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Progress in Neurobiology Jan 2018Placebo treatments are pharmacologically inert, but are known to alleviate symptoms across a variety of clinical conditions. Associative learning and cognitive... (Review)
Review
Placebo treatments are pharmacologically inert, but are known to alleviate symptoms across a variety of clinical conditions. Associative learning and cognitive expectations both play important roles in placebo responses, however we are just beginning to understand how interactions between these processes lead to powerful effects. Here, we review the psychological principles underlying placebo effects and our current understanding of their brain bases, focusing on studies demonstrating both the importance of cognitive expectations and those that demonstrate expectancy-independent associative learning. To account for both forms of placebo analgesia, we propose a dual-process model in which flexible, contextually driven cognitive schemas and attributions guide associative learning processes that produce stable, long-term placebo effects. According to this model, the placebo-induction paradigms with the most powerful effects are those that combine reinforcement (e.g., the experience of reduced pain after placebo treatment) with suggestions and context cues that disambiguate learning by attributing perceived benefit to the placebo. Using this model as a conceptual scaffold, we review and compare neurobiological systems identified in both human studies of placebo analgesia and behavioral pain modulation in rodents. We identify substantial overlap between the circuits involved in human placebo analgesia and those that mediate multiple forms of context-based modulation of pain behavior in rodents, including forebrain-brainstem pathways and opioid and cannabinoid systems in particular. This overlap suggests that placebo effects are part of a set of adaptive mechanisms for shaping nociceptive signaling based on its information value and anticipated optimal response in a given behavioral context.
Topics: Analgesia; Animals; Humans; Models, Neurological; Pain; Pain Perception; Placebo Effect
PubMed: 29108801
DOI: 10.1016/j.pneurobio.2017.10.008 -
JAMA Network Open Jul 2022Nonspecific effects, particularly placebo effects, are thought to contribute significantly to the observed effect in surgical trials. (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Nonspecific effects, particularly placebo effects, are thought to contribute significantly to the observed effect in surgical trials.
OBJECTIVE
To estimate the proportion of the observed effect of surgical treatment that is due to nonspecific effects (including the placebo effect).
DATA SOURCES
Published Cochrane reviews and updated, extended search of MEDLINE, Embase, and CENTRAL until March 2019.
STUDY SELECTION
Published randomized placebo-controlled surgical trials and trials comparing the effect of the same surgical interventions with nonoperative controls (ie, no treatment, usual care, or exercise program).
DATA EXTRACTION AND SYNTHESIS
Pairs of authors independently screened the search results, assessed full texts to identify eligible studies and the risk of bias of included studies, and extracted data. The proportion of all nonspecific effects was calculated as the change in the placebo control divided by the change in the active surgery and pooled in a random-effect meta-analysis. To estimate the magnitude of the placebo effect, we pooled the difference in outcome between placebo and nonoperative controls and used metaregression to estimate the association between the type of control group and the treatment effect (difference between the groups), adjusting for risk of bias, sample size, and type of outcome.
MAIN OUTCOMES AND MEASURES
Between- and within-group effect sizes expressed as Hedges g.
RESULTS
In this review, 100 trials were included comprising data from 62 trials with placebo controls (3 also included nonoperative controls), and 38 trials with nonoperative controls (32 interventions; 10 699 participants). Risk of bias across trials was comparable except for performance and detection bias, which was high in trials with nonoperative controls. The mean nonspecific effects accounted for 67% (95% CI, 61% to 73%) of the observed change after surgery; however, this varied widely between different procedures. The estimated surgical placebo effect had a standardized mean difference (SMD) of 0.13 (95% CI, -0.26 to 0.51). Trials with placebo and nonoperative controls found comparable treatment effects (SMD, -0.09 [95% CI, -0.35 to 0.18]; 15 interventions; 73 between-group effects; adjusted analysis: SMD, -0.11 [95% CI, -0.37 to 0.15]).
CONCLUSIONS AND RELEVANCE
In this review, the change in health state after surgery was composed largely of nonspecific effects, but no evidence supported a large placebo effect. Placebo-controlled surgical trials may be redundant when trials with nonoperative controls consistently report no substantial association from surgery compared with nonoperative treatment.
Topics: Control Groups; Exercise; Humans; Placebo Effect
PubMed: 35895060
DOI: 10.1001/jamanetworkopen.2022.23903 -
International Journal of Molecular... Apr 2022The placebo effect can be defined as the improvement of symptoms in a patient after the administration of an innocuous substance in a context that induces expectations... (Review)
Review
The placebo effect can be defined as the improvement of symptoms in a patient after the administration of an innocuous substance in a context that induces expectations regarding its effects. During recent years, it has been discovered that the placebo response not only has neurobiological functions on analgesia, but that it is also capable of generating effects on the immune and endocrine systems. The possible integration of changes in different systems of the organism could favor the well-being of the individuals and go hand in hand with conventional treatment for multiple diseases. In this sense, classic conditioning and setting expectations stand out as psychological mechanisms implicated in the placebo effect. Recent advances in neuroimaging studies suggest a relationship between the placebo response and the opioid, cannabinoid, and monoaminergic systems. Likewise, a possible immune response conditioned by the placebo effect has been reported. There is evidence of immune suppression conditioned through the insular cortex and the amygdala, with noradrenalin as the responsible neurotransmitter. Finally, a conditioned response in the secretion of different hormones has been determined in different studies; however, the molecular mechanisms involved are not entirely known. Beyond studies about its mechanism of action, the placebo effect has proved to be useful in the clinical setting with promising results in the management of neurological, psychiatric, and immunologic disorders. However, more research is needed to better characterize its potential use. This review integrates current knowledge about the psycho-neuro-endocrine-immune basis of the placebo effect and its possible clinical applications.
Topics: Analgesia; Endocrine System; Humans; Pain; Pain Management; Placebo Effect
PubMed: 35457014
DOI: 10.3390/ijms23084196 -
Health Psychology : Official Journal of... Dec 2016Medication side effects are common, often leading to reduced quality of life, nonadherence, and financial costs for health services. Many side effects are the result of... (Review)
Review
OBJECTIVES
Medication side effects are common, often leading to reduced quality of life, nonadherence, and financial costs for health services. Many side effects are the result of a psychologically mediated "nocebo effect." This review identifies the risk factors involved in the development of nocebo effects.
METHOD
Web of Science, Scopus, MEDLINE, PsycINFO, Journals@Ovid full text, and Global Health were searched using the terms "nocebo" and "placebo effect." To be included, studies must have exposed people to an inert substance and have assessed 1 or more baseline or experimental factor(s) on its ability to predict symptom development in response to the inert exposure.
RESULTS
Eighty-nine studies were included; 70 used an experimental design and 19 used a prospective design, identifying 14 different categories of risk factor. The strongest predictors of nocebo effects were a higher perceived dose of exposure, explicit suggestions that the exposure triggers arousal or symptoms, observing people experiencing symptoms from the exposure, and higher expectations of symptoms.
CONCLUSIONS
To reduce nocebo induced symptoms associated with medication or other interventions clinicians could reduce expectations of symptoms, limit suggestions of symptoms, correct unrealistic dose perceptions, and reduce exposure to people experiencing side effects. There is some evidence that we should do this especially for persons with at-risk personality types, though exactly which personality types these are requires further research. These suggestions have a downside in terms of consent and paternalism, but there is scope to develop innovative ways to reduce nocebo effects without withholding information. (PsycINFO Database Record
Topics: Adult; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Nocebo Effect; Prospective Studies; Quality of Life; Risk Factors
PubMed: 27657801
DOI: 10.1037/hea0000416 -
Biology Letters Nov 2017The placebo effect is widely recognized but important questions remain, for example whether the capacity to respond to a placebo is an evolved, and potentially... (Review)
Review
The placebo effect is widely recognized but important questions remain, for example whether the capacity to respond to a placebo is an evolved, and potentially ubiquitous trait, or an unpredictable side effect of another evolved process. Understanding this will determine the degree to which the physiology underlying placebo effects might be manipulated or harnessed to optimize medical treatments. We argue that placebo effects are cases of phenotypic plasticity where once predictable cues are now unpredictable. Importantly, this explains why placebo-like effects are observed in less complex organisms such as worms and flies. Further, this indicates that such species present significant opportunities to test hypotheses that would be ethically or pragmatically impossible in humans. This paradigm also suggests that data informative of human placebo effects pre-exist in studies of model organisms.
Topics: Animals; Biological Variation, Population; Cues; Humans; Models, Animal; Placebo Effect
PubMed: 29187606
DOI: 10.1098/rsbl.2017.0585 -
Contemporary Clinical Trials Aug 2021The desire to reduce high placebo response rates in clinical trials is a popular concept. However, few studies have rigorously examined the effectiveness of methods to... (Review)
Review
The desire to reduce high placebo response rates in clinical trials is a popular concept. However, few studies have rigorously examined the effectiveness of methods to control for placebo responses that are relevant to randomized controlled trials. The primary objective of this review was to evaluate the effect of experimental placebo manipulations in randomized controlled trials (RCTs). We critically reviewed studies designed to manipulate placebo responses including positive expectations regarding the effectiveness of the placebo treatment, manipulating the time spent with subjects, and training study staff and subjects to accurately report symptom severity. These efforts have generally resulted in reduced placebo response and improved discrimination between drug and placebo. Interventions that neutralize staff and subject expectations and improve the ability of subjects to accurately report symptom severity have shown the most promise. Reduction of the placebo response has the potential to accelerate the development of new therapeutics.
Topics: Humans; Placebo Effect
PubMed: 34237458
DOI: 10.1016/j.cct.2021.106503 -
The Lancet. Psychiatry Mar 2015A strong placebo response in psychiatric disorders has been noted for the past 50 years and various attempts have been made to identify predictors of it, by use of... (Meta-Analysis)
Meta-Analysis Review
A strong placebo response in psychiatric disorders has been noted for the past 50 years and various attempts have been made to identify predictors of it, by use of meta-analyses of randomised controlled trials and laboratory studies. We reviewed 31 meta-analyses and systematic reviews of more than 500 randomised placebo-controlled trials across psychiatry (depression, schizophrenia, mania, attention-deficit hyperactivity disorder, autism, psychosis, binge-eating disorder, and addiction) for factors identified to be associated with increased placebo response. Of 20 factors discussed, only three were often linked to high placebo responses: low baseline severity of symptoms, more recent trials, and unbalanced randomisation (more patients randomly assigned to drug than placebo). Randomised controlled trials in non-drug therapy have not added further predictors, and laboratory studies with psychological, brain, and genetic approaches have not been successful in identifying predictors of placebo responses. This comprehensive Review suggests that predictors of the placebo response are still to be discovered, the response probably has more than one mediator, and that different and distinct moderators are probably what cause the placebo response within psychiatry and beyond.
Topics: Humans; Mental Disorders; Placebo Effect; Randomized Controlled Trials as Topic
PubMed: 25815249
DOI: 10.1016/S2215-0366(14)00092-3 -
International Review of Neurobiology 2018The investigation of placebo effects in animal pain models has received less attention than human research. This may be related to a number of difficulties, including... (Review)
Review
The investigation of placebo effects in animal pain models has received less attention than human research. This may be related to a number of difficulties, including the fact that animals lack the ability to use language and establish expectancies verbally, that animals cannot report and rate the extent to which they experience pain, and the inadequacy of current models of pain. Here, we describe the relatively small number of studies that have been published, communicating the opportunities and excitement of this research. We critically discuss pitfalls and limitations with the hope that this will advance future animal placebo-related research.
Topics: Acute Pain; Analgesia; Animals; Chronic Pain; Conditioning, Classical; Mice; Placebo Effect; Rats
PubMed: 29681320
DOI: 10.1016/bs.irn.2018.02.001 -
Revue Medicale de Liege May 2023Functional disorders are clinical entities corresponding to complaints mimicking diseases without a clearly identified organic substrate despite a rigorous history and...
Functional disorders are clinical entities corresponding to complaints mimicking diseases without a clearly identified organic substrate despite a rigorous history and clinical examination. Sometimes, complementary examinations are necessary to rule out an organic lesion that could explain the symptomatology. The notion of a diagnosis of exclusion is therefore very present. The physician must constantly re-evaluate the diagnosis of functional disorder in order not to «miss» a diagnosis with an organic cause.The treatment of these functional disorders is sometimes based on psychological treatment when a psychogenic dimension seems to be involved. This is not always the case. In such cases it is necessary to be able to consider a placebo approach with the hope that the placebo effect may improve the patient's condition. This article discusses the placebo effect in functional disorders without omitting to address ethical and philosophical considerations.
Topics: Humans; Placebo Effect; Disease
PubMed: 37350197
DOI: No ID Found -
NeuroImage Dec 2023Literature suggests that attention is a critical cognitive process for pain perception and modulation and may play an important role in placebo and nocebo effects. Here,... (Randomized Controlled Trial)
Randomized Controlled Trial
Modulation effects of repeated transcranial direct current stimulation on the dorsal attention and frontal parietal networks and its association with placebo and nocebo effects.
Literature suggests that attention is a critical cognitive process for pain perception and modulation and may play an important role in placebo and nocebo effects. Here, we investigated how repeated transcranial direct current stimulation (tDCS) applied at the dorsolateral prefrontal cortex (DLPFC) for three consecutive days can modulate the brain functional connectivity (FC) of two networks involved in cognitive control: the frontoparietal network (FPN) and dorsal attention network (DAN), and its association with placebo and nocebo effects. 81 healthy subjects were randomized to three groups: anodal, cathodal, and sham tDCS. Resting state fMRI scans were acquired pre- and post- tDCS on the first and third day of tDCS. An Independent Component Analysis (ICA) was performed to identify the FPN and DAN. ANCOVA was applied for group analysis. Compared to sham tDCS, 1) both cathodal and anodal tDCS increased the FC between the DAN and right parietal operculum; cathodal tDCS also increased the FC between the DAN and right postcentral gyrus; 2) anodal tDCS led to an increased FC between the FPN and right parietal operculum, while cathodal tDCS was associated with increased FC between the FPN and left superior parietal lobule/precuneus; 3) the FC increase between the DAN and right parietal operculum was significantly correlated to the placebo analgesia effect in the cathodal group. Our findings suggest that both repeated cathodal and anodal tDCS could modulate the FC of two important cognitive brain networks (DAN and FPN), which may modulate placebo / nocebo effects.
Topics: Humans; Transcranial Direct Current Stimulation; Nocebo Effect; Prefrontal Cortex; Brain; Pain
PubMed: 37939891
DOI: 10.1016/j.neuroimage.2023.120433