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To test the effects of cortisol on affective experience, the authors orally administered a placebo, 20 mg cortisol, or 40 mg cortisol to 85 men. Participants' affective responses to negative and neutral stimuli were measured. Self-reported affective state was also assessed. Participants in the 40-mg group (showing extreme cortisol elevations within the physiological range) rated neutral stimuli as more highly arousing than did participants in the placebo and 20-mg groups. Furthermore, within the 20-mg group, individuals with higher cortisol elevations made higher arousal ratings of neutral stimuli. However, cortisol was unrelated to self-reported affective state. Thus, findings indicate that acute cortisol elevations cause heightened arousal in response to objectively nonarousing stimuli, in the absence of effects on mood.
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The experience of aversion is shaped by multiple physiological and psychological factors including one's expectations. Recent work has shown that expectancy manipulation can alter perceptions of aversive events and concomitant brain activation. Accruing evidence indicates a primary role of altered expectancies in the placebo effect. Here, we probed the mechanism by which expectation attenuates sensory taste transmission by examining how brain areas activated by misleading information during an expectancy period modulate insula and amygdala activation to a highly aversive bitter taste. In a rapid event-related fMRI design, we showed that activations in the rostral anterior cingulate cortex (rACC), orbitofrontal cortex (OFC), and dorsolateral prefrontal cortex to a misleading cue that the taste would be mildly aversive predicted decreases in insula and amygdala activation to the highly aversive taste. OFC and rACC activation to the misleading cue were also associated with less aversive ratings of that taste. Additional analyses revealed consistent results demonstrating functional connectivity among the OFC, rACC, and insula. Altering expectancies of upcoming aversive events are shown here to depend on robust functional associations among brain regions implicated in prior work on the placebo effect.
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Little is known about placebo effects with scientific precision. Poor methodology has confounded our understanding of the magnitude and even the existence of the placebo effect. Investigating placebo effects presents special research challenges including: the design of appropriate controls for studying placebo effects including separating such effects from natural history and regression to the mean, the need for large sample sizes to capture expected small effects, and the need to understand such potential effects from a patient's perspective. This article summarizes the methodology of an ongoing NIH-funded randomized controlled trial aimed at investigating whether the placebo effect in irritable bowel syndrome (IBS) exists and whether the magnitude of such an effect can be manipulated to vary in a manner analogous to “dose dependence.” The trial also uses an innovative combination of quantitative and qualitative methods.
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Patients in the placebo arms of randomized controlled trials (RCT) often experience positive changes from baseline. While multiple theories concerning such “placebo effects” exist, peculiarly, none has been informed by actual interviews of patients undergoing placebo treatment. Here, we report on a qualitative study (n = 27) embedded within a RCT (n = 262) in patients with irritable bowel syndrome. Besides identical placebo acupuncture treatment in the RCT, the qualitative study patients also received an additional set of interviews at the beginning, midpoint, and end of the trial. Interviews of the 12 qualitative subjects who underwent and completed placebo treatment were transcribed. We found that patients (1) were persistently concerned with whether they were receiving placebo or genuine treatment; (2) almost never endorsed “expectation” of improvement but spoke of “hope” instead and frequently reported despair; (3) almost all reported improvement ranging from dramatic psychosocial changes to unambiguous, progressive symptom improvement to tentative impressions of benefit; and (4) often worried whether their improvement was due to normal fluctuations or placebo effects. The placebo treatment was a problematic perturbation that provided an opportunity to reconstruct the experiences of the fluctuations of their illness and how it disrupted their everyday life. Immersion in this RCT was a co-mingling of enactment, embodiment and interpretation involving ritual performance and evocative symbols, shifts in bodily sensations, symptoms, mood, daily life behaviors, and social interactions, all accompanied by self-scrutiny and re-appraisal. The placebo effect involved a spectrum of factors and any single theory of placebo—e.g. expectancy, hope, conditioning, anxiety reduction, report bias, symbolic work, narrative and embodiment—provides an inadequate model to explain its salubrious benefits.
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Patients in the placebo arms of randomized controlled trials (RCT) often experience positive changes from baseline. While multiple theories concerning such “placebo effects” exist, peculiarly, none has been informed by actual interviews of patients undergoing placebo treatment. Here, we report on a qualitative study (n = 27) embedded within a RCT (n = 262) in patients with irritable bowel syndrome. Besides identical placebo acupuncture treatment in the RCT, the qualitative study patients also received an additional set of interviews at the beginning, midpoint, and end of the trial. Interviews of the 12 qualitative subjects who underwent and completed placebo treatment were transcribed. We found that patients (1) were persistently concerned with whether they were receiving placebo or genuine treatment; (2) almost never endorsed “expectation” of improvement but spoke of “hope” instead and frequently reported despair; (3) almost all reported improvement ranging from dramatic psychosocial changes to unambiguous, progressive symptom improvement to tentative impressions of benefit; and (4) often worried whether their improvement was due to normal fluctuations or placebo effects. The placebo treatment was a problematic perturbation that provided an opportunity to reconstruct the experiences of the fluctuations of their illness and how it disrupted their everyday life. Immersion in this RCT was a co-mingling of enactment, embodiment and interpretation involving ritual performance and evocative symbols, shifts in bodily sensations, symptoms, mood, daily life behaviors, and social interactions, all accompanied by self-scrutiny and re-appraisal. The placebo effect involved a spectrum of factors and any single theory of placebo – e.g. expectancy, hope, conditioning, anxiety reduction, report bias, symbolic work, narrative and embodiment – provides an inadequate model to explain its salubrious benefits.
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Objective  To explore participants’ experience in placebo-controlled randomized clinical trials (RCTs) specifically in relationship to their expectations. Background  Aspects of being in RCTs, such as informed consent, perception of benefit and understanding of randomization, have been examined. In contrast, little is known concerning the formation of patient expectations before and during trials. Methods  Qualitative methods using in-depth interviews with a semi-structured interview guide of nine patients from four different RCTs. Data analysis was conducted using a codebook format arranging participant responses under broad analytical headings. The interviewer used a semi-structured interview guide to direct the conversation from one broad topic to the next within the context of the ongoing conversation. A checklist of topics encouraged participants to describe their experiences in RCTs. Narratives concerning expectation, blinding and placebo  were compared  to  identify  common  themes. Results  Patient anticipatory processes were influenced and modified both before and during the trial from multiple inputs. Such factors as past experiences in RCTs, past experiences of ineffective treatment, stress of being off regular medications, fear of being a ‘placebo responder’, input of non-study doctors or other health professionals, the experience of other participants, measurements of health parameters made during the trial and the presence or absence of side-effects all   affected   patient   expectation. Conclusion  Expectations in RCTs are not fixed and instead may be viewed as continuously shaped by multiple inputs that include experience and information received both before and during the trial. Variability in placebo response observed in previous studies may be related to the fluid nature of expectations. Trying to control and equalize expectations in RCTs may be more difficult than previously assumed.
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Evidence that placebo acupuncture is an effective treatment for chronic pain presents a puzzle: how do placebo needles appearing to patients to penetrate the body, but instead sitting on the skin’s surface in the manner of a tactile stimulus, evoke a healing response? Previous accounts of ritual touch healing in which patients often described enhanced touch sensations (including warmth, tingling or flowing sensations) suggest an embodied healing mechanism. In this qualitative study, we asked a subset of patients in a singleblind randomized trial in irritable bowel syndrome to describe their treatment experiences while undergoing placebo treament. Analysis focused on patients’ unprompted descriptions of any enhanced touch sensations (e.g., warmth, tingling) and any significance patients assigned to the sensations. We found in 5/6 cases, patients associated sensations including “warmth” and “tingling” with treatment efficacy. The conclusion offers a “neurophenomenological” account of the placebo effect by considering dynamic effects of attentional filtering on early sensory cortices, possibly underlying the phenomenology of placebo acupuncture.
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BACKGROUND: Despite the apparent high placebo response rate in randomized placebo-controlled trials (RCT) of patients with irritable bowel syndrome (IBS), little is known about the variability and predictors of this response. OBJECTIVES: To describe the magnitude of response in placebo arms of IBS clinical trials and to identify which factors predict the variability of the placebo response. METHODS: We performed a meta-analysis of published, English language, RCT with 20 or more IBS patients who were treated for at least 2 weeks. This analysis is limited to studies that assessed global response (improvement in overall symptoms). The variables considered as potential placebo modifiers were study design, study duration, use of a run-in phase, Jadad score, entry criteria, number of office visits, number of office visits/study duration, use of diagnostic testing, gender, age and type of medication studied. FINDINGS: Forty-five placebo-controlled RCTs met the inclusion criteria. The placebo response ranged from 16.0 to 71.4% with a population-weighted average of 40.2%, 95% CI (35.9-44.4). Significant associations with lower placebo response rates were fulfillment of the Rome criteria for study entry (P=0.049) and an increased number of office visits (P=0.026). CONCLUSIONS: Placebo effects in IBS clinical trials measuring a global outcome are highly variable. Entry criteria and number of office visits are significant predictors of the placebo response. More stringent entry criteria and an increased number of office visits appear to independently decrease the placebo response.
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Abstract  Background:  Despite the apparent high placebo response rate in randomized placebo-controlled trials (RCT) of patients with irritable bowel syndrome (IBS), little is known about the variability and predictors of this response. Objectives:  To describe the magnitude of response in placebo arms of IBS clinical trials and to identify which factors predict the variability of the placebo response. Methods:  We performed a meta-analysis of published, English language, RCT with 20 or more IBS patients who were treated for at least 2 weeks. This analysis is limited to studies that assessed global response (improvement in overall symptoms). The variables considered as potential placebo modifiers were study design, study duration, use of a run-in phase, Jadad score, entry criteria, number of office visits, number of office visits/study duration, use of diagnostic testing, gender, age and type of medication studied. Findings:  Forty-five placebo-controlled RCTs met the inclusion criteria. The placebo response ranged from 16.0 to 71.4% with a population-weighted average of 40.2%, 95% CI (35.9–44.4). Significant associations with lower placebo response rates were fulfilment of the Rome criteria for study entry (P = 0.049) and an increased number of office visits (P = 0.026). Conclusions:  Placebo effects in IBS clinical trials measuring a global outcome are highly variable. Entry criteria and number of office visits are significant predictors of the placebo response. More stringent entry criteria and an increased number of office visits appear to independently decrease the placebo response.

The experience of pain arises from both physiological and psychological factors, including one's beliefs and expectations. Thus, placebo treatments that have no intrinsic pharmacological effects may produce analgesia by altering expectations. However, controversy exists regarding whether placebos alter sensory pain transmission, pain affect, or simply produce compliance with the suggestions of investigators. In two functional magnetic resonance imaging (fMRI) experiments, we found that placebo analgesia was related to decreased brain activity in pain-sensitive brain regions, including the thalamus, insula, and anterior cingulate cortex, and was associated with increased activity during anticipation of pain in the prefrontal cortex, providing evidence that placebos alter the experience of pain.
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Patient–physician interactions significantly contribute to placebo effects and clinical outcomes. While the neural correlates of placebo responses have been studied in patients, the neurobiology of the clinician during treatment is unknown. This study investigated physicians’ brain activations during patient–physician interaction while the patient was experiencing pain, including a ‘treatment‘, ‘no-treatment’ and ‘control’ condition. Here, we demonstrate that physicians activated brain regions previously implicated in expectancy for pain–relief and increased attention during treatment of patients, including the right ventrolateral and dorsolateral prefrontal cortices. The physician’s ability to take the patients’ perspective correlated with increased brain activations in the rostral anterior cingulate cortex, a region that has been associated with processing of reward and subjective value. We suggest that physician treatment involves neural representations of treatment expectation, reward processing and empathy, paired with increased activation in attention-related structures. Our findings further the understanding of the neural representations associated with reciprocal interactions between clinicians and patients; a hallmark for successful treatment outcomes.
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