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Over the past 30 years there has been a surge of research on the placebo effect using a neuroscientific approach. The interesting aspects of this effort are related to the identification of several biological mechanisms of both the placebo and nocebo effects, the latter of which is defined as a negative placebo effect. Some important translational implications have emerged both in the setting of clinical trials and in routine medical practice. One of the principal contributions of neuroscience has been to draw the attention of the scientific and medical communities to the important role of psychobiological factors in therapeutic outcomes, be they drug related or not. Indeed, many biological mechanisms triggered by placebos and nocebos resemble those modulated by drugs, suggesting a possible interaction between psychological factors and drug action. Unfortunately, this new knowledge regarding placebos has the potential of being dangerously exploited by pseudoscience.

Introduction: The widespread use of the word 'placebo' in the medical literature emphasizes the importance of this phenomenon in modern biomedical sciences. Neuroscientific research over the past thirty years shows that placebo effects are genuine psychobiological events attributable to the overall therapeutic context, and can be robust in both laboratory and clinical settings., Areas Covered: Here the authors describe the biological mechanisms and the clinical implications of placebo effects with particular emphasis on neurology and psychiatry, for example in pain, movement disorders, depression. In these conditions, a number of endogenous systems have been identified, such as endogenous opioids, endocannabinoids, and dopamine, which contribute to the placebo-induced benefit., Expert Opinion: Every effort should be made to maximize the placebo effect and reduce its evil twin, the nocebo effect, in medical practice. This does not require the administration of a placebo, but rather the enhancement of the effects of pharmacological and nonpharmacological treatments through a good doctor-patient interaction.

Participants of clinical trials who receive a placebo treatment often report a variety of adverse events, sometimes called nocebo effects. The reason why these adverse events occur is not clear, and understanding the underlying mechanisms represents a challenge that is likely to improve the interpretation of clinical trials as well as medical practice. Here, we studied 192 healthy subjects who received placebo oxygen through a mask after reading (READ) or not reading (NO-READ) a list of possible adverse events of oxygen breathing: headache, chest pain, abdominal pain, and cough. The whole hypothalamus-pituitary-adrenal axis was assessed just before and right after placebo breathing by measuring the hypothalamic corticotropin-releasing hormone (CRH), pituitary adrenocorticotropic hormone (ACTH), and adrenal cortisol (COR). In addition, both state and trait anxiety were assessed. We found that 64.5% of the NO-READ group reported no adverse events, 30.2% had one, and only 5.2% had two adverse events. In contrast, only 20.8% of the READ group reported no adverse events, whereas 1, 2, 3, and 4 adverse events were reported with a frequency of 21.8%, 19.8%, 19.8%, and 17.7%, respectively. In addition, when the READ group reported three and four adverse events, CRH, ACTH, and COR were significantly increased compared to the NO-READ group, along with an increase in state anxiety scores. These data indicate that hypothalamic-pituitary-adrenal activity and state anxiety are increased in those subjects who report many adverse events after reading a list of adverse events, thus highlighting a possible neuroendocrine mechanism after placebo administration., (© 2021 The Authors. Clinical Pharmacology & Therapeutics © 2021 American Society for Clinical Pharmacology and Therapeutics.)

Evidence from pain research shows that the effectiveness of active pharmacological treatments can be enhanced by placebo effects. The "open drug administration" is superior to "hidden drug administration.​" In a randomized controlled trial, we aimed to show that the targeted use of placebo effects increases the efficacy of an antihistamine (dimetindene) infusion in participants with atopic dermatitis. We openly infused dimetindene (drug) in full sight with information (intervention group 1: OPEN-DRUG+INST), openly infused drug with an additional classical conditioning learning experience (intervention group 2: OPEN-DRUG+INST+COND) or infused drug without any information or sight (i.e., hidden administration (control group 1: HIDDEN-DRUG)). Control group 2 received a placebo infusion (saline) declared as dimetindene and also experienced the conditioning experience (PLAC+INST+COND). Itch was experimentally induced with histamine via a skin prick test. Outcome was assessed at the subjective (primary end point: experimental itch intensity, numeric rating scale), and objective level (secondary end point: wheal size, mm 2 ). Experimental-induced itch intensity decreased in all groups but at different rates (P < 0.001). The groups with the open administration, whether it was dimetindene or placebo, had significantly stronger reductions in itch compared to the HIDDEN-DRUG group (OPEN-DRUG+INST+COND: P < 0.001; OPEN-DRUG+INST: P = 0.009; and PLAC+INST+COND: P < 0.001). Additional drug conditioning mediated via expectation led to a stronger reduction of itching (P = 0.001). Results on wheal size were similar (P = 0.048), however, no significant difference between the HIDDEN-DRUG group and the PLAC+INST+COND group (P = 0.967) was found. We conclude that specifically generated targeted placebo effects can significantly increase the action of a drug (dimetindene) and should be used in clinical practice., (© 2021 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Introduction: Clinical and laboratory studies demonstrate that placebo and nocebo effects influence various symptoms and conditions after the administration of both inert and active treatments., Objective: There is an increasing need for up-to-date recommendations on how to inform patients about placebo and nocebo effects in clinical practice and train clinicians how to disclose this information., Methods: Based on previous clinical recommendations concerning placebo and nocebo effects, a 3-step, invitation-only Delphi study was conducted among an interdisciplinary group of internationally recognized experts. The study consisted of open- and closed-ended survey questions followed by a final expert meeting. The surveys were subdivided into 3 parts: (1) informing patients about placebo effects, (2) informing patients about nocebo effects, and (3) training clinicians how to communicate this information to the patients., Results: There was consensus that communicating general information about placebo and nocebo effects to patients (e.g., explaining their role in treatment) could be beneficial, but that such information needs to be adjusted to match the specific clinical context (e.g., condition and treatment). Experts also agreed that training clinicians to communicate about placebo and nocebo effects should be a regular and integrated part of medical education that makes use of multiple formats, including face-to-face and online modalities., Conclusions: The current 3-step Delphi study provides consensus-based recommendations and practical considerations for disclosures about placebo and nocebo effects in clinical practice. Future research is needed on how to optimally tailor information to specific clinical conditions and patients' needs, and on developing standardized disclosure training modules for clinicians., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Purpose: This study seeks to evaluate effects of expectations and conditioning on dry breath holding., Methods: Sixty healthy volunteers were subdivided into 3 groups and were tested across 4 breath holding trials. Participants of the Control group (C) did not undergo any manipulation. Participants of the placebo (P) and nocebo (N) groups were told that they would inhale O2 (actually sham O2) or CO2 (actually sham CO2) along with opposite information that this would enhance or worsen their breath holding time, respectively. Opposite conditioning paradigms based on false visual feedback were employed to reinforce participants' positive (placebo) and negative (nocebo) beliefs., Results: The P group showed the greater increase in breath holding time from baseline to the last trial (p = 0.0001) and the longest breath holding time in the last trial compared to the C group (p = 0.02) and the N group (p = 0.0001). Additionally, in the last trial the P group showed a greater decrease in peripheral oxygen saturation (SpO2) as compared to the C group (p = 0.04) and the N group (p = 0.001). Heart rate (HR) was accelerated in the N group during breath holding (in comparison to the P group [p = 0.04] and C group [p = 0.04])., Conclusions: Psychological components can affect behavioral and physiological parameters in breath holding. This study may inform future research about the role of placebo and nocebo effects for conditions in which critical functions are at play., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Aim: Despite recent publications, practitioners remain unfamiliar with the current terminology related to the placebo and nocebo phenomena observed in clinical trials and practice, nor with the factors that modulate them. To cover the gap, the European Headache Federation appointed a panel of experts to clarify the terms associated with the use of placebo in clinical trials., Methods: The working group identified relevant questions and agreed upon recommendations. Because no data were required to answer the questions, the GRADE approach was not applicable, and thus only expert opinion was provided according to an amended Delphi method. The initial 12 topics for discussion were revised in the opinion of the majority of the panelists, and after a total of 6 rounds of negotiations, the final agreement is presented., Results/recommendations: Two primary and mechanism-based recommendations are provided for the results of clinical trials: [1] to distinguish the placebo or nocebo response from the placebo or nocebo effect; and [2] for any favorable outcome observed after placebo administration, the term "placebo response" should be used, and for any unfavorable outcome recorded after placebo administration, the term "nocebo response" should be used (12 out of 17 panelists agreed, 70.6% agreement). The placebo or nocebo responses are attributed to a set of factors including those that are related to the medical condition (e.g. natural history, random comorbidities, etc.), along with idiosyncratic ones, in which the placebo or nocebo effects are attributed to idiosyncratic, or nonspecific mechanisms, exclusively (e.g. expectation, conditioning, observational learning etc.). To help investigators and practitioners, the panel summarized a list of environmental factors and idiosyncratic dynamics modulating placebo and nocebo effects. Some of them are modifiable, and investigators or physicians need to know about them in order to modify these factors appropriately to improve treatment. One secondary recommendation addresses the use of the terms "placebo" and "nocebo" ("placebos" and "nocebos" in plural), which refer to the triggers of the placebo/nocebo effects or responses, respectively, and which are inert agents or interventions that should not be confused with the placebo/nocebo responses or effects themselves (all panelists agreed, 100% agreement)., Conclusion: The working group recommends distinguishing the term response from effect to describe health changes from before to after placebo application and to distinguish the terms placebo(s) or nocebo(s) from the health consequences that they cause (placebo/nocebo responses or effects).

Although placebos have long been considered a nuisance in clinical research, over recent years they have become an active and productive field of research. Indeed, the placebo effect represents an elegant model to understand how the brain works. It is worth knowing that there is not a single but many placebo effects, with different mechanisms across different systems, medical conditions and therapeutic interventions. For example, brain mechanisms of expectation, anxiety and reward are all involved, as well as a variety of learning phenomena. There is also some experimental evidence of different genetic variants in placebo responsiveness. Pain and Parkinson&rsquo;s disease represent the most productive models to better understand the neurobiology of the placebo effect. In these medical conditions the neural networks involved have indeed been identified: that is, opioid, cannabinoid, cholecystokinin, cyclooxygenase, and dopamine modulatory networks in pain; and part of the basal ganglia circuitry in Parkinson&rsquo;s disease. Overall, there is today compelling evidence that placebos and drugs share common biochemical pathways and activate the same receptor pathways, which suggests possible interference between social stimuli and therapeutic rituals on one hand and pharmacological agents on the other. The same holds true for the nocebo effect, the opposite phenomenon of placebo. The assessment of patients&rsquo; expectations should become the rule in clinical trials in order to allow us a better interpretation of therapeutic outcomes when comparing placebo and active treatment groups. Administering drugs covertly is another way to identify the placebo psychobiological component without the administration of any placebo, and this provides important information on the role of patient&rsquo;s expectations in the therapeutic outcome. A further in-depth analysis of placebo and nocebo phenomena will certainly provide important information in the near future for a better understanding of human biology, medicine and society.

Placebo and nocebo effects are a factor in sports performance. However, the majority of published studies in sport science are descriptive and speculative regarding mechanisms. It is therefore not unreasonable for the sceptic to argue that placebo and nocebo effects in sport are illusory, and might be better explained by variations in phenomena such as motivation. It is likely that, in sport at least, placebo and nocebo effects will remain in this empirical grey area until researchers provide stronger mechanistic evidence. Recent research in neuroscience has identified a number of consistent, discrete and interacting neurobiological and physiological pathways associated with placebo and nocebo effects, with many studies reporting data of potential interest to sport scientists, for example relating to pain, fatigue and motor control. Findings suggest that placebos and nocebos result in activity of the opioid, endocannabinoid and dopamine neurotransmitter systems, brain regions including the motor cortex and striatum, and measureable effects on the autonomic nervous system. Many studies have demonstrated that placebo and nocebo effects associated with a treatment, for example an inert treatment presented as an analgesic or stimulant, exhibit mechanisms similar or identical to the verum or true treatment. Such findings suggest the possibility of a wide range of distinct placebo and nocebo mechanisms that might influence sports performance. In the present paper, we present some of the findings from neuroscience. Focussing on fatigue as an outcome and caffeine as vehicle, we propose three approaches that researchers in sport might incorporate in their studies in order to better elucidate mechanisms of placebo/nocebo effects on performance.

Introduction: This meta-analysis investigates the placebo response in generalized myasthenia gravis (MG) trials by means of Quantitative Myasthenia Gravis (QMG) scores., Methods: PubMed, Scopus, Web of Science, Cochrane Controlled Trial Register, and EMBASE were searched. QMG score, dropouts rate, adverse events (AEs), and AEs responsible for dropouts were examined, together with treatment moderators., Results: The magnitude of placebo response showed an effect size of 0.24, which was significantly lower than 0.67 of the drug response (P = 0.019). Furthermore, the forest plot revealed that, overall, active treatments showed a significantly higher impact on QMG scores than placebos., Conclusions: Placebo and drug responses in MG trials are small and moderate, respectively. The lack of MG trials with a pure placebo arm or a no-treatment control arm made it impossible to disentangle improvements due to the placebo psychological effect from other effects such as natural history and/or regression to the mean. Muscle Nerve 59:671-678, 2019., (© 2019 Wiley Periodicals, Inc.)

In June 2017 a group of experts in anthropology, biology, kinesiology, neuroscience, physiology, and psychology convened in Canterbury, UK, to address questions relating to the placebo effect in sport and exercise. The event was supported exclusively by Quality Related (QR) funding from the Higher Education Funding Council for England (HEFCE). The funder did not influence the content or conclusions of the group. No competing interests were declared by any delegate. During the meeting and in follow-up correspondence, all delegates agreed the need to communicate the outcomes of the meeting via a brief consensus statement. The two specific aims of this statement are to encourage researchers in sport and exercise science to 1. Where possible, adopt research methods that more effectively elucidate the role of the brain in mediating the effects of treatments and interventions. 2. Where possible, adopt methods that factor for and/or quantify placebo effects that could explain a percentage of inter-individual variability in response to treatments and intervention.

The placebo effect alongside the detrimental nocebo and lessebo effects associated with the use of placebos are well-recognized phenomena. Research conducted in the last two decades has demonstrated that the placebo effect is a measurable health benefit with well-known neurobiological correlates. In this review, we describe the current knowledge about how to best make use of the placebo effect to improve clinical research and optimize clinical care. We will cover four key topics: (1) setting the stage: historical perspectives on the use of placebos; (2) optimizing the use of placebos in clinical trials; (3) use of placebos in clinical practice; and (4) how can we minimize the ethical risks of using placebos? The adoption of the placebo-controlled trial as a standard in the therapeutic development reduced the placebo effect to background noise in a therapeutic signal. Strategies to minimize the placebo effect in clinical trials have been used to obtain positive efficacy results. In more recent years, new study paradigms encouraged a change in the views on placebos and the placebo effect. Alternative study designs and the development of biomarkers for a placebo response permit a better understanding of the contribution of the placebo effect to the results of interventional studies, without minimizing it. In clinical practice, optimizing the placebo effect (and reducing nocebo effects) has the potential to improve care for our patients, but raises ethical challenges. An enhanced patient-physician relationship would be central to any evidence-based intervention used in clinical care to heighten the placebo effect. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

A crucial question in placebo research is related to which conditions and physiological functions are affected by placebos. Here we present evidence that critical life functions, like ventilation, oxygenation, circulation, and perfusion, can be sensitive to placebo treatments in some circumstances. Indeed, we have investigated the role of placebo effects at an altitude of 3500m, where oxygen pressure is 64% compared to the sea level. In these extreme conditions, hypoxia triggers several compensatory responses, such as hyperventilation, increased cardiac output, and increased brain perfusion. A conditioned placebo procedure was found to mimic the effects of oxygen on these compensatory responses, and these effects are still present at altitudes as high as 4500 and 5500m, where oxygen pressure is only 57% and 50%, respectively, compared to the sea level. Thus, placebo effects also take place for those functions that are critical for life and whereby oxygen is the key element., (© 2018 Elsevier Inc. All rights reserved.)

Background: Placebo and nocebo effects occur in clinical or laboratory medical contexts after administration of an inert treatment or as part of active treatments and are due to psychobiological mechanisms such as expectancies of the patient. Placebo and nocebo studies have evolved from predominantly methodological research into a far-reaching interdisciplinary field that is unravelling the neurobiological, behavioural and clinical underpinnings of these phenomena in a broad variety of medical conditions. As a consequence, there is an increasing demand from health professionals to develop expert recommendations about evidence-based and ethical use of placebo and nocebo effects for clinical practice., Methods: A survey and interdisciplinary expert meeting by invitation was organized as part of the 1st Society for Interdisciplinary Placebo Studies (SIPS) conference in 2017. Twenty-nine internationally recognized placebo researchers participated., Results: There was consensus that maximizing placebo effects and minimizing nocebo effects should lead to better treatment outcomes with fewer side effects. Experts particularly agreed on the importance of informing patients about placebo and nocebo effects and training health professionals in patient-clinician communication to maximize placebo and minimize nocebo effects., Conclusions: The current paper forms a first step towards developing evidence-based and ethical recommendations about the implications of placebo and nocebo research for medical practice, based on the current state of evidence and the consensus of experts. Future research might focus on how to implement these recommendations, including how to optimize conditions for educating patients about placebo and nocebo effects and providing training for the implementation in clinical practice., (© 2018 S. Karger AG, Basel.)

Background: Placebo effects represent a major drawback in clinical trials, and their magnitude hampers the development of new treatments. Previous research showed that prior exposure to active treatments increases the placebo response for muscle rigidity in Parkinson's disease., Methods: We investigated the effects of prior exposure to apomorphine on the placebo response of another cardinal symptom of Parkinson's disease, bradykinesia, by a movement time analyzer., Results: We found no placebo response if the placebo was given for the first time, whereas the placebo response was substantial after prior pharmacological conditioning with apomorphine., Conclusions: These findings indicate that prior exposure to drugs is a critical factor in the occurrence and magnitude of placebo effects. These learning effects should be carefully assessed in clinical trials in which patients receive the active treatment first and then are randomized. Indeed, this sequence may generate high placebo responders. © 2017 International Parkinson and Movement Disorder Society., (© 2017 International Parkinson and Movement Disorder Society.)

The placebo response in neuromuscular disorders is not well understood. The only available data regarding its underlying mechanisms are related to neuropathic pain. In this review, we describe the factors that contribute to improved outcomes in the placebo arm, with specific attention to pain and fatigue, as well as some of the most important psychobiological mechanisms that may explain such a response. This approach may also improve our insight into the symptomatology and therapeutic responses of other neuromuscular disorders. The fact that >90% of tested analgesics for neuropathic pain have failed in advanced phases of clinical trials should prompt a greater investment of effort and resources into understanding the mechanisms and impact of placebos in clinical research. Such an endeavor will help improve the design of clinical trials and will provide information that informs clinical neuromuscular practice. Muscle Nerve 56: 358-367, 2017., (© 2017 Wiley Periodicals, Inc.)

As modern research continues to unravel the details of the placebo phenomenon in CNS disorders, uncertainty about therapeutic outcomes in trials of treatments for several neurological conditions is growing. Advances in understanding the mechanisms of different placebo effects have emphasised the substantial challenges inherent in interpreting the results of CNS clinical trials. In the past few years, new mechanisms and concepts have emerged in the study of placebo, nocebo, and Hawthorne effects in CNS clinical trials. For example, the mere step of recruitment in a trial or social interaction among trial participants can change the baseline conditions and therefore affect the interpretation of therapeutic outcomes. Moreover, different genotypes have been shown to respond differently to placebos-eg, in studies of social anxiety, depression, and pain. Increasing recognition of these factors in the general population raises the question of whether attempts should be made to reduce placebo responses in CNS clinical trials. Both clinical trial design and medical practice could benefit from further investigation of these effects across a range of neuropsychiatric disorders., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Among the many contributions by Henry Beecher to science and clinical practice, pain and the placebo effect certainly represent two of the most important aspects. On the one hand, Beecher considered the pain experience not only as arising from the peripheral injured tissues, but also as an emotional experience that is capable of modulating the nociceptive input. On the other hand, he analyzed the placebo effect at an unprecedented level for that time. His ideas sparked from his work on wounded soldiers during World War II. In spite of the unusual situation and the lack of sophisticated experimental tools on the battlefield, Beecher succeeded in putting forward several important concepts, and his ideas still pervade modern health care and research.

Placebos have long been considered a nuisance in clinical research, for they have always been used as comparators for the validation of new treatments. By contrast, today they represent an active field of research, and, due to the involvement of many mechanisms, the study of the placebo effect can actually be viewed as a melting pot of concepts and ideas for neuroscience. There is not a single placebo effect, but many, with different mechanisms across different medical conditions and therapeutic interventions. Expectation, anxiety, and reward are all involved, as well as a variety of learning phenomena and genetic variants. The most productive models to better understand the neurobiology of the placebo effect are pain and Parkinson's disease. In these medical conditions, several neurotransmitters have been identified, such as endogenous opioids, cholecystokinin, dopamine, as well as lipidic mediators, for example, endocannabinoids and prostaglandins. Since the placebo effect is basically a psychosocial context effect, these data indicate that different social stimuli, such as words and therapeutic rituals, may change the chemistry of the patient's brain, and these effects are similar to those induced by drugs., (© 2016 Elsevier B.V. All rights reserved.)

Background: The exact role of expectation in conditioned analgesia is still elusive as it is not clear whether conditioning is an automatic process or rather it is cognitively mediated. This study is aimed at understanding the role of explicit verbal information in conditioned analgesia., Methods: Two groups of healthy subjects received a conditioning procedure whereby two visual cues were paired with increase and decrease in stimulus intensity. In the 'conditioning/verbal information' group (VER), subjects were informed about the meaning of the cues, whereas no information was given to the second group (noVER). After two conditioning blocks, an evocation session was run in which the stimulus intensity was the same, irrespective of the cues. Pain perception was assessed according to a numerical rating scale from 0 (no pain) to 10 (maximal pain). The N2-P2 component of laser-evoked potentials (LEP) was used as an index of index of brain responses to nociceptive stimuli., Results: In the evocation session, only the VER group reported a decrease in pain rating and LEP amplitude when the cues were presented, suggesting that the visual-analgesic association does not occur without explicit verbal information., Conclusions: In line with the cognitive theory of conditioning, our results indicate that just pairing a cue with different pain stimulus intensities is not sufficient, per se, to produce a learning process. What matters is the informational cognitive content of the cue, i.e. the meaning assigned to the cue itself. These findings may help understand the mechanisms of conditioned analgesia and more in general of learning., (© 2014 European Pain Federation - EFIC®)

Placebo and nocebo effects have recently emerged as an interesting model to understand some of the intricate underpinnings of the mind-body interaction. A variety of psychological mechanisms, such as expectation, conditioning, anxiety modulation, and reward, have been identified, and a number of neurochemical networks have been characterized across different conditions, such as pain and motor disorders. What has emerged from the recent insights into the neurobiology of placebo and nocebo effects is that the psychosocial context around the patient and the therapy, which represents the ritual of the therapeutic act, may change the biochemistry and the neuronal circuitry of the patient's brain. Furthermore, the mechanisms activated by placebos and nocebos have been found to be the same as those activated by drugs, which suggests a cognitive/affective interference with drug action. Overall, these findings highlight the important role of therapeutic rituals in the overall therapeutic outcome, including hypnosis, which may have profound implications both in routine medical practice and in the clinical trials setting.

Research on placebo analgesia and nocebo hyperalgesia has primarily included healthy subjects or acute pain patients, and it is unknown whether these effects can be obtained in ongoing pain in patients with chronic pain caused by an identifiable nerve injury. Eighteen patients with postthoracotomy neuropathic pain were exposed to placebo and nocebo manipulations, in which they received open and hidden administrations of pain-relieving (lidocaine) or pain-inducing (capsaicin) treatment controlled for the natural history of pain. Immediately after the open administration, patients rated their expected pain levels on a mechanical visual analogue scale (M-VAS). They also reported their emotional feelings via a quantitative/qualitative experiential method. Subsequently, patients rated their ongoing pain levels on the M-VAS and underwent quantitative sensory testing of evoked pain (brush, pinprick, area of hyperalgesia, wind-up-like pain). There was a significant placebo effect on both ongoing (P=.009 to .019) and evoked neuropathic pain (P=.0005 to .053). Expected pain levels accounted for significant amounts of the variance in ongoing (53.4%) and evoked pain (up to 34.5%) after the open lidocaine administration. Furthermore, patients reported high levels of positive and low levels of negative emotional feelings in the placebo condition compared with the nocebo condition (P⩽.001). Pain increases during nocebo were nonsignificant (P=.394 to 1.000). To our knowledge, this is the first study to demonstrate placebo effects in ongoing neuropathic pain. It provides further evidence for placebo-induced reduction in hyperalgesia and suggests that patients' expectations coexist with emotional feelings about treatments., (Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Today we are witnessing a new science of placebo, a complex discipline that encompasses several experimental approaches and translational implications. Modern neurobiological tools have been used to answer important questions in placebo research, such as the top-down modulation of sensory and motor systems as well as the influence of cognition, emotions, and learning on symptoms, diseases, and responses to treatments. What we have learned is that there is not one single placebo effect, but many. This review highlights the translational implications of this new knowledge, ranging from clinical trial design to medical practice to social and ethical issues., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Placebo and nocebo effects are essential components of medical practice and efficacy research, and can be regarded as a special case of context learning. A fundamental function of the central nervous system is to configure the way in which previous learned context becomes linked to corresponding responses. These responses could be either automatic procedures with little flexibility or highly adaptive procedures modified by associated contexts and consequences. Placebo and nocebo effects may represent a typical example of the combination of the two: conditioning effect, which is an inflexible, instinctual, and automatic response, and cognitive expectancy effect, which is a flexible adaptive response modified by prevailing conscious context. Given the fact that contextual learning originates in the brain, neuroimaging tools have been widely used to study placebo and nocebo effects. In addition, pretest resting state fMRI may be a valuable biomarker to predict placebo responses.

The concept of placebo response has evolved in the past few years from the clinical trial setting and medical practice to a psychobiological model that gives us important information on how the patient's brain is modified by the psychosocial context around the therapy. In this review, some examples will be given where physiological or pathological conditions are altered following the administration of an inert substance along with verbal instructions tailored to induce expectation of a change, and explanations will be presented with details on neurotransmitter changes and neural pathways activated. Although nothing is known about the biological underpinnings of the placebo response in the respiratory system, this review may help extending the neurobiological investigation of placebos from conditions such as pain and Parkinson's disease to respiratory disorders and symptoms such as cough., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Modern medicine has progressed in parallel with the advancement of biochemistry, anatomy, and physiology. By using the tools of modern medicine, the physician today can treat and prevent a number of diseases through pharmacology, genetics, and physical interventions. Besides this materia medica, the patient's mind, cognitions, and emotions play a central part as well in any therapeutic outcome, as investigated by disciplines such as psychoneuroendocrinoimmunology. This review describes recent findings that give scientific evidence to the old tenet that patients must be both cured and cared for. In fact, we are today in a good position to investigate complex psychological factors, like placebo effects and the doctor-patient relationship, by using a physiological and neuroscientific approach. These intricate psychological factors can be approached through biochemistry, anatomy, and physiology, thus eliminating the old dichotomy between biology and psychology. This is both a biomedical and a philosophical enterprise that is changing the way we approach and interpret medicine and human biology. In the first case, curing the disease only is not sufficient, and care of the patient is of tantamount importance. In the second case, the philosophical debate about the mind-body interaction can find some important answers in the study of placebo effects. Therefore, maybe paradoxically, the placebo effect and the doctor-patient relationship can be approached by using the same biochemical, cellular and physiological tools of the materia medica, which represents an epochal transition from general concepts such as suggestibility and power of mind to a true physiology of the doctor-patient interaction.

Placebo analgesia (PA) is one of the most studied placebo effects. Brain imaging studies published over the last decade, using either positron emission tomography (PET) or functional magnetic resonance imaging (fMRI), suggest that multiple brain regions may play a pivotal role in this process. However, there continues to be much debate as to which areas consistently contribute to placebo analgesia-related networks. In the present study, we used activation likelihood estimation (ALE) meta-analysis, a state-of-the-art approach, to search for the cortical areas involved in PA in human experimental pain models. Nine fMRI studies and two PET studies investigating cerebral hemodynamic changes were included in the analysis. During expectation of analgesia, activated foci were found in the left anterior cingulate, right precentral, and lateral prefrontal cortex and in the left periaqueductal gray (PAG). During noxious stimulation, placebo-related activations were detected in the anterior cingulate and medial and lateral prefrontal cortices, in the left inferior parietal lobule and postcentral gyrus, anterior insula, thalamus, hypothalamus, PAG, and pons; deactivations were found in the left mid- and posterior cingulate cortex, superior temporal and precentral gyri, in the left anterior and right posterior insula, in the claustrum and putamen, and in the right thalamus and caudate body. Our results suggest on one hand that the modulatory cortical networks involved in PA largely overlap those involved in the regulation of emotional processes, on the other that brain nociceptive networks are downregulated in parallel with behavioral analgesia., (Copyright © 2011 Wiley Periodicals, Inc.)

The effect of placebo observed in schizophrenia clinical trials represents a growing problem that interferes with signal detection for treatments, increases costs of development, discourages investment in schizophrenia research and delays the introduction of new treatments. This paper seeks to clarify key issues related to this problem and identify potential solutions to them. Differences between placebo effect and response are characterized. Recent insights into the central nervous system mechanisms of placebo effect are described. This is followed by a description of protocol/study design and study conduct issues that are contributing to a growing placebo effect in clinical trials. Potential solutions to these problems are provided.

Purpose of Review: Recent placebo literature provides the scientific basis for the different psychological factors that influence the outcome of a medical treatment. The aim of the present review is to summarize the recent findings of placebo research offering useful tools for everyday medical routine., Recent Findings: Treatment efficacy is influenced by the patient's expectations of therapeutic benefit. Indeed, positive or negative expectations may lead to symptom improvement or worsening, respectively. Therefore, in clinical practice, patients' expectations and beliefs need to be considered and controlled appropriately. In addition, previous experience influences the healing process, as shown by classical conditioning studies. This knowledge can be used to increase the effect of pharmacological or procedural treatments, to reduce drug intake, and to minimize psychological adverse events. Overall, a significant enhancement of the therapeutic outcome can be obtained by potentiating empathic communication and establishing a cooperative patient-provider relationship., Summary: Placebo research provides solid scientific ground for all those psychological aspects that characterize every medical treatment. It also gives us information on the functioning of the human brain, with the possibility to exploit some of these mechanisms in routine medical practice.

Placebo analgesia is mediated by both opioid and nonopioid mechanisms, but so far nothing is known about the nonopioid component. Here we show that the specific CB1 cannabinoid receptor antagonist 5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (rimonabant or SR141716) blocks nonopioid placebo analgesic responses but has no effect on opioid placebo responses. These findings suggest that the endocannabinoid system has a pivotal role in placebo analgesia in some circumstances when the opioid system is not involved.

Purpose of Review: In the last two decades, some of the neuroanatomical and neurophysiological substrates of the placebo effect have been elucidated. What has emerged is the multifactorial nature of the placebo effect, such that there is not a single placebo effect but many. Here we report on recent advances in our understanding of this phenomenon, with particular emphasis on its use as an experimental model to better clarify different brain mechanisms., Recent Findings: One of the most interesting findings in the past few years is that the placebo effect is a learning phenomenon, which is powerfully influenced by the manipulation of different variables. The involvement of opioid mechanisms is supported by several studies on pain, but also by the exploration of new fields such as memory and cognition. Nonopioid mechanisms have been described as well, for example, in pain, Parkinson's disease and anxiety. Recent evidence confirms and extends previous findings on the key role of prefrontal regions in the placebo response., Summary: The study of the placebo effect is paying dividends and bodes well for the future. Whereas in clinical practice it can increase the efficacy of a therapy, in the experimental setting it represents an excellent tool for neuroscience.

Objective: The placebo effect, or response, has evolved from being thought of as a nuisance in clinical and pharmacological research to a biological phenomenon worthy of scientific investigation in its own right. The study of the placebo effect and of its negative counterpart, the nocebo effect, is basically the study of the psychosocial context around the treatment and the patient, and it plays a crucial role in the therapeutic outcome., Methods: In recent years, different types of placebo responses have been analyzed with sophisticated biological tools that have uncovered specific mechanisms at the anatomical, physiological, biochemical and cellular level., Results: Most of our knowledge about the neurobiological mechanisms of the placebo response comes from pain and Parkinson's disease, whereby the neuronal circuits involved in placebo responsiveness have been identified. In the first case, opioidergic, dopaminergic and cholecystokinergic networks have been found to be involved. In the second case, dopaminergic activation in the striatum and neuronal changes in basal ganglia have been described., Conclusion: This recent research has revealed that these placebo-induced biochemical and cellular changes in a patient's brain are very similar to those induced by drugs. This new way of thinking may have profound implications both for clinical trials and for medical practice., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Although the great increase in interest in the placebo phenomenon was spurred by the clinical implications of its use, the progressive elucidation of the neurobiological and pharmacological mechanisms underlying the placebo effect also helps cast new light on the relationship between mind (and brain) and body, a topic of foremost philosophical importance but also a major medical issue in light of the complex interactions between the brain on the one hand and body functions on the other. While the concept of placebo can be a general one, with a broad definition generally applicable to many different contexts, the description of the cerebral processes called into action in specific situations can vary widely. In this paper, examples will be given where physiological or pathological conditions are altered following the administration of an inert substance or verbal instructions tailored to induce expectation of a change, and explanations will be offered with details on neurotransmitter changes and neural pathways activated. As an instance of how placebo effects can extend beyond the clinical setting, data in the physical performance domain and implications for sport competitions will also be presented and discussed.

Rationale: Placebos are known to induce analgesia through the activation of μ-opioid receptors in some circumstances, such as after morphine pre-conditioning, an effect that is blocked by opioid antagonists., Objectives: On the basis of the anti-opioid action of cholecystokinin, here we tested whether the activation of the cholecystokinin type-2 receptors abolishes opioid-induced placebo responses., Methods: The activation of the cholecystokinin type-2 receptors was performed by means of the agonist pentagastrin, and placebo responses were obtained after morphine pre-conditioning in an experimental human model of pain (tourniquet technique)., Results: Opioid-induced placebo responses were completely disrupted by pentagastrin administration. In addition, a high correlation between the response to morphine and the response to placebo was found, and this correlation was completely abolished by pentagastrin., Conclusion: These results show that the cholecystokinin-2 receptor agonist, pentagastrin, has the same effect as the μ-opioid receptor antagonist, naloxone, on placebo analgesia induced by morphine pre-conditioning, which suggests that the balance between cholecystokinergic and opioidergic systems is crucial in placebo responsiveness in pain. These findings also suggest that cholecystokinin type-2 receptor hyperactivity might be present in placebo non-responders.

Although placebos have long been considered a nuisance in clinical research, today they represent an active and productive field of research and, because of the involvement of many mechanisms, the study of the placebo effect can actually be viewed as a melting pot of concepts and ideas for neuroscience. Indeed, there exists not a single but many placebo effects, with different mechanisms and in different systems, medical conditions, and therapeutic interventions. For example, brain mechanisms of expectation, anxiety, and reward are all involved, as well as a variety of learning phenomena, such as Pavlovian conditioning, cognitive, and social learning. There is also some experimental evidence of different genetic variants in placebo responsiveness. The most productive models to better understand the neurobiology of the placebo effect are pain and Parkinson's disease. In these medical conditions, the neural networks that are involved have been identified: that is, the opioidergic-cholecystokinergic-dopaminergic modulatory network in pain and part of the basal ganglia circuitry in Parkinson's disease. Important clinical implications emerge from these recent advances in placebo research. First, as the placebo effect is basically a psychosocial context effect, these data indicate that different social stimuli, such as words and rituals of the therapeutic act, may change the chemistry and circuitry of the patient's brain. Second, the mechanisms that are activated by placebos are the same as those activated by drugs, which suggests a cognitive/affective interference with drug action. Third, if prefrontal functioning is impaired, placebo responses are reduced or totally lacking, as occurs in dementia of the Alzheimer's type.

Conditioning procedures are used in many placebo studies because evidence suggests that conditioning-related placebo responses are usually more robust than those induced by verbal suggestions alone. However, it has not been shown whether there is a causal relation between the number of conditioning trials and the resistance to extinction of placebo and nocebo responses. Here we test the effects of either one or four sessions of conditioning on the modulation of both non-painful and painful stimuli delivered to the dorsum of the foot. Placebo and nocebo manipulations were obtained by pairing green or red light to a series of stimuli that were made lower or higher with respect to a yellow light associated with a series of control stimuli. Subjects were told that the lights would indicate a treatment that would reduce or increase non-painful and painful stimuli to the foot. They were randomly assigned to either Group 1 or 2. Group 1 underwent one session of conditioning and Group 2 received four sessions of conditioning. We found that one session of conditioning (Group 1) induced nocebo responses, but not placebo responses in no pain condition. After one session of conditioning, we observed both nocebo and placebo responses to painful stimulation. However, these effects extinguished over time. Conversely, four sessions of conditioning (Group 2) induced robust placebo and nocebo responses to both non-painful and painful stimuli that persisted over the entire experiment. These findings suggest that the strength of learning may be clinically important for producing long-lasting placebo effects., (Published by Elsevier B.V.)

For many years, placebos have been defined by their inert content and their use as controls in clinical trials and treatments in clinical practice. Recent research shows that placebo effects are genuine psychobiological events attributable to the overall therapeutic context, and that these effects can be robust in both laboratory and clinical settings. There is also evidence that placebo effects can exist in clinical practice, even if no placebo is given. Further promotion and integration of laboratory and clinical research will allow advances in the ethical use of placebo mechanisms that are inherent in routine clinical care, and encourage the use of treatments that stimulate placebo effects., (Copyright 2010 Elsevier Ltd. All rights reserved.)

The recent upsurge in placebo research has demonstrated the sound neurobiological substrate of a phenomenon once believed to be only patient mystification, or at best a variable to control in clinical trials, bringing about a new awareness of its potential exploitation to the patient's benefit and framing it as a positive context effect, with the power to influence the therapy outcome. Placebo effects have been described both in the experimental setting and in different clinical conditions, many of which are of neurological interest. Multiple mechanisms have been described, namely conditioning and cognitive factors like expectation, desire, and reward. A body of evidence from neurochemical, pharmacological, and neuroimaging studies points to the involvement of neural pathways specific to single conditions, such as the activation of the endogenous antinociceptive system during placebo analgesia or the release of dopamine in the striatum of parkinsonian patients experiencing placebo reduction of motor impairment. The possible clinical applications of placebo studies range from the design of clinical trials incorporating specific recommendations and minimizing the use of placebo arms to the optimization of the context surrounding the patient, in order to maximize the placebo component present in any treatment.

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.

In modern medicine, the placebo response or placebo effect has often been regarded as a nuisance in basic research and particularly in clinical research. The latest scientific evidence has demonstrated, however, that the placebo effect and the nocebo effect, the negative effects of placebo, stem from highly active processes in the brain that are mediated by psychological mechanisms such as expectation and conditioning. These processes have been described in some detail for many diseases and treatments, and we now know that they can represent both strength and vulnerability in the course of a disease as well as in the response to a therapy. However, recent research and current knowledge raise several issues that we shall address in this review. We will discuss current neurobiological models like expectation-induced activation of the brain reward circuitry, Pavlovian conditioning, and anxiety mechanisms of the nocebo response. We will further explore the nature of the placebo responses in clinical trials and address major questions for future research such as the relationship between expectations and conditioning in placebo effects, the existence of a consistent brain network for all placebo effects, the role of gender in placebo effects, and the impact of getting drug-like effects without drugs.

Recent interest in the neurobiology of the placebo effect has brought about a new awareness of its potential exploitation for patient benefit, framing it as a positive context effect with the power to influence therapy outcome. Among the different placebo effects described in clinical conditions and experimental settings, placebo analgesia is of particular relevance to the rheumatologist. Placebo analgesia is the field that has most contributed to our understanding of the multiple mechanisms underlying this phenomenon. The possible clinical applications of placebo studies range from the design of clinical trials incorporating specific recommendations and minimizing the use of placebo arms to the optimization of the context surrounding the patient so that the placebo component in any treatment is maximized.

The placebo effect has intrigued scientists since it was proposed. The debate has now centered on how it works. Significant progress has been made and most of our knowledge about the neurobiological mechanisms comes from the field of pain and analgesia. The appropriateness of the experimental/clinical paradigms is crucial when we want to investigate the mechanisms of the placebo phenomenon. Recently, functional imaging techniques, such as positron emission tomography, magnetic resonance imaging, and electro/magnetoencephalography have also given the opportunity to define the neuroanatomical bases of placebo analgesia. This work systematically reviews the literature that deals with placebo analgesia, emphasizing both the methodological aspects and the neurobiological advances. The understanding of placebo mechanisms is fundamental and necessary to identify ways of accessing and harnessing these mechanisms in clinical practice to the patient's benefit.