To assess the quantity and quality of randomised, sham-controlled studies of surgery and invasive... more To assess the quantity and quality of randomised, sham-controlled studies of surgery and invasive procedures and estimate the treatment-specific and non-specific effects of those procedures. Systematic review and meta-analysis. We searched PubMed, EMBASE, CINAHL, CENTRAL (Cochrane Library), PILOTS, PsycInfo, DoD Biomedical Research, clinicaltrials.gov, NLM catalog and NIH Grantee Publications Database from their inception through January 2015. We included randomised controlled trials of surgery and invasive procedures that penetrated the skin or an orifice and had a parallel sham procedure for comparison. Three authors independently extracted data and assessed risk of bias. Studies reporting continuous outcomes were pooled and the standardised mean difference (SMD) with 95% CIs was calculated using a random effects model for difference between true and sham groups. 55 studies (3574 patients) were identified meeting inclusion criteria; 39 provided sufficient data for inclusion in the...
The nocebo effect is a phenomenon that is opposite to the placebo effect, whereby expectation of ... more The nocebo effect is a phenomenon that is opposite to the placebo effect, whereby expectation of a negative outcome may lead to the worsening of a symptom. Thus far, its study has been limited by ethical constraints, particularly in patients, as a nocebo procedure is per se stressful and anxiogenic. It basically consists in delivering verbal suggestions of negative outcomes so that the subject expects clinical worsening. Although some natural nocebo situations do exist, such as the impact of negative diagnoses upon the patient and the patient's distrust in a therapy, the neurobiological mechanisms have been understood in the experimental setting under strictly controlled conditions. As for the placebo counterpart, the study of pain has been fruitful in recent years to understand both the neuroanatomical and the neurochemical bases of the nocebo effect. Recent experimental evidence indicates that negative verbal suggestions induce anticipatory anxiety about the impending pain increase, and this verbally-induced anxiety triggers the activation of cholecystokinin (CCK) which, in turn, facilitates pain transmission. CCK-antagonists have been found to block this anxiety-induced hyperalgesia, thus opening up the possibility of new therapeutic strategies whenever pain has an important anxiety component. Other conditions, such as Parkinson's disease, although less studied, have been found to be affected by nocebo suggestions as well. All these findings underscore the important role of cognition in the therapeutic outcome, and suggest that nocebo and nocebo-related effects might represent a point of vulnerability both in the course of a disease and in the response to a therapy.
Objective To examine the attitudes of US patients about the use of placebo treatments in medical ... more Objective To examine the attitudes of US patients about the use of placebo treatments in medical care.
ABSTRACT A commentary on "What's Not Being Shared in Shared Decision-Making?&... more ABSTRACT A commentary on "What's Not Being Shared in Shared Decision-Making?" from the July-August 2013.
Placebo analgesia makes individuals experience relief of their pain simply by virtue of the antic... more Placebo analgesia makes individuals experience relief of their pain simply by virtue of the anticipation of a benefit. A reduction of pain can occur also when placebos follow the administration of active and effective painkillers. In fact, studies indicate that placebos mimic the action of active treatments and promote the endogenous release of opioids in both humans and animals. Finally, social support and obser-vational learning also lead to analgesic effects. Thus, different psychological factors and situations induce expectations of analgesia facilitating the activation of the top-down systems for pain control along with the release of endogenous media-tors crucially involved in placebo-induced benefits. Recent scientific investigation in the field of brain imaging is opening new avenues to understanding the cognitive mechanisms and neurobiological substrates of expectation-induced pain mod-ulation. Gaining deeper knowledge of top-down mechanisms of pain modulation has enormous ...
The placebo effect has been a source of fascination, irritation, and confusion within biomedicine... more The placebo effect has been a source of fascination, irritation, and confusion within biomedicine over the past 60 years. Although scientific investigation has accelerated in the past decade, with particular attention to neurobiological mechanisms, there has been a dearth of attention to developing a general theory of the placebo effect. In this article, we attempt to address this gap. To set the stage, we review evidence relating to the reality and clinical significance of the placebo effect. Next we investigate the scope and limits of the placebo effect by examining the hypothesis that the placebo effect operates predominantly by modifying the experience and perceptions of illness symptoms, such as pain, anxiety, and fatigue, rather than by modifying the pathophysiology of disease. Based on this background, we characterize the placebo effect as a form of interpersonal healing, as distinct from spontaneous natural healing and from technological healing dependent on physiologically active pharmaceuticals or procedures. Finally, we argue that research on the placebo effect has the potential to revitalize the art of medicine.
Belief in the effectiveness of a placebo treatment is widely thought to be critical for placebo a... more Belief in the effectiveness of a placebo treatment is widely thought to be critical for placebo analgesia. Many types of placebo responses-even those that depend on conditioning-appear to be mediated by expectations that are strengthened as treatment cues are reinforced with positive outcomes. However, placebo effects may occur even when participants are aware they are receiving placebo. To address the question of whether conditioned placebo analgesia can persist in the absence of expectations, we studied the effects of long (4 days) versus short (1 day) conditioning to a placebo treatment. After an initial placebo test, a "reveal" manipulation convincingly demonstrated to participants that they had never received an active drug. Placebo analgesia persisted after the reveal in the long conditioning group only. These findings suggest that reinforcing treatment cues with positive outcomes can create placebo effects that are independent of reported expectations for pain relief. This article demonstrates a form of placebo analgesia that relies on prior conditioning rather than current expected pain relief. This highlights the importance of prior experience on pain relief and offers insight into the variability of placebo effects across individuals.
This article appeared in a journal published by Elsevier. The attached copy is furnished to the a... more This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues.
Pain modulation by placebo mechanisms is one of the most robust and best-studied phenomena, yet a... more Pain modulation by placebo mechanisms is one of the most robust and best-studied phenomena, yet almost all research investigating the mechanisms and implications of the placebo analgesia are based on adult research. After highlighting crucial aspects that need to be considered in studying pain modulation in children, this comprehensive review examines studies related to pain modulation with an emphasis on factors such as age, neural development and pain measures. We critically discuss psychological mechanisms underlying placebo effects, including (1) verbally induced expectations, (2) conditioning and learning mechanisms, and (3) child-parent-physician interactions. Taken together, research suggests that placebo mechanisms can affect therapeutic outcomes and potentially be exploited clinically to improve clinical outcomes in pediatric population. Recommendations for further investigating the mechanistic bases and harnessing placebo effects for supportive therapeutic applications are given.
Recent findings on placebo research corroborate the evidence that the placebo effect represents a... more Recent findings on placebo research corroborate the evidence that the placebo effect represents a promising model to shed new light on the brain-mind-body interactions. In particular, this research has partially elucidated the role of how patients' expectations and the quality of physician-patient communication can influence the efficacy of interventions and overall clinical outcomes. Accordingly, the study of the placebo effect should be incorporated in the core clinical practice curriculum of all health practitioners. While the growing knowledge of the placebo effect points to it as an irreducible primary reality of the medical sciences, an ethical analysis aimed at avoiding the misuse of placebos is needed, while maximizing the opportunity for beneficial placebo effects.
Expectation and conditioning are supposed to be the two main psychological mechanisms for inducin... more Expectation and conditioning are supposed to be the two main psychological mechanisms for inducing a placebo response. Here, we further investigate the effects of both expectation, which was induced by verbal suggestion alone, and conditioning at the level of N1 and N2-P2 components of CO2 laser-evoked potentials (LEPs) and subjective pain reports. Forty-four healthy volunteers were pseudorandomly assigned to one of three experimental groups: Group 1 was tested with verbal suggestion alone, Group 2 was tested with a conditioning procedure, whereby the intensity of painful stimulation was reduced surreptitiously, so as to make the volunteers believe that the treatment was effective, Group 3 was a control group that allowed us to rule out phenomena of sensitization and/or habituation. Pain perception was assessed according to a Numerical Rating Scale (NRS) ranging from 0=no pain sensation to 10=maximum imaginable pain. Both verbal suggestions (Group 1) and conditioning (Group 2) modified the N2-P2 complex, but not the N1 component of LEPs. However, the suggestion-induced LEP changes occurred without subjective perception of pain decrease. Conversely, the N2-P2 amplitude changes that were induced by the conditioning procedure were associated with the subjective perception of pain reduction. Compared to natural history, conditioning produced more robust reductions of LEP amplitudes than verbal suggestions alone. Overall, these findings indicate that prior positive experience plays a key role in maximizing both behavioral and neurophysiological placebo responses, emphasizing that the placebo effect is a learning phenomenon which affects the early central nociceptive processing.
The investigation of nocebo effects is evolving, and a few literature reviews have emerged, altho... more The investigation of nocebo effects is evolving, and a few literature reviews have emerged, although so far without quantifying such effects. This meta-analysis investigated nocebo effects in pain. We searched the databases PubMed, EMBASE, Scopus, and the Cochrane Controlled Trial Register with the term ''nocebo.'' Only studies that investigated nocebo effects as the effects that followed the administration of an inert treatment along with verbal suggestions of symptom worsening and that included a no-treatment control condition were eligible. Ten studies fulfilled the selection criteria. The effect sizes were calculated using Cohen's d and Hedges' g. The overall magnitude of the nocebo effect was moderate to large (lowest g = 0.62 [0.24-1.01] and highest g = 1.03 [0.63-1.43]) and highly variable (range of g = À0.43 to 4.05). The magnitudes and range of effect sizes was similar to those of placebo effects (d = 0.81) in mechanistic studies. In studies in which nocebo effects were induced by a combination of verbal suggestions and conditioning, the effect size was larger (lowest g = 0.76 [0.39-1.14] and highest g = 1.17 [0.52-1.81]) than in studies in which nocebo effects were induced by verbal suggestions alone (lowest g = 0.64 [À0.25 to 1.53] and highest g = 0.87 [0.40-1.34]). These findings are similar to those in the placebo literature. As the magnitude of the nocebo effect is variable and sometimes large, this meta-analysis demonstrates the importance of minimizing nocebo effects in clinical practice.
Placebo administration is known to affect the brain both in pain and in Parkinson disease. Here w... more Placebo administration is known to affect the brain both in pain and in Parkinson disease. Here we show that placebo treatment caused reduced activity in single neurons in the subthalamic nucleus of placebo-responsive Parkinsonian patients. These changes in activity were tightly correlated with clinical improvement; no decrease in activity occurred when the clinical placebo response was absent.
Imaging in CNS Drug Discovery and Development, 2009
Over the past few years, there have been an increasing number of studies investigating placebo re... more Over the past few years, there have been an increasing number of studies investigating placebo responses, with sophisticated techniques, such as positron emission tomography (PET), functional magnetic resonance imaging (fMRI), electroencephalography (EEG), magnetoencephalography (MEG) and recording from single neurons in awake patients. Most of our knowledge about the mechanisms that underlie the placebo effect comes from the field of pain
To assess the quantity and quality of randomised, sham-controlled studies of surgery and invasive... more To assess the quantity and quality of randomised, sham-controlled studies of surgery and invasive procedures and estimate the treatment-specific and non-specific effects of those procedures. Systematic review and meta-analysis. We searched PubMed, EMBASE, CINAHL, CENTRAL (Cochrane Library), PILOTS, PsycInfo, DoD Biomedical Research, clinicaltrials.gov, NLM catalog and NIH Grantee Publications Database from their inception through January 2015. We included randomised controlled trials of surgery and invasive procedures that penetrated the skin or an orifice and had a parallel sham procedure for comparison. Three authors independently extracted data and assessed risk of bias. Studies reporting continuous outcomes were pooled and the standardised mean difference (SMD) with 95% CIs was calculated using a random effects model for difference between true and sham groups. 55 studies (3574 patients) were identified meeting inclusion criteria; 39 provided sufficient data for inclusion in the...
The nocebo effect is a phenomenon that is opposite to the placebo effect, whereby expectation of ... more The nocebo effect is a phenomenon that is opposite to the placebo effect, whereby expectation of a negative outcome may lead to the worsening of a symptom. Thus far, its study has been limited by ethical constraints, particularly in patients, as a nocebo procedure is per se stressful and anxiogenic. It basically consists in delivering verbal suggestions of negative outcomes so that the subject expects clinical worsening. Although some natural nocebo situations do exist, such as the impact of negative diagnoses upon the patient and the patient's distrust in a therapy, the neurobiological mechanisms have been understood in the experimental setting under strictly controlled conditions. As for the placebo counterpart, the study of pain has been fruitful in recent years to understand both the neuroanatomical and the neurochemical bases of the nocebo effect. Recent experimental evidence indicates that negative verbal suggestions induce anticipatory anxiety about the impending pain increase, and this verbally-induced anxiety triggers the activation of cholecystokinin (CCK) which, in turn, facilitates pain transmission. CCK-antagonists have been found to block this anxiety-induced hyperalgesia, thus opening up the possibility of new therapeutic strategies whenever pain has an important anxiety component. Other conditions, such as Parkinson's disease, although less studied, have been found to be affected by nocebo suggestions as well. All these findings underscore the important role of cognition in the therapeutic outcome, and suggest that nocebo and nocebo-related effects might represent a point of vulnerability both in the course of a disease and in the response to a therapy.
Objective To examine the attitudes of US patients about the use of placebo treatments in medical ... more Objective To examine the attitudes of US patients about the use of placebo treatments in medical care.
ABSTRACT A commentary on "What's Not Being Shared in Shared Decision-Making?&... more ABSTRACT A commentary on "What's Not Being Shared in Shared Decision-Making?" from the July-August 2013.
Placebo analgesia makes individuals experience relief of their pain simply by virtue of the antic... more Placebo analgesia makes individuals experience relief of their pain simply by virtue of the anticipation of a benefit. A reduction of pain can occur also when placebos follow the administration of active and effective painkillers. In fact, studies indicate that placebos mimic the action of active treatments and promote the endogenous release of opioids in both humans and animals. Finally, social support and obser-vational learning also lead to analgesic effects. Thus, different psychological factors and situations induce expectations of analgesia facilitating the activation of the top-down systems for pain control along with the release of endogenous media-tors crucially involved in placebo-induced benefits. Recent scientific investigation in the field of brain imaging is opening new avenues to understanding the cognitive mechanisms and neurobiological substrates of expectation-induced pain mod-ulation. Gaining deeper knowledge of top-down mechanisms of pain modulation has enormous ...
The placebo effect has been a source of fascination, irritation, and confusion within biomedicine... more The placebo effect has been a source of fascination, irritation, and confusion within biomedicine over the past 60 years. Although scientific investigation has accelerated in the past decade, with particular attention to neurobiological mechanisms, there has been a dearth of attention to developing a general theory of the placebo effect. In this article, we attempt to address this gap. To set the stage, we review evidence relating to the reality and clinical significance of the placebo effect. Next we investigate the scope and limits of the placebo effect by examining the hypothesis that the placebo effect operates predominantly by modifying the experience and perceptions of illness symptoms, such as pain, anxiety, and fatigue, rather than by modifying the pathophysiology of disease. Based on this background, we characterize the placebo effect as a form of interpersonal healing, as distinct from spontaneous natural healing and from technological healing dependent on physiologically active pharmaceuticals or procedures. Finally, we argue that research on the placebo effect has the potential to revitalize the art of medicine.
Belief in the effectiveness of a placebo treatment is widely thought to be critical for placebo a... more Belief in the effectiveness of a placebo treatment is widely thought to be critical for placebo analgesia. Many types of placebo responses-even those that depend on conditioning-appear to be mediated by expectations that are strengthened as treatment cues are reinforced with positive outcomes. However, placebo effects may occur even when participants are aware they are receiving placebo. To address the question of whether conditioned placebo analgesia can persist in the absence of expectations, we studied the effects of long (4 days) versus short (1 day) conditioning to a placebo treatment. After an initial placebo test, a "reveal" manipulation convincingly demonstrated to participants that they had never received an active drug. Placebo analgesia persisted after the reveal in the long conditioning group only. These findings suggest that reinforcing treatment cues with positive outcomes can create placebo effects that are independent of reported expectations for pain relief. This article demonstrates a form of placebo analgesia that relies on prior conditioning rather than current expected pain relief. This highlights the importance of prior experience on pain relief and offers insight into the variability of placebo effects across individuals.
This article appeared in a journal published by Elsevier. The attached copy is furnished to the a... more This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues.
Pain modulation by placebo mechanisms is one of the most robust and best-studied phenomena, yet a... more Pain modulation by placebo mechanisms is one of the most robust and best-studied phenomena, yet almost all research investigating the mechanisms and implications of the placebo analgesia are based on adult research. After highlighting crucial aspects that need to be considered in studying pain modulation in children, this comprehensive review examines studies related to pain modulation with an emphasis on factors such as age, neural development and pain measures. We critically discuss psychological mechanisms underlying placebo effects, including (1) verbally induced expectations, (2) conditioning and learning mechanisms, and (3) child-parent-physician interactions. Taken together, research suggests that placebo mechanisms can affect therapeutic outcomes and potentially be exploited clinically to improve clinical outcomes in pediatric population. Recommendations for further investigating the mechanistic bases and harnessing placebo effects for supportive therapeutic applications are given.
Recent findings on placebo research corroborate the evidence that the placebo effect represents a... more Recent findings on placebo research corroborate the evidence that the placebo effect represents a promising model to shed new light on the brain-mind-body interactions. In particular, this research has partially elucidated the role of how patients' expectations and the quality of physician-patient communication can influence the efficacy of interventions and overall clinical outcomes. Accordingly, the study of the placebo effect should be incorporated in the core clinical practice curriculum of all health practitioners. While the growing knowledge of the placebo effect points to it as an irreducible primary reality of the medical sciences, an ethical analysis aimed at avoiding the misuse of placebos is needed, while maximizing the opportunity for beneficial placebo effects.
Expectation and conditioning are supposed to be the two main psychological mechanisms for inducin... more Expectation and conditioning are supposed to be the two main psychological mechanisms for inducing a placebo response. Here, we further investigate the effects of both expectation, which was induced by verbal suggestion alone, and conditioning at the level of N1 and N2-P2 components of CO2 laser-evoked potentials (LEPs) and subjective pain reports. Forty-four healthy volunteers were pseudorandomly assigned to one of three experimental groups: Group 1 was tested with verbal suggestion alone, Group 2 was tested with a conditioning procedure, whereby the intensity of painful stimulation was reduced surreptitiously, so as to make the volunteers believe that the treatment was effective, Group 3 was a control group that allowed us to rule out phenomena of sensitization and/or habituation. Pain perception was assessed according to a Numerical Rating Scale (NRS) ranging from 0=no pain sensation to 10=maximum imaginable pain. Both verbal suggestions (Group 1) and conditioning (Group 2) modified the N2-P2 complex, but not the N1 component of LEPs. However, the suggestion-induced LEP changes occurred without subjective perception of pain decrease. Conversely, the N2-P2 amplitude changes that were induced by the conditioning procedure were associated with the subjective perception of pain reduction. Compared to natural history, conditioning produced more robust reductions of LEP amplitudes than verbal suggestions alone. Overall, these findings indicate that prior positive experience plays a key role in maximizing both behavioral and neurophysiological placebo responses, emphasizing that the placebo effect is a learning phenomenon which affects the early central nociceptive processing.
The investigation of nocebo effects is evolving, and a few literature reviews have emerged, altho... more The investigation of nocebo effects is evolving, and a few literature reviews have emerged, although so far without quantifying such effects. This meta-analysis investigated nocebo effects in pain. We searched the databases PubMed, EMBASE, Scopus, and the Cochrane Controlled Trial Register with the term ''nocebo.'' Only studies that investigated nocebo effects as the effects that followed the administration of an inert treatment along with verbal suggestions of symptom worsening and that included a no-treatment control condition were eligible. Ten studies fulfilled the selection criteria. The effect sizes were calculated using Cohen's d and Hedges' g. The overall magnitude of the nocebo effect was moderate to large (lowest g = 0.62 [0.24-1.01] and highest g = 1.03 [0.63-1.43]) and highly variable (range of g = À0.43 to 4.05). The magnitudes and range of effect sizes was similar to those of placebo effects (d = 0.81) in mechanistic studies. In studies in which nocebo effects were induced by a combination of verbal suggestions and conditioning, the effect size was larger (lowest g = 0.76 [0.39-1.14] and highest g = 1.17 [0.52-1.81]) than in studies in which nocebo effects were induced by verbal suggestions alone (lowest g = 0.64 [À0.25 to 1.53] and highest g = 0.87 [0.40-1.34]). These findings are similar to those in the placebo literature. As the magnitude of the nocebo effect is variable and sometimes large, this meta-analysis demonstrates the importance of minimizing nocebo effects in clinical practice.
Placebo administration is known to affect the brain both in pain and in Parkinson disease. Here w... more Placebo administration is known to affect the brain both in pain and in Parkinson disease. Here we show that placebo treatment caused reduced activity in single neurons in the subthalamic nucleus of placebo-responsive Parkinsonian patients. These changes in activity were tightly correlated with clinical improvement; no decrease in activity occurred when the clinical placebo response was absent.
Imaging in CNS Drug Discovery and Development, 2009
Over the past few years, there have been an increasing number of studies investigating placebo re... more Over the past few years, there have been an increasing number of studies investigating placebo responses, with sophisticated techniques, such as positron emission tomography (PET), functional magnetic resonance imaging (fMRI), electroencephalography (EEG), magnetoencephalography (MEG) and recording from single neurons in awake patients. Most of our knowledge about the mechanisms that underlie the placebo effect comes from the field of pain
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