that you are seeing a physician to manage your pain. The doctor tells you that you will randoml y receive either a standard drug treatment or a placebo treatment for your pain. Two weeks after the treatment, you report that your condition has improved. You received a placebo. Rate your level of trust in this physician Trust when randomly assigned an d pain improved 58.44 (32.44) Imagine that you are seeing a physician to manage your pain. The doctor tells you that you are going to randomly receive either a standard drug treatment or a placebo treatment for your pain. Two weeks after the treatment, you report that there is no change in your condition. You received a placebo. Rate your level of trust in this physician Trust when randomly assigned and pain is unchanged 59.86 (30.69) Imagine that you are seeing a physician to manage your pain. The doc tor tells you that you will randomly receive either a standard drug treatment or a placebo treatment for your pain. Two weeks after the treatment, you report that your condition has gotten worse. You received a placebo. How deceptive would this be? Trust when randomly assigned and pain worsens 54.70 (54.70) Note: M , mean; SD , standard deviation .

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47 Table 3 6 . Pretest negative m ood (VAS 0 100: no negative mood; m ost negative mood imaginable) Treatment Scenarios Question Abbreviation M (SD) Imagine that you are seeing a physician to manage your pain. The doctor provides you with a prescription for your pain, and states that what you have been given has been shown to be a powerful pain reliever in some people. Two weeks after the treatment, yo u report that your condition has improved. You received a placebo. Rate the level of negative mood you would experience Negative mood when enhanced placebo instructions used and pain improves 37.53 (29.39) Imagine that you are seeing a physician to manage your pain. The doctor provides you with a prescription for your pain, and states that what you have been given has been shown to be a powerful pain reliever in some people. Two weeks after the treatment, you report that there is no change in your conditio n. You received a placebo. Rate the level of negative mood you would experience Negative mood when enhanced placebo instructions used and pain is unchanged 55.56 (30.99) Imagine that you are seeing a physician to manage your pain. The doctor provides you with a prescription for your pain, and states that what you have been given has been shown to be a powerful pain reliever in some people. Two weeks after the treatment, you report that your condition has gotten worse. You received a placebo. Rate the level of negative mood you would experience Negative mood when enhanced placebo instructions used and pain worsens 72.14 (28.16) Imagine that you are seeing a physician to manage your pain. The doctor tells you that you will randomly receive either a standard drug treatment or a placebo treatment for your pain. Two weeks the treatment, you report that your condition has improved. You received a placebo. Rate the level of negative mood you would experience Negative mood when randomly assigned and pain improved 23.79 (25.70) Imagine that you are seeing a physician to manage your pain. The doctor tells you that you are going to randomly receive either a standard drug treatment or a placebo treatment for your pain. Two weeks after the treatment, you report that th ere is no change in your condition. You received a placebo. Rate the level of negative mood you would experience Negative mood when randomly assigned and pain is unchanged 31.25 (26.94) Imagine that you are seeing a physician to manage your pain. The doct or tells you that you will randomly receive either a standard drug treatment or a placebo treatment for your pain. Two weeks after the treatment, you report that your condition has gotten worse. You received a placebo. Rate the level of negative mood you w ould experience Negative mood when randomly assigned and pain worsens 43.16 (33.76) Note: M , mean; SD , standard deviation .

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48 Table 3 7. Pretest acceptability one factor ANOVA Main effect x Contrasts P 2 ) Acceptability Contexts <.001** .175 Deceptive Placebo Explicit Placebo .039* .074 Deceptive Placebo < Treatment Enhancer <.001** .264 Deceptive Placebo When other EBTs are available .514 .008 Deceptive Placebo < when NO other EBTs are available <.001** .388 Deceptive Placebo < Diagnostic Placebo <.001** .223 Explicit Placebo < Treatment Enhancer .001* .174 Explicit Placebo when other EBTs are available .026* .085 Explicit Placebo < when NO other EBTs are available .001* .185 Explicit Placebo Diagnostic Placebo .273 .021 Treatment Enhancer > When other EBTs are available <.001** .276 Treatment Enhancer when NO other EBTs are available .182 .032 Treatment Enhancer Diagnostic Placebo .332 .017 When other EBTs are available < when NO other EBTs are available <.001** .407 When other EBTs are available Diagnostic Placebo .002* .160 When NO other EBTs are available Diagnostic Placebo .036* .076 Note: P , p value; ES 2 ), partial eta squared effect size; *, Indicates significant difference ( p < .05); **, Indicates significant difference ( p < .001)

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49 T able 3 8 . Pretest deception, t rust, and negative m ood r epeated m easures (2 x 3) ANOVAs Factors/Contrast F P 2 ) Deception Instructions F(1, 56) = 66.85 <.001** 2 = .544 Enhanced placebo > RA <.001** 2 = .544 Tx Outcome F(2, 112) = 2.69 .072 2 = .046 Instruction x Tx Outcome F(2, 122) = 1.36 .260 2 = .024 Trust in Healthcare Provider Instructions F(1, 56) = 33.97 <.001** 2 = .378 RA > Enhanced placebo <.001** 2 = .378 Tx Outcome F(2, 112) = 7.86 .001* 2 = .123 Improves > Worsens .001* 2 = .180 No Change > Worsens <.001** 2 = .204 Improves No Change .823 2 = .001 Instructions x Tx Outcome F(1.71, 95.81) = 2.93 .066 2 = .050 Negative Mood Instructions F(1, 56) = 40.80 <.001** 2 = .421 Enhanced placebo > RA <.001** 2 = .421 Tx Outcome F(2, 112) = 42.08 <.001** 2 = .429 Worsens > Improves <.001** 2 = .546 Worsens > No Change <.001** 2 = .324 No Change > Improves <.001** 2 = .275 Instructions x Tx Outcome F(2, 112) = 3.27 .042 2 = .055 Enhanced Placebo Improves < No Change <.001** d = .602 Improves < Worsens <.001** d = 1.213 No Change < Worsens .001 * d = .564 Random Assignment Improves No Change .190 d = .286 Improves < Worsens <.001** d = .651 No Change < Worsens .014 * d = .393 Pain Improves Enhanced Placebo > RA .006 * d = .502 No Change in Pain Enhanced Placebo > RA <.001** d = .845 Pain Worsens Enhanced Placebo > RA <.001 ** d = .629 Note: RA, Random assignment instructions; F , F statistics; P 2 ), partial eta squared effects size; *, Indicates significant de viation ( p < .05); **, Indica tes significant deviation ( p < .001) .

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50 Table 3 9 . Posttest r atings for t otal s ample , c ontrol g roup , and intervention g roup Factors and Outcomes Total Sample (n = 57) Control (n = 28) Intervention (n = 29) M SD M SD M SD Knowledge Placebo Conceptualization 43.60 32.60 28.64 24.89 58.03 33.00 Placebo Knowledge 49.30 31.99 33.32 30.43 64.72 25.55 Efficacy Placebo Analgesia Effectiveness 27.40 24.08 18.68 18.32 35.83 26.21 Acceptability Deceptive Placebo Acceptability 29.51 29.76 18.21 23.24 40.41 31.63 Explicit Placebo Acceptability 52.35 34.72 38.96 33.72 65.28 31.03 Treatment Enhancer Placebo Acceptability 60.18 31.06 47.86 33.20 72.07 23.82 Placebo Acceptability when other EBTs are available 34.46 27.17 20.07 21.21 48.34 25.21 Placebo Acceptability when NO other EBTs are available 64.84 33.28 55.14 35.77 74.21 28.22 Diagnostic Placebo Acceptability 39.19 37.42 35.71 36.66 42.55 38.48 Deception Deceptiveness of enhanced placebo instructions when pain improves 53.35 32.94 62.18 29.91 44.83 33.97 Deceptiveness of enhanced placebo instructions when pain is unchanged 56.26 34.48 59.39 33.95 53.24 35.31 Deceptiveness of enhanced placebo instructions when pain worsens 60.89 36.06 67.00 34.25 55.00 37.37 Deceptiveness when randomly assigned and pain improved 21.21 27.43 24.32 32.21 18.21 22.05 Deceptiveness when randomly assigned and pain remains the same 25.47 30.72 25.50 30.47 25.45 31.49 Deceptiveness when randomly assigned and pain worsens 20.04 26.31 23.54 28.12 16.66 24.44 Trust in Health Care Provider Trust when enhanced placebo instructions when pain improves 46.88 30.96 37.68 31.02 55.76 28.68 Trust when enhanced placebo instructions when pain is unchanged 34.16 28.68 27.07 26.75 41.00 29.26 Trust when enhanced placebo instructions when pain worsens 27.65 28.64 24.54 26.47 30.66 30.75 Trust when randomly assigned and pain improved 64.37 29.01 62.71 29.25 65.97 29.20 Trust when randomly assigned and pain remains unchanged 49.33 31.91 50.75 29.56 47.97 34.50 Trust when randomly assigned and pain worsens 45.33 32.96 40.54 32.84 49.97 32.97 Negative Mood Negative mood when enhanced placebo instructions when pain improves 28.39 26.89 30.46 25.99 26.38 28.04 Negative mood when enhanced placebo instructions when pain is unchanged 49.02 28.19 52.32 25.48 45.83 30.69 Negative mood when enhanced placebo instructions when pain worsens 59.47 33.99 62.61 34.86 56.45 33.45 Negative mood when randomly assigned and pain improved 18.12 23.78 17.68 21.88 18.55 25.86 Negative mood when randomly assigned and pain remains unchanged 33.18 24.72 35.50 22.73 30.93 26.70 Negative mood when randomly assigned and pain worsens 45.26 32.98 52.32 33.02 38.45 32.04 Note: M , mean; SD , standard deviation .

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51 Table 3 10 . Posttest placebo knowledge, c onceptualization, and effectiveness u nivariate ANOVAs Factors/Contrast F P 2 ) Placebo Knowledge F (1, 55) = 17.85 <.001** .245 Education > Control <.001** .245 Placebo Conceptualization F (1, 55) = 14.34 <.001** .207 Education > Control <.001** .207 Placebo Efficacy F (1, 55) = 8.14 .006* .129 Education > Control .006* .129 Note: F , f statistic; P , p 2 ), partial eta squared effect size.

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52 Table 3 1 1 . Posttest placebo a cceptability mi xed m odel (6 x 2) ANOVA Main effect x c ontrasts P 2 ) Education .001* .188 Intervention > Control .001* .188 Acceptability Contexts <.001** .291 Deceptive Placebo Explicit Placebo <.001** .305 Deceptive Placebo < Treatment Enhancer <.001** .506 Deceptive Placebo When other EBTs are available .192 .031 Deceptive Placebo < when NO other EBTs are available <.001** .503 Deceptive Placebo < Diagnostic Placebo .027* .085 Explicit Placebo < Treatment Enhancer .018* .097 Explicit Placebo when other EBTs are available <.001** .322 Explicit Placebo < when NO other EBTs are available .004* .139 Explicit Placebo Diagnostic Placebo .016* .101 Treatment Enhancer > When other EBTs are available <.001** .449 Treatment Enhancer when NO other EBTs are available .109 .046 Treatment Enhancer < Diagnostic Placebo <.001** .245 When other EBTs are available < when NO other EBTs are available <.001** .516 When other EBTs are available Diagnostic Placebo .309 .019 When NO other EBTs are available Diagnostic Placebo <.001** .283 Education x Acceptability .158 .028 Note: P , p 2 ), partial eta squared effect size; *, Indicat es significant difference ( p < .05); **, Indicates significant difference ( p < .001).

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53 Table 3 1 2 . Posttest deception, trust, and negative mood mixed m odel (2 x 3 x 2) ANOVAs Factors/Levels/Contrasts F P 2 ) Deception Education F (1, 55) = 2.27 .138 .040 Instructions F (1, 55) = 52.47 <.001** .488 Enhanced Placebo > RA <.001** .488 Instructions x Education F (1, 55) = .612 .438 .011 Tx Outcome F (2, 110) = 1.13 .327 .020 Tx Outcome x Education F (2, 110) = 1.51 .226 .027 Instruction x Tx Outcome F (2, 110) = 2.28 .108 .040 Instruction x Tx Outcome x Education F ( 2, 110)= .21 .814 .004 Trust in Healthcare Provider Education F (1, 55) = 1.77 .188 .031 Instructions F (1, 55) = 26.22 <.001** .323 RA > Enhanced Placebo <.001** .323 Instructions x Education F (1, 55) = 2.04 .159 .036 Tx Outcome F (2, 110) = 25.85 <.001** .320 Improved > No Change <.001** .287 Improved > Worsened <.001** .415 No Change > Worsened .017* .099 Outcome x Education F (2, 110) = .433 .650 .008 Instruction x Outcome F (2, 110) = .169 .845 .003 Instructions x Outcome x Education F (2, 110) = 2.87 .060 .050 Negative Mood Education F (1, 55) = 1.08 .304 .019 Instructions F (1, 55) = 26.28 <.001** .323 Enhanced Placebo > RA <.001** .323 Instructions x Education F (1, 55) = .00 .958 .000 Tx Outcome F (1.61, 88.47) = 36.52 <.001** .399 Improved < Worsened <.001** .463 Improved < No Change <.001** .400 No Change < Worsened <.001** .207 Outcome x Education F (2, 110) = .75 .476 .013 Instruction x Outcome F (2, 110) = 1.12 .328 .020 Instructions x Outcome x Education F (2, 110) = 1.52 .223 .027 Note: RA, Random assignment; F , f statistics; P 2 , partial eta squared; *, Indica tes significant deviation ( p < .05); **, Indica tes significant deviation ( p < .001) .

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54 Figure 3 1. Pretest deceptiveness ratings by treatment instructions and treatment outcome. * = significant main effect ( p < .05); error bars are 95% confidence intervals. 10 20 30 40 50 60 70 80 90 Enhanced Placebo Random Assignment Deception (VAS 0 100) Instructions Pretest Deception Pain Improved No Change in Pain Pain Worsens *

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55 Figure 3 2. P retest trust in physician ratings by treatment instruction s and treatment outcome. * = significant main effect ( p < .05); e rror bars are 95% confidence intervals. 10 20 30 40 50 60 70 Enhanced Placebo Random Assignment Trust (VAS 0 100) Instructions Pretest Trust Pain Improved No Change in Pain Pain Worsens * *

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56 Figure 3 3. P retest negative mood ratings by treatment instruction s and treatment outcome . * = significant main effect ( p < .05); p < .05); e rror bars are 95% confidence intervals. 10 20 30 40 50 60 70 80 Enhanced Placebo Random Assignment Negative Mood (VAS 0 100) Instructions Pretest Negative Mood Pain Improved No Change in Pain Pain Worsens * *

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57 Figure 3 4. Posttest deceptiveness ratings by educational interventions, treatment instructions, and treatment outcome. * = significant main effect ( p < .05); error bars are 95% confidence intervals.

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58 Figure 3 5 . P osttest trust ratings by education al intervention, treatment instructions , and treatment outcome. * = significant main effect ( p < .05); e rror bars are 95% confidence intervals.

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59 Figure 3 6. Posttest negative mood ratings by educational intervention, treatment instructions, and treatment outcome. * = significant main effect ( p < .05); error bars are 95% confidence intervals.

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60 Figure 3 7 . The effect of the placebo educational intervention on placebo a cceptability contexts ratings . * = significant main effect ( p < .05); e rror bars are 95% confidence intervals.

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61 CHAPTER 4 DISCUSSION Placebos analgesia effects real, potentially potent events mediated by psychological and neurobiological factors likely have the power to augment the efficacy of virtually all active treatments for pain ( Colloca, et al., 2013 ) . Although the mechanisms underlying these effects are well understood among those who study endogenous analgesia, this knowledge has not disseminated to the lay public (Kisaalita & Robinson, 2012) . Interventional placebo use is highly contested among clinicians, perspectives. The objective of the present study was to investigate chronic pain d attitudes towards the clinical use of placebos, as well as examine the effects of placebo education on perceptions of treatment acceptability. Specifically, the first aim of the study sought to examine the effects of different placebo descriptions and tr eatment outcomes on perceptions of treatment deceptiveness, patient negative mood and trust in the prescribing healthcare provider; the second aim sought to explore the effects of a brief, mechanism based educational intervention on placebo treatment knowl edge, acceptability, and the perceived negative consequences of placebo use. The overarching goal of this line of scientific inquiry was to utilize an empirical, patient centered approach to address essential questions about placebo treatment ethics. For the first aim, it was hypothesized that placebo treatments that were overt and efficacious for alleviating pain would be perceived as less deceptive, and patients would endorse decreased negative mood and greater trust in their prescribing clinician. Simil ar to findings seen in studies with non patient samples (Kisaalita, Roditi, & Robinson,

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62 2011), the deceptiveness of a placebo treatment was exclusively determined by the explicitness of the treatment instructions, accounting for over half the variance in t 2 instructions as highly deceptive, a finding coinciding with previous studies by our where the possibility of receiving a placebo treatment for pain was explicit were rated as relatively non deceptive. Although in previous survey studies there was a small effect of treatment outcome on deception, treatment effectiveness was not statistically significant in the present in vestigation ( p 2 = .046). Trust in the prescribing clinician and patient negative mood were influenced by instructions and treatment outcome, supporting our 2 = .378) than its 2 = .123). Specifically, trust was primarily driven by pain worsening status; there were no differences between pain improved and no change outcomes. Negative mood was strongly and approximately equally influenced by treatment instruction 2 = .42 1 2 = . 429 ), with graded increases in negative mood observed as intervention outcomes worsened and when patients received the The interaction of these two factors suggest that patient would be mu ch more upset if their pain remained the same following a deceptive placebo treatment, as opposed to random assignment. In the second aim, it was hypothesized that the educational intervention would improve perceptions of placebo knowledge, effectiveness, and acceptability, and that patients receiving the intervention would perceive placebo treatments as less deceptive,

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63 wou ld experience less negative mood, and would have greater trust in their prescribing healthcare providers. These hypotheses were partially supported. placebo analgesic treatments ( 2 = . 245 ) and increased placebo conceptualizations to be mor 2 = . 207 ). Those receiving the educational intervention also rated placebo analgesic treatments as more effective 2 = . 129 ). Regardless of treatment group assignment, placebo acceptability was highly 2 = .291), a finding supported by previous research (Kisaalita & Robinson, 2012). Patients viewed placebo treatments as most acceptable when there were no other well establishe d treatments for their pain condition available, when placebo was used as a treatment enhancer/adjunct, and when healthcare providers were open in disclosing their use of a placebo. Treatments were least acceptable when administered covertly/deceptively, w hen other established treatments were available, and when placebo was used diagnostically to determine whether a 2 = .188) on increasing acceptability for almost ever y treatment context, including the deceptive scenario. The only context that was not perceived as significantly more acceptable between the intervention and control group was diagnostic placebo use. The latter represented an important finding that served a s one validly check for our educational intervention, as diagnostic placebo use is an area in which informed researchers, ethicists, and clinicians can reasonably agree constitutes unacceptable use ( Sullivan, et al., 2005 ) .

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64 The educational slides had the effect of increasing placebo treatment acceptability arguably one of the most important factors (along with efficacy) in evaluating the appropriateness of this treatment modality ( Franklin G. Miller & Colloca, 2009 ) . Our findings have important implications for the acceptable use of placebo analgesic interventions, as results sugge st that patients suffering from pain conditions bereft of well established treatments may find placebo treatments as acceptable alternatives. Also, patients were more accepting of placebos if they were used in conjunction with existing pain treatments to i mprove overall treatment effectiveness. be one of its most acceptable applications. Although dose extending models have not been demonstrated for the treatment of pain, placebos have been used in this manner to treat both attention deficit disorder ( Sandler, Glesne, & Bodfish, 2010 ) and psoriasis ( Ader, et al., 2010 ) . Finally, and most importantly, independent of the treatment context, educating patients about the role of endogenous opiates, expectancy, and classical conditioning improved perce ptions of treatment acceptability, even in highly deceptive scenarios. Although education greatly increased placebo acceptability, it did not mitigate negative consequences of decreased trust, perceived deceptiveness, nor increased negative mood. One potential interpretation could be that these findings lend some support to the belief that placebos are inherently deceptive when used clinically, regardless of the information given to a patient. However, the authors would argue against this view due to the nature of the deceptive instructions used in this study. The what

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65 you have been given has been shown to be a powerful pain reliever in some people may be considered d eceptive because the use of placebo is not explicitly stated (i.e., powerful pain reliever may describe many different interventions) . Although an arguments could be made that non significant effects on deception, mood, and provider attributions reflect a failure of the educational intervention (i.e., patients were not we would argue that our overall significant results (e.g., regarding placebo acceptability, efficacy) suggests otherwise. Thus, i t is more plausible that educated patients do in fact but are perhaps not necessarily convinced that they produce large effects comparable to existing pain treatments. Future studies are needed to determine which descriptions o f placebo accurately enhance expectations and subsequent placebo responses while also attenuating potential negative sequelae. For example, we would hypothesize that those receiving the educational intervention would have found the following edited descrip tions as non the placebo/expectation intervention/conditioning intervention that you have been given has been shown to be a powerful pain reliever in some people s a hypothesis worth exploring in the future, ultimate ly the m ore important signifier of placebo ethics should be patient acceptability not perceived deceptiveness and our findings suggest that education improved the acceptably of even the most deceptive treatment contexts. Despite widespread impressions tha t deceptive treatment administration is inherently unacceptable, findings from several survey studies suggest that deception is placebos are multifactorial ( Margrit Fassler, et al., 2010 ) , and may include a desire to

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66 rstood the mechanisms underlying their placebo treatments, they may be more open with their patients about their placebo use. While this investigation constitutes a promising first step, more research is needed in understanding the effects of education on enhancing placebo acceptability in patients and healthcare providers. There were some limitations to the present study. Although we were able to successfully manipulate graded levels of deception through two treatment instructions, clinical encounter. Although the possibility of being randomly assigned to a treatment is common in the clinical trial setting, this scenario does not exist in the average medical setting. Thus, future iterations of this line of research should substitute the random assignment instruction set with something equally non deceptive and clinically applicable. It is also possible that the brevity and simplicity of the educational intervention may not h ave achieved maximum effectiveness. Although future investigations should examine the costs and benefits of different intervention formats and lengths, we argue that the nature of our brief intervention has utility. While Kaptchuk and colleagues (2010) dem onstrated clinically meaningful effects following a patient education, their education was 15 minutes long longer than the average primary care encounter. The sizable effects seen in our briefer educational intervention are perhaps more ecologically vali d given the time restrictions inherent in most clinical encounters. Additionally, as these findings were with chronic musculoskeletal pain

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67 patients, they may not generalize to patients suffering from acute pain or chronic pain from a different etiology (e. g., neuropathic pain). While our findings provide a significant contribution to the placebo acceptability / ethics literature, additional studies are warranted. Although the educational intervention produced sizable effects, more research is needed on how t o optimize the educational prompt. It is possible that a slightly longer intervention may yield greater effects, or that comparable effects could be seen with an even briefer prompt. Additionally, the exact mechanisms underlying the efficacy of the educati onal (i.e., endorphins, expectancy, and classical conditioning) may differentially contribute to acceptability. A s our understanding of placebo analgesia mechanisms inc reases, new information may be incorporated into the intervention, such as highlighting treatment effect sizes and placebo effects on the spinal cord. Finally, additional studies are needed to examine how the delivery of the placebo information (e.g., verb al, written, video presentation) may influence acceptability. Additional studies are also needed in order to better understand how to utilize placebo in clinical practice. Although the present investigation highlighted the importance of treatment effecti veness broadly, more information is needed about how the exact magnitude and duration of pain relief relates to perceptions of treatment satisfaction. For example, would a patient find a placebo treatment acceptable if pain was reduced by seventy five, for ty, or twenty percent? And how would this interact with duration if the effects lasted a day, a week, a month, or longer? Understanding potential mediating factors (e.g., current pain intensity, pain disease) will also be

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68 imperative. Although there have been previously published clinical analogs of the placebo clinical encounter ( S. K. Chung, D. D. Price, G. N. Verne, & M. E. Robinson, 2007 ; Kaptchuk, et al., 2010 ) , additional studies are needed to r eplicate the current findings in a clinical environment. Finally, more research is needed exploring individual differences in placebo effects and identifying patient characteristics that may predict placebo responding. Advances in t hese areas may open the doors to a truly personalized approach to pain management that takes into account individual differences in endogenous analgesia. area of investig ation . Although several studies using neuroimaging methodologies claim to have identified such markers ( Hashmi, et al., 2012 ; Wager, Atlas, Leotti, & Rilling, 2011 ) , the degree to which these techniques have advanced placebo prediction beyond self report measures is equivocal. Nevertheless, neuroimaging has greatly advanced our knowledge of p lacebo analgesia mechanisms and underlying neural substrates ( Stein, Sprenger, Scholz, Wiech, & Bingel, 2012 ) . The search for placebo responder psychological traits, such as personality factors, has also seen a recent resurgence ( Jaksic, et al., 2013 ) . While historically the search for has largely been a failure, recent studies utilizing improved methodologies have highlighted the importance of personality traits such as extraversion and agreeableness. The strongest evidence for the contributions of a per sonality factors may be for dispositional optimism, as the predictive relationship between it and placebo analgesic responses has been shown when subjects are given explicit and ambiguous placebo instructions ( Geers, Helfer, Kosbab, Weiland, & Landry, 2005 ; Geers, Wellman, Fowler,

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69 Helfer, & France, 2010 ; Morton, Watson, El Deredy, & Jones, 2009 ) . An interactio nist perspective has been proposed w h ere situational variables (e.g., expectation) and dispositional factors (e.g., optimism) work together to produce placebo effects. In conclusion, the present study represents a significant addition to the placebo accep tability literature. Using validated survey methodology, we were able to assess a wide range of placebo conceptualizations among patients suffering from musculoskeletal pain, as well as examine the importance of treatment effectiveness and deception on moo d and relationship with healthcare providers. A placebo educational intervention greatly improved perceptions of treatment knowledge, efficacy , and acceptability compared to an active control intervention. We believe that the rigorous methodology used in o f this investigation and the magnitudes of our effects are considerable strengths. We hope that this line of research will continue to generate testable hypotheses to extend knowledge of placebo benefits to chronic pain patients and clinicians, with the ul timate goal of eventually improving existing pain management practices.

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70 L IST OF REFERENCES Ader, R., Mercurio, M. G., Walton, J., James, D., Davis, M., Ojha, V., Kimball, A. B., & Fiorentino, D. (2010). Conditione d pharmacotherapeut ic effects: A preliminary study. Psychosomatic Medicine, 72 , 192 97. Amanzio, M., & Benedetti, F. (1999). Neuropharmacological di ssection of placebo analgesia: E xpectation activated opioid systems versus conditioning activated specific subsystems. The Jou rnal of Neuroscience, 19 , 484 94. Amanzio, M., Pollo, A., Maggi, G., & Benedetti, F. (2001). Respo nse variability to analgesics: A role for non specific activation of endogenous opioids. PAIN, 90 , 205 15. Amit, Z., & Galina, Z. H. (1988). Stressed induce d analgesia plays an adaptive role in the organization of behavioral responding. Brain Research Bulletin, 21 , 955 58. Andersson, G. B. J. (1999). Epidemiological features of chronic low back pain. The Lancet, 354 , 581 85. Aronson, J. (1999). Please, please me. BMJ, 318 , 716. Asai, A., Ohnishi, M., Nishigaki, E., Sekimoto, M., Fukuhara, S., & Fukui, T. (2004). Focus group interviews examining attitudes towa rds medical research among the Japanese: A qualitative study. Bioeth ics, 18 , 448 70. Astin, J. A. (1998). Why patients use alternative medicine: results of a national study. JAMA, 279 , 1548 53. Bardo, M. T., & Valone, J. M. (1994). Morphine conditioned analgesia using a taste cue dissociation of taste aversion and anal gesia. Psychopharmacology, 114 , 269 74. Beecher, H. K. (1955). The powerful placebo JAMA, 159 , 1602 06. Benedetti, F. (1996). The opposite effects of the opiate antagonist naloxone and the cholecystokinin antagonist proglumide on placebo analgesia. PAIN, 64 , 535 43. Benedetti, F., Amanzio, M., Casadio, C., Oliaro, A., & Maggi, G. (1997). Blockade of nocebo hyperalgesia by the cholecystokinin antagonist proglumide. PAIN, 71 , 135 40. Benedetti, F., Amanzio, M., Rosato, R., & Blanchard, C. (2011). Nonopioi d placebo analgesia is mediated by CB1 cannabinoid receptors. Nat Med, 17 , 1228 30.

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79 BIOGRAPHICAL SKETCH Nkaku Kisaalita was born in Vancouver, British Columbia. He is the son of William and Rose Kisaalita. Nkaku has an older brother, Ntumwa, a younger sister, Namirembe, a nd a younger brother, Ssempa . Nkaku graduated with honors from the University of North Carolin a at Chapel Hill in May 2007 with a Bachelor of Science in p sychology. As part of his college honors thesis, Nkaku conducted research examining tactile and auditory sensory syste m interactions. After graduating , h e coordinated a 2 year study through the University of North Carolina Psychology Department examining cognitive and perceptual factors that influence pain perception in individuals with sickle cell disease. Nkaku joined the Clinical and Heath Psychology doctoral program at the University of Flor erests include chronic pain, placebo analgesia, and placebo ethics . Nkaku is currently completing a one year residency at the Medical College of Georgia/Charlie Norwood V eteran A ffairs Medi cal Center Psychology Residency in Augusta, Georgia.