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Annual Review of Neuroscience Jul 2023Treatment outcomes are strongly influenced by expectations, as evidenced by the placebo effect. Meta-analyses of clinical trials reveal that placebo effects are... (Review)
Review
Treatment outcomes are strongly influenced by expectations, as evidenced by the placebo effect. Meta-analyses of clinical trials reveal that placebo effects are strongest in pain, indicating that psychosocial factors directly influence pain. In this review, I focus on the neural and psychological mechanisms by which instructions, learning, and expectations shape subjective pain. I address new experimental designs that help researchers tease apart the impact of these distinct processes and evaluate the evidence regarding the neural mechanisms by which these cognitive factors shape subjective pain. Studies reveal that expectations modulate pain through parallel circuits that include both pain-specific and domain-general circuits such as those involved in affect and learning. I then review how expectations, learning, and verbal instructions impact clinical outcomes, including placebo analgesia and responses to pharmacological treatments, and discuss implications for future work.
Topics: Humans; Motivation; Pain; Analgesia; Learning; Placebo Effect
PubMed: 36917820
DOI: 10.1146/annurev-neuro-101822-122427 -
Molecular Psychiatry Apr 2015Endogenous opioid and non-opioid mechanisms (for example, dopamine (DA), endocannabinoids (eCB)) have been implicated in the formation of placebo analgesic effects, with... (Review)
Review
Endogenous opioid and non-opioid mechanisms (for example, dopamine (DA), endocannabinoids (eCB)) have been implicated in the formation of placebo analgesic effects, with initial reports dating back three decades. Besides the perspective that placebo effects confound randomized clinical trials, the information so far acquired points to neurobiological systems that when activated by positive expectations and maintained through conditioning and reward learning are capable of inducing physiological changes that lead to the experience of analgesia and improvements in emotional state. Molecular neuroimaging techniques with positron emission tomography and the selective μ-opioid and D2/3 radiotracers [(11)C]carfentanil and [(11)C]raclopride have significantly contributed to our understanding of the neurobiological systems involved in the formation of placebo effects. This line of research has described neural and neurotransmitter networks implicated in placebo responses and provided the technical tools to examine inter-individual differences in the function of placebo-responsive mechanisms, and potential surrogates (biomarkers). As a consequence, the formation of biological placebo effects is now being linked to the concept of resiliency mechanisms, partially determined by genetic factors, and uncovered by the cognitive emotional integration of the expectations created by the therapeutic environment and its maintenance through learning mechanisms. Further work needs to extend this research into clinical conditions where the rates of placebo responses are high and its neurobiological mechanisms have been largely unexplored (for example, mood and anxiety disorders, persistent pain syndromes or even Parkinson disease and multiple sclerosis). The delineation of these processes within and across diseases would point to biological targets that have not been contemplated in traditional drug development.
Topics: Analgesics, Opioid; Brain; Humans; Neuroimaging; Neurotransmitter Agents; Personality; Placebo Effect
PubMed: 25510510
DOI: 10.1038/mp.2014.164 -
International Review of Neurobiology 2018Scientific research indicates that open-label and dose-extending placebos (that patients know are placebos) can elicit behavioral, biological, and clinical outcome... (Review)
Review
Scientific research indicates that open-label and dose-extending placebos (that patients know are placebos) can elicit behavioral, biological, and clinical outcome changes. In this chapter, we present the state-of-the-art evidence and ethical considerations about open-label and dose-extending placebos, discussing the perspective of giving placebos with a rational, as dose extension of active drugs, or expectancy boosters. Previous comprehensive reviews of placebo use have considered how to harness placebo effects in medicine and the need to focus on elements of the clinical encounter as well as patient-clinician relations. Here, we illustrate the similarities and differences between standard (deceptive) placebos, open-label placebos and dose-extending placebos. We conclude that placebos without deception would override ethical barriers to their clinical use. This paves the way to future large-scale, pragmatic randomized trials that investigate the potential of ethical open-label and dose-extending placebos to improve patients' outcomes, and reduce side effects.
Topics: Analgesia; Anticipation, Psychological; Conditioning, Classical; Deception; Ethics, Medical; Humans; Placebo Effect
PubMed: 29681327
DOI: 10.1016/bs.irn.2018.01.005 -
Lung Aug 2021This review discusses how the placebo effect related to treatment side effects may confound clinical trials on antitussives and specifically looks at the implications... (Review)
Review
This review discusses how the placebo effect related to treatment side effects may confound clinical trials on antitussives and specifically looks at the implications for trials on ATP antagonists. These new antitussives have distinctive side effects on the sensation of taste, and investigators have expressed concerns that this may unblind the clinical trials. Blinding is an essential component of trial design, but the degree of blinding in trials is rarely assessed. The assumptions of additivity and balance in clinical trials are discussed as important factors that allow assessment of the pharmacological activity of an antitussive. How side effects unbalance a clinical trial by amplifying the placebo effect of active treatments is discussed. The point is made that unblinding of trials invalidates any assessment of efficacy but that there is little interest or discussion about this fundamental aspect of trials. Proposals are discussed which may improve the blinding of trials and control placebo effects by changes to participant information, trial design, patient selection and use of active placebos. The issue of unblinding of clinical trials is not a new issue, but if real progress is to be made in developing new antitussives, then it is an issue that needs to be urgently addressed.
Topics: Antitussive Agents; Humans; Placebo Effect
PubMed: 34279718
DOI: 10.1007/s00408-021-00458-2 -
Pain Nov 2014Pain 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... (Review)
Review
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.
Topics: Analgesia; Humans; Pain; Pediatrics; Physician-Patient Relations; Placebo Effect
PubMed: 25180010
DOI: 10.1016/j.pain.2014.08.036 -
Journal of Clinical Sleep Medicine :... May 2021Vgontzas AN, Puzino K, Fernandez-Mendoza J. Response to: Real effect vs placebo effect. 2021;17(5):1143–1144.
Vgontzas AN, Puzino K, Fernandez-Mendoza J. Response to: Real effect vs placebo effect. 2021;17(5):1143–1144.
Topics: Double-Blind Method; Humans; Placebo Effect
PubMed: 33560209
DOI: 10.5664/jcsm.9130 -
Psychosomatic Medicine Jan 2021Placebo effects may occur when it is known that an inert substance is given (i.e., open-label placebo). It is not yet clear whether these effects are similar to...
OBJECTIVE
Placebo effects may occur when it is known that an inert substance is given (i.e., open-label placebo). It is not yet clear whether these effects are similar to concealed (i.e., closed-label) placebo effects for itch or whether nocebo effects can be induced under open-label conditions.
METHODS
Healthy volunteers (n = 112) were randomized to an open-label (I) or closed-label (II) positive suggestions group, or an open-label (III) or closed-label (IV) negative suggestions group. Participants were told, as cover story, that a transdermal caffeine patch would be applied that positively influences cognitive abilities and, as a side effect, positively or negatively (depending on group allocation) influences itch. Participants in the open-label groups were given a rationale explaining placebo and nocebo effect mechanisms. Itch (the primary outcome) was induced at baseline and postsuggestions by histamine iontophoresis.
RESULTS
Analyses of variance revealed significantly lower itch in the positive compared with the negative suggestions groups for both open- and closed-label contexts (all, p ≤ .008, Cohen d ≥ 0.47). Self-rated skin response was less severe after positive versus negative suggestions (all, p ≤ .017, Cohen d ≥ 0.33), but no effects on physical skin response were found (all, p ≥ .23, Cohen d ≤ 0.30).
CONCLUSIONS
Itch can be reduced by positive compared with negative suggestions under both open- and closed-label conditions. These findings indicate that open-label suggestions may potentially be a tool to use placebo effects for self-reported outcomes in clinical practice, for example, by explaining the role of expectancy in treatment. It needs to be investigated further under which circumstances an open-label rationale may impact placebo and nocebo effects.Trial Registration:www.trialregister.nl; NTR7174.
Topics: Humans; Nocebo Effect; Placebo Effect; Pruritus; Suggestion; Transdermal Patch
PubMed: 32969962
DOI: 10.1097/PSY.0000000000000862 -
Translational Psychiatry Oct 2022The genetic architecture of antidepressant response is poorly understood. Polygenic risk scores (PRS), exploration of placebo response and the use of sub-scales might... (Randomized Controlled Trial)
Randomized Controlled Trial
The genetic architecture of antidepressant response is poorly understood. Polygenic risk scores (PRS), exploration of placebo response and the use of sub-scales might provide insights. Here, we investigate the association between PRSs for relevant complex traits and response to vortioxetine treatment and placebo using clinical scales, including sub-scales and self-reported assessments. We collected a clinical test sample of Major Depressive Disorder (MDD) patients treated with vortioxetine (N = 907) or placebo (N = 455) from seven randomized, double-blind, clinical trials. In parallel, we obtained data from an observational web-based study of vortioxetine-treated patients (N = 642) with self-reported response. PRSs for antidepressant response, psychiatric disorders, and symptom traits were derived using summary statistics from well-powered genome-wide association studies (GWAS). Association tests were performed between the PRSs and treatment response in each of the two test samples and empirical p-values were evaluated. In the clinical test sample, no PRSs were significantly associated with response to vortioxetine treatment or placebo following Bonferroni correction. However, clinically assessed treatment response PRS was nominally associated with vortioxetine treatment and placebo response given by several secondary outcome scales (improvement on HAM-A, HAM-A Psychic Anxiety sub-scale, CPFQ & PDQ), (P ≤ 0.026). Further, higher subjective well-being PRS (P ≤ 0.033) and lower depression PRS (P = 0.01) were nominally associated with higher placebo response. In the self-reported test sample, higher schizophrenia PRS was significantly associated with poorer self-reported response (P = 0.0001). The identified PRSs explain a low proportion of the variance (1.2-5.3%) in placebo and treatment response. Although the results were limited, we believe that PRS associations bear unredeemed potential as a predictor for treatment response, as more well-powered and phenotypically similar GWAS bases become available.
Topics: Humans; Vortioxetine; Depressive Disorder, Major; Multifactorial Inheritance; Genome-Wide Association Study; Treatment Outcome; Antidepressive Agents; Double-Blind Method; Placebo Effect
PubMed: 36309483
DOI: 10.1038/s41398-022-02221-4 -
Molecular Psychiatry Jun 2022Significant clinical improvement is often observed in patients who receive placebo treatment in randomized double-blind placebo-controlled trials. While a proportion of... (Review)
Review
Significant clinical improvement is often observed in patients who receive placebo treatment in randomized double-blind placebo-controlled trials. While a proportion of this "improvement" reflects experimental design limitations (e.g., reliance on subjective outcomes, unbalanced groups, reporting biases), some of it reflects genuine improvement corroborated by physiological change. Converging evidence across diverse medical conditions suggests that clinically-relevant benefits from placebo treatment are associated with the activation of brain reward circuits. In parallel, evidence has accumulated showing that such benefits are facilitated by clinicians that demonstrate warmth and proficiency during interactions with patients. Here, we integrate research on these neural and social aspects of placebo effects with evidence linking oxytocin and social reward to advance a neurobiological account for the social facilitation of placebo effects. This account frames oxytocin as a key mediator of treatment success across a wide-spectrum of interventions that increase social connectedness, thereby providing a biological basis for assessing this fundamental non-specific element of medical care.
Topics: Administration, Intranasal; Double-Blind Method; Humans; Oxytocin; Placebo Effect; Randomized Controlled Trials as Topic; Reward; Social Facilitation
PubMed: 35338314
DOI: 10.1038/s41380-022-01515-9 -
Scientific Reports Feb 2023The placebo effect demonstrates how positive expectancies shape the effectiveness of various treatments. Across studies, placebo treatments are interventions (creams,... (Clinical Trial)
Clinical Trial
The placebo effect demonstrates how positive expectancies shape the effectiveness of various treatments. Across studies, placebo treatments are interventions (creams, pills, etc.) that are presented to individuals as, and are learned to be, beneficial for them. This study tested whether placebo-induced expectancies can be harnessed to improve individuals' internal emotion regulation attempts. Participants implemented two types of distraction, an emotion regulation strategy involving attentional disengagement, to attenuate fear of pain. In a typical conditioning paradigm, the placebo-distraction was introduced as an effective strategy (verbal suggestion) and was surreptitiously paired with reduced pain (conditioning), whereas the control-distraction was introduced as noneffective and was surreptitiously paired with increased pain. As predicted, we found that during a later test phase, where pain intensity was identical, the placebo-distraction resulted in reduced self-reported fear of pain, relative to the control-distraction. Moreover, we utilized a robust behavioral choice measure, demonstrating increased preferences for the placebo-distraction. We additionally tested whether these effects generalize to a different emotional context of fear of unpleasant pictures. In that context, the placebo-distraction was as effective as the control-distraction, but was substantially preferred. This study demonstrates that the placebo effect can be expanded to include individuals' internal attempts to influence their conditions.
Topics: Humans; Emotional Regulation; Emotions; Fear; Pain; Placebo Effect
PubMed: 36759537
DOI: 10.1038/s41598-023-29045-6