Placebo Phenomenon Research Articles

Placebo stimulates neuroplasticity in depression: implications for clinical practice and research.

Neither psychological nor neuroscientific investigations have been able to fully explain the paradox that placebo is designed to be inert in randomized controlled trials (RCTs), yet appears to be effective in evaluations of clinical interventions in all fields of medicine and alternative medicine. This article develops the Neuroplasticity Placebo Theory, which posits that neuroplasticity in fronto-limbic areas is the unifying factor in placebo response (seen in RCTs) and placebo effect (seen in clinical interventions) where it is not intended to be inert. Depression is the disorder that has the highest placebo response of any medical condition and has the greatest potential for understanding how placebos work: recent developments in understanding of the pathophysiology of depression suggest that fronto-limbic areas are sensitized in depression which is associated with a particularly strong placebo phenomenon. An innovative linkage is made between diverse areas of the psychology and the translational psychiatry literature to provide supportive evidence for the Neuroplasticity Placebo Theory. This is underpinned by neuro-radiological evidence of fronto-limbic change in the placebo arm of antidepressant trials. If placebo stimulates neuroplasticity in fronto-limbic areas in conditions other than depression - and results in a partially active treatment in other areas of medicine - there are far reaching consequences for the day-to-day use of placebo in clinical practice, the future design of RCTs in all clinical conditions, and existing unwarranted assertions about the efficacy of antidepressant medications. If fronto-limbic neuroplasticity is the common denominator in designating placebo as a partially active treatment, the terms placebo effect and placebo response should be replaced by the single term "placebo treatment."

Placebo effects in osteoarthritis: implications for treatment and drug development.

Osteoarthritis (OA) is the most common form of arthritis worldwide, affecting ~500 million people, yet there are no effective treatments to halt its progression. Without any structure-modifying agents, management of OA focuses on ameliorating pain and improving function. Treatment approaches typically have modest efficacy, and many patients have contraindications to recommended pharmacological treatments. Drug development for OA is hindered by the gradual and progressive nature of the disease and the targeting of established disease in clinical trials. Additionally, new medications for OA cannot receive regulatory approval without demonstrating improvements in both structure (pathological features of OA) and symptoms (reduced pain and/or improved function). In clinical trials, people with OA show high 'placebo responses', which hamper the ability to identify new effective treatments. Placebo responses refer to the individual variability in response to placebos given in the context of clinical trials and other settings. Placebo effects refer specifically to short-lasting improvements in symptoms that occur because of physiological changes. To mitigate the effects of the placebo phenomenon, we must first understand what it is, how it manifests, how to identify placebo responders in OA trials and how these insights can be used to improve clinical trials in OA. Leveraging placebo responses andeffects in clinical practice might provide additional avenues to augment symptom management of OA.

Zsigeri fájdalom, nocebo-hatások, placebo-analgézia

Összefoglaló. A belső szervek működési zavarai gyakran származnak viselkedési, lelki vagy pszichoszociális okokból, amelyeknek nem mindig vagyunk tudatában. Minthogy ebben a folyamatban egy bonyolult neuronális hálózat játssza a fő szerepet, ezeknek a zavaroknak a diagnózisa és terápiája számos tényező manipulálását igényli. A funkcionális gyomor-bélhuzam rendellenességek (FGID), például az irritábilisbél-szindróma (IBS), jellemző példái ennek: olyan működési zavarokról van szó, amelyek mögött jól detektálható szervi vagy biokémiai elváltozásokat nem találnak. Ilyenkor szükségesnek tűnik a komplex megközelítés, amely többféle szakember együttműködését kívánja meg. Szerepe lehet a pszichés vagy életmód terápiának, a gyógyszeres és fizikai kezelésnek is, és – ahogy ebben a cikkben megmutatjuk – a placebo-terápiának is. Summary. Functional disorders of the internal organs frequently are results of behavioral, mental or psycho-social dysfunctions, although we are usually not conscious about it. A typical example isirritable bowel syndrome (IBS), a characteristic functional gastro-intestinal disorder (FGID), which is regularly accompanied by abdominal pain and irregular intestinal motility and defecation. It has been shown that this disorder cannot be due to a single factor, nor is it a result of a local cause. Recently researchers have proven that malfunction of a complicated neuronal network, including several brain sites, may be responsible for IBS. It is believed now that IBS is the consequence of several nocebo-effects. IBS is a typical source of visceral pain or discomfort, a source that is frequently difficult to identify. Main factors are stimuli originating from the gastro-intestinal tract, passing through the spinal cord and reaching several brain structures, including cortical and sub-cortical sites. It has been shown that some structures become thicker while others thinner as a result of lasting visceral pain, resulting in altered top-down effects on the visceral organs. Several hormones accompany these processes resulting in a complicated network activity. Recent research has revealed that IBS requires a complex approach, optimally provided by a therapeutic team of physicians, psychologist/psychiatrist, associates, and even the patient himself/herself. They may apply or suggest medicines, physiotherapy, lifestyle modifications, alimentary changes etc. An important feature is that the nocebo-effect plays an important role in the generation of IBS, thus one may think the opposite phenomenon, placebo-effect could be used in the therapeutic process. And really, placebo-analgesia is a method frequently used in the therapy of IBS. Placebo-analgesia affects brain processes, including pain processing, release of hormones, including endogenous opioids, the primary pain-decreasing factors. A top-down pain-modification system exists which can be affected and activated by the placebo-analgesia thus counteracting the nocebo-effects and improving the condition of the individual. The placebo phenomenon is interesting in itself, too. By now, the major question is not the existence of the placebo-effect but the mechanisms behind it. Recently, as brain-mapping techniques have gained their role in research, a lot of new information proves that the placebo-effect (as well as the nocebo-effect) is a complex phenomenon that involves several different brain sites, including the brain cortex and the limbic system, respectively.P The placebo-effect is widely used in clinical practice, first of all as a reference treatment when new drugs or medicines are tested for their effectivity. There are numerous ethical problems in this area, recently, for example, when testing Covid-19 vaccines. The main problem is whether it is legal to keep a non-treated population, whether the placebo-group should be treated immediately after the trial ends, whether the members of the placebo-group should get adequate information.

The placebo phenomenon and the underlying mechanisms

The clinical role of the placebo effect is a topic of increasing interest for the scientific community. Focus is shifting from the inert role of placebos in randomized controlled trials (RCTs) to potential effects in clinical applications, since the phenomenon is thought to be inherent in routine clinical practice, affecting therapy success rates. Mediation of the mind-brain-body relationship involves both psychosocial and neurobiological factors, the interaction of which comprises the placebo mechanisms. Psychosocial factors include environmentally induced expectations, reward expectations, and even conditioned responses to certain stimuli. Expectations also depend on previous experience of the patient with a similar procedure and can affect future responses. Moreover, the supportive bedside behavior of the clinician and the positive framing of information provided to the patient have proven to be of great importance, setting the foundations for reconsideration of standardized practices. Neurobiological mechanisms mediate these effects through neurotransmitter and neuromodulator pathways. The best understood mechanisms are those regulating non-opioid- and opioid-mediated analgesic responses that implicate specific brain regions of pain control and activation of endogenous opioids. Other responses concern, among others, hormonal control, motor performance, and antidepressant responses. Although mechanisms underlying placebo responses are not as yet completely elucidated, there is substantial evidence suggesting that placebo effects are indicative of healthy functioning of intact brain structures and occur through actual functional changes, and are not simply subjective symptom reports. These effects can be utilized in treatment optimization while maintaining an ethical and respectful manner toward the patient and the standardized disclosure procedures.

Placebo effects in pain therapy

In the past few decades, research on pain and placebo analgesia has gained importance both scientifically and clinically. In this article, the current findings and focus of research as well as the significance of placebo research for assessing the effectiveness of pain medication are illustrated. The underlying mechanisms of placebo analgesia not only have implications for theoretical models but also offer clinically relevant guidelines for everyday interventions in pain treatment. However, many placebo phenomena are not fully understood and have to be investigated further in order to exploit the full potential of placebo effects. Interindividual differences and their inclusion in treatment will play amajor role in this aspect.

The placebo medication phenomenon - Moral issues

The purpose of this review is to analyze the placebo medication phenomenon or placebo effect. In modern medical research, placebo is an important methodological tool, as it is used to control the usefulness of another substance (e.g a medication) in controlled laboratory conditions. There are various forms of use of placebo such as “sugar pills” up to surgery. The placebo effect raises both legal and ethical issues, as part of scientific research should be adapted to the rules of Greek and European legislation. From an ethical point of view, research will be subject to ethical principles in order to respect human existence and protect health and human rights. Nowadays, the placebo phenomenon is recognized by the scientific community as a whole, while at the same time it is the same subject of study aimed at clarifying its mechanisms of action. After researching books and articles of the past decade about the placebo effect, an attempt was made to present the bioethical side of this issue. The placebo effect has been known since the 14th century; however, it was first used in 1955 by Henry Beecher. This was catalytic in terms of changing the way clinical trials were conducted. Plus, when trying any drug it should be compared with a placebo. This method is an important help because we can measure the efficacy of a drug. It is known that approval of a drug will only be done if it has more positive results than placebo.

Феномен плацебо как перспективное направление психологических и психофизиологических исследований

Феномен плацебо как перспективное направление психологических и психофизиологических исследований

Nocebo in cerebellar ataxia: A systematic review and meta-analysis of placebo-controlled clinical trials

IntroductionNocebo, the negative counterpart of the placebo phenomenon results in the induction of adverse events (AEs) following the administration of an inert substance. Nocebo has been demonstrated to be associated with low treatment compliance in clinical trials, thus affecting treatment outcomes. This study sought to determine the prevalence of nocebo in cerebellar ataxia. MethodsA systematic literature search was conducted on Pubmed for randomized controlled trials (RCTs) for cerebellar ataxia treatments. The number of drug-related AEs and the number of withdrawals due to drug intolerance in the placebo group were statistically analysed. ResultsThe literature search identified 214 studies, of which 6 studies fulfilled the inclusion criteria. Approximately 1 in 20 (4.8%) placebo-treated patients withdrew treatment due to AEs and approximately 1 in 7 (13.8%) placebo-treated participants reported at least one AE. Participants in cerebellar ataxia trials reported similar AEs across both treatment groups (active and placebo). ConclusionOur results demonstrate that the nocebo effect in cerebellar ataxia is amongst the lowest in neurological diseases.

Ancillary factors in the treatment of orofacial pain: A topical narrative review.

Ancillary factors, not directly related to treatment, often play a significant role by affecting therapeutic outcome. A search of the literature was conducted including words related to the placebo phenomenon and orofacial diseases. Therefore, critical factors have been grouped into three major categories: (a) the natural course of the diseases; (b) the regression of the symptoms to their mean intensity; and (c) placebo response. This topical narrative review describes the elements mentioned above, provides an up-to-date overview of the hot topics and gaps in the field and indicates developing and future research direction of the orofacial pain field. Such a knowledge might be positively used during daily clinical practice to optimise the management of orofacial pain diseases, as well as in conducting future clinical trials for validating new interventions.

The Fallacy of Sham-Controlled Neurofeedback Trials: A Reply to Thibault and Colleagues (2018)

Background: Sham-controlled neurofeedback (NFB) trials consistently find no separation on ADHD outcome measures leading many to conclude that NFB’s beneficial effects are due to placebo. Method: We deconstruct the NFB training methodology and findings of six sham-controlled trials that assessed for evidence of learning. Results: All six studies found no evidence NFB subjects learned to self-modulate the targeted electroencephalogram (EEG). Careful analyses revealed these studies’ training methodologies were antithetical to the established science of operant conditioning thereby preventing subjects from learning to self-modulate. These findings are in marked contrast to NFB studies whose methodology mirror the best practices of operant conditioning. Conclusion: The premise that NFB’s beneficial effects are due to placebo phenomenon is unproven as these studies compared two forms of false-feedback, not operant conditioning of the EEG. Because these studies are highly cited and considered the gold standard in scientific rigor, a reappraisal of the evidence is urgently needed.

What Are the Benefits of a New Placebo Language?

This article examines three common strategies for dealing with the problems generated by the terms placebo and "placebo effect." These strategies are to redefine, to reconceptualize, and to eliminate our placebo language. The promise of these strategies is that a new language for talking about placebo phenomena may deliver clinical, ethical, and methodological advances. However, the nature and impact of these advances is rarely explored in detail. This article surveys some of the promised benefits of new terms such as "meaning response" and "contextual healing." The benefits are broadly similar across these strategies, but while they allow for clearer descriptions of phenomena and wider appreciation of the contextual aspects of medical practice, the open challenge for these strategies is not just to promise, but to show, the practical significance of their approaches to understanding placebo phenomena.

The Role of Patient-Practitioner Relationships in Placebo and Nocebo Phenomena.

Placebo and nocebo effects form part of all therapeutic environments and play a significant role in the effectiveness of treatment outcomes. Patient expectancies drive these phenomena, which can be shaped through contextual factors including verbal suggestions, conditioning, and social observation. This review seeks to identify the biopsychosocial factors of the patient-practitioner interaction that play a role in the development of placebo and nocebo effects, as well as the anthropological elements of the biodynamic process of relating that are meaningful in the development of expectancies. We conducted a narrative review of frameworks of the placebo and nocebo effect, including the impact of expectancies and interpersonal relationships in the context of healing and the clinical setting. Expectancies leading to placebo and nocebo effects can be modified by macro and micro factors, such as culture and society, as well as individual psychobiological traits, respectively. The developmental sociobiological adaptations that form and consolidate mindsets and meaningful contexts play an important role in shaping patient expectancies, as well as patients' conscious and subconscious reactions to signs and actions taking place within the clinical environment. Practitioner characteristics, like empathy, friendliness, and competence, favor the formation of positive expectancies. Caring and warm patient-practitioner interactions can enhance the therapeutic value of clinical encounters when patients' positive expectancies are actively encouraged and engaged. A patient-centered approach rooted in demonstrating care and empathy can positively enhance a patient's experience within the clinical environment and activate psychosociobiological adaptations associated with the placebo phenomenon. Pain patients could particularly benefit from non-invasive approaches for improving treatment effectiveness and quality-of-life.

The Placebo Phenomenon: A Narrow Focus on Psychological Models.

The placebo effect is a complex phenomenon that can be described from neurobiological, psychosocial, and epistemological perspectives. Different leaders in the field have proposed multiple theories and models that attempt to describe both the nature and the mechanisms of action underlying placebo effects. This article focuses on the most relevant psychological models that have been suggested for characterizing the different mechanisms underlying the placebo effect. We outline how the dynamic psychoneurobiological aspects of the placebo phenomenon can be a potential reliable and useful tool in daily clinical practice for illness and symptom management within a wide variety of specialties and health-care practices.

Describing Placebo Phenomena in Medicine: A Linguistic Approach.

The present paper reviews how language and communication are used to describe placebo phenomena in medicine, with particular reference at key points to the question of pain. Selected aspects of placebo language are submitted to lexical, grammatical and semantic analysis. We distinguish three uses of placebo, with three semantic components: "pleasing," inert medication or procedure, and what is often called "deception." The three uses of placebo are: Placebo-treatment, which combines all three semantic components: "pleasing" patients with inert treatments, and possibly with "deception." Placebo-trial, which refers to the closely defined inert control in Randomized Controlled Trials. Placebo-rapport, which covers all aspects of the health care encounter, excluding therapeutic interventions, but including psychosocial factors which can have a beneficial effect on the patient. Three key conclusions emerge from this analysis. First, the "deception" connotation of placebo found in placebo-treatment can contaminate the use of placebo-trial and especially placebo-rapport. Second, the enlarged "pleasing" framework of placebo-rapport, which includes the benefits of quality appropriate and helpful medical care, forces us to ask whether placebo-trial in Randomized Controlled Trials has in fact been a neutral baseline control. Biopsychosocial and other factors in placebo-rapport may have influenced the outcomes of many trials in medicine and pharmacology. And third, extending placebo-rapport to embrace all aspects of clinical care (except specific medication or procedural interventions) and psychosocial factors of the health care encounter engages patient beliefs, mindsets and interpersonal dynamics, as well as values and contextual and cultural issues. These take placebo-rapport substantially beyond what is currently seen as its identity and modes of operation.

Placebo Effects: Historical and Modern Evaluation.

The history of the placebo phenomenon is both interesting and informative. The placebo effect is a core component of health care, and if one considers a contemporary view of placebo effects, this has likely been the case for as long as records exist. An exploration of placebos and placebo effects across several centuries demonstrates many interesting facts, ranging from very early writings and experiments to the modern investigation of placebo mechanisms. A longitudinal review reveals the many challenges that have been faced, whether this is understanding what a placebo is, why it may work, and the meaning of such responses for routine clinical practice. At the core of this process are the concepts surrounding placebo, as these are imperative in the application of placebo to both routine clinical care and in the context of clinical trial design. This narrative review will look at the history of placebo, particularly key aspects over time, with a view to presenting a modern re-conceptualization of this field so as to facilitate ongoing scientific inquiry and to improve health care.

A Functional-Cognitive Perspective on the Relation Between Conditioning and Placebo Research.

From a functional-cognitive perspective, conditioning is relevant for placebo research because it (a) highlights stimulus pairings (e.g., taking a pill that contains an active pharmacological substance causing a drop in blood pressure) as a potential environmental cause of creating or boosting placebo effects (e.g., reduction in blood pressure after taking a similar pill that no longer contains the active substance) and (b) orients researchers to potential mental mechanisms that might underlie those effects (e.g., the formation of associations or propositions). After describing the functional-cognitive perspective on conditioning, I provide a brief overview of three generations of conditioning theories (stimulus-response, stimulus-stimulus, and propositional theories) and evaluate different ways in which conditioning and placebo research can be related. Finally, I discuss the implications of the functional-cognitive perspective on conditioning for the status of the placebo phenomenon.

Nocebo Effects and Experimental Models in Visceral Pain.

Despite its clinical relevance and the potential to extend insights into the processing and modulation of pain derived from investigations of placebo phenomena, the nocebo effect has received comparably little attention over the past decades. Research from experimental and clinical studies is only beginning to unravel the behavioral, functional, and psychoneurobiological mechanisms underlying the nocebo effect. Herein, we summarize current evidence regarding nocebo effects in the field of pain, with a particular emphasis on visceral pain. We provide an overview over behavioral and neuroimaging findings on the impact of expectations and learning and propose promising future directions to help fostering the transition of experimental research from bench to bedside.

Cognitive structuring and placebo effect

In much of the research concerning the placebo phenomenon, the idea that placebo effects may vary in strength depending on a patient's personal characteristics or traits has been investigated. Findings regarding possible personality differences in placebo response, however, are conflicting and non-systematic. In this article a new theoretical attempt to explain the placebo phenomenon is offered. The authors postulate that the power of the placebo effect is moderated by the extent of use of cognitive structuring, which in turn is influenced by the interaction between the individuals' level of need for cognitive closure and their ability to achieve this state. To test this assumption, a study using a placebo with information given to participants that this “medicine” improves mood and well-being was conducted. The results obtained fully support the predictions. The impact of this finding both for the theoretical understanding and practical implications of the placebo effect is presented.

Placebo and nocebo phenomena from the perspective of evidence based and person centered medicine

Placebo and nocebo phenomena from the perspective of evidence based and person centered medicine

"Managing" the Placebo Effect: The Single-Blind Placebo Lead-in Response in Two Pain Models.

"Placebo effects" in analgesic medication trials for chronic pain are pervasive; however, little is known regarding mechanisms or factors that may influence the presence or magnitude of these effects. Our objective is to consider elements of the placebo response in the context of two pain models using a "single-blind placebo lead-in" design (SBPLI). As part of two pilot drug trials using knee osteoarthritis (KOA) and non-radicular low back pain (LBP) subjects, SBPLI protocols were conducted. We examined whether gender and/or diagnosis affected placebo responses as observed in changes in patient self-reported pain, depressive and pain anxiety symptoms. We also evaluated the placebo response on performance-based tests (stair climbing, range of motion (ROM), sit to stand repetitions, and 6-minute treadmill distance). VAS Pain Intensity (Now) values decreased significantly during the SBPLI for the sample as a whole, but the effects appeared stronger among LBP subjects. CES-D short form values (depressive symptoms) did not decrease significantly during the SBPLI for the sample as a whole, but some placebo effects appeared to emerge for women in the KOA group. PASS values (pain anxiety symptoms) decreased significantly, albeit mildly, during the SBPLI for the sample as a whole.Stair Climb (time) revealed no significant SBPLI effects. Bend Forward to Floor (ROM) increased significantly at the end of the SBPLI period for the sample as a whole, but the effects appeared stronger among KOA subjects. Sit to Stand Repetitions increased during the SBPLI for the sample as a whole. Treadmill Distance did not change significantly from Visit 1 to Visit 2; however, a significant Sex difference for the KOA group was found such that women showed greater Treadmill Distance at Visit 2. Placebo effects emerged across psychometric and performance-based measures, indicating the pervasiveness of this phenomenon. In this design, diagnostic and (to a lesser extent) gender categories differentials were observed during the placebo period. The SBPLI design may prove not only a robust method in studying the placebo phenomena, but also as a design element to mitigate some aspects of the placebo response in clinical trials.