What Do Placebo and Nocebo Effects Have to Do With Health Equity? The Hidden Toll of Nocebo Effects on Racial and Ethnic Minority Patients in Clinical Care

A placebo effect is a positive clinical response to non-specific elements of treatment with a sham or inert replica of a drug, device, or surgical intervention. There is considerable evidence that placebo effects are driven by expectation of benefit from the intervention. Expectation is shaped by a patient’s past experience, observations of the experience of others, and written, verbal, or non-verbal information communicated during treatment. Not surprisingly, expectation in the clinical setting is strongly influenced by the attitude, affect, and communication style of the healthcare provider. While positive expectations can produce beneficial effects, negative information and experiences can lead to negative expectations, and consequently negative or nocebo effects. Key components identified and studied in the placebo and nocebo literature intersect with factors identified as barriers to quality care in the clinical setting for Black patients and other patients of color, including poor patient-clinician communication, medical mistrust, and perceived discrimination. Thus, in the context of discrimination and bias, the absence of placebo and presence of nocebo-generating influences in clinical settings could potentially reinforce racial and ethnic inequities in clinical outcomes and care. Healthcare inequities have consequences that ripple through the medical system, strengthening adverse short- and long-term outcomes. Here, we examine the potential for the presence of nocebo effects and absence of placebo effects to play a role in contributing to negative outcomes related to unequal treatment in the clinical encounter.

Efficacy of open-label counterconditioning for reducing nocebo effects on pressure pain

Nocebo effects can adversely affect the experience of physical symptoms, such as pain and itch. Nocebo effects on itch and pain have shown to be induced by conditioning with thermal heat stimuli and reduced by counterconditioning. However, open-label counterconditioning, in which participants are informed about the placebo content of the treatment, has not been investigated, while this can be highly relevant for clinical practice. Furthermore, (open-label) conditioning and counterconditioning has not been investigated for pain modalities relevant to musculoskeletal disorders, such as pressure pain. In a randomized controlled trial, we investigated in 110 healthy female participants whether nocebo effects on pressure pain combined with open-label verbal suggestions can be 1) induced via conditioning and 2) reduced via counterconditioning. Participants were allocated to either a nocebo or sham conditioning group. Next, the nocebo group was allocated to either counterconditioning, extinction, or continued nocebo conditioning; sham conditioning was followed by placebo conditioning. Nocebo effects were significantly larger after nocebo conditioning than sham conditioning (d = 1.27). Subsequently, a larger reduction of the nocebo effect was found after counterconditioning than after extinction (d = .99) and continued nocebo conditioning (d = 1.63), with effects similar to placebo conditioning (following sham conditioning). These results show that (counter)conditioning combined with open-label suggestions can modulate nocebo effects on pressure pain, which provides promise in designing learning-based treatments to reduce nocebo effects in patients with chronic pain disorders, particularly for musculoskeletal disorders.

COVID-19 vaccination, from first dose to booster: New insights into the frequency of most common systemic adverse events and possible booster nocebo effects based on a systematic review

Background: Based on placebo data, it has been recently demonstrated that the frequencies of most common adverse events (AEs) of COVID-19 vaccination are overestimated due to negative expectation bias of vaccine recipients (nocebo effect). Since booster studies lack comparators, estimating the extent of the nocebo effect is difficult. We aimed to overcome this obstacle through a systematic comparison of most common AE frequencies across vaccine doses (first, second, booster), age groups, and vaccine vs. placebo arms. Methods: We systematically assessed systemic AEs in approved COVID-19 vaccines according to the PRISMA guidelines. All documents regarding COVID-19 vaccines with a booster dose authorized by the FDA (cutoff date 19 November 2021) were systematically searched on PubMed and the FDA website. Solicited systemic AEs from all documents supporting approval/authorization were collected. After standardization of doses and age groups, AE frequencies were compared between vaccine and placebo. Findings: Two trials were identified for BNT162b2 (n=21,785 participants), two for mRNA-1273 (n=22,324), and one for Ad26.COV2.S (n=4,085). Fever cases dropped to about half with the booster dose in all vaccines, whereas all other systemic AE frequencies were similar to the preceding dose. Almost no fever cases occurred with placebo (first/second dose); all other systemic AEs occurred at high frequencies. After subtracting placebo arm values from vaccine values, the frequencies for the various AEs were roughly comparable within each dose for each vaccine. Interpretation: Fever is the only solicited systemic AE that can be assessed objectively. It occurs about 50% less often with the booster than with the preceding dose. This may indirectly indicate a considerable overestimation of systemic AEs in the case of booster vaccinations and a pronounced nocebo effect. The nocebo effect appears to substantially contribute to the differences in the frequencies of the various systemic AEs.

Associations Between Interindividual Differences, Expectations and Placebo and Nocebo Effects in Itch

Introduction: Placebo and nocebo effects are positive and negative health outcomes that can be elicited by the psychosocial context. They can be mediated by expectations, and may emerge in somatic symptoms even when people are aware of these effects. Interindividual differences (e.g., in personality, affective states) could impact placebo and nocebo responding, but findings are inconsistent.Methods: The current work examined expectation as a mediator of the association between verbal placebo and nocebo suggestions (VSs) and histamine-induced itch across three experimental studies. Moreover, we examined whether interindividual differences (e.g., in optimism, neuroticism, behavioral activation system (BAS), body ignorance) modulated: (1) the direct association between VSs and itch (direct moderation), and (2) the indirect, expectation-mediated association between VSs and itch (moderated mediation). Positive VSs were compared to neutral instructions (Study 1; n = 92) or negative VSs (Studies 2+3; n = 203) in an open-label (i.e., explaining placebo and nocebo effects) or closed-label (concealed) context using PROCESS. First, mediation of VSs effects on itch by expectations was tested. Next, moderation by individual traits was explored using conditional process analyses.Results: The effects of VSs on itch were significantly mediated by expectation in Study 1 and in the open-label (but not closed-label) contexts of Studies 2 and 3. Ignorance of bodily signals marginally moderated the direct effects of VSs on itch when closed-label suggestions were given: at low levels of body ignorance, effects of positive and negative VSs were stronger. Moreover, moderated mediation was observed in the open-label groups of Studies 2 and 3: The expectation-mediated effects of VSs on itch were stronger when BAS drive was lower.Conclusion: Overall, the effects of VSs on itch were mediated by expectations in the open-label, but not the closed-label context. Moreover, the current work suggests that placebo and nocebo effects may be moderated by ignorance of bodily signals and the BAS. There was limited evidence that other interindividual differences modulated placebo and nocebo responding in itch.

The Role of Expectation and Beliefs on the Effects of Non-Invasive Brain Stimulation

Non-invasive brain stimulation (NIBS) techniques are used in clinical and cognitive neuroscience to induce a mild magnetic or electric field in the brain to modulate behavior and cortical activation. Despite the great body of literature demonstrating promising results, unexpected or even paradoxical outcomes are sometimes observed. This might be due either to technical and methodological issues (e.g., stimulation parameters, stimulated brain area), or to participants’ expectations and beliefs before and during the stimulation sessions. In this narrative review, we present some studies showing that placebo and nocebo effects, associated with positive and negative expectations, respectively, could be present in NIBS trials, both in experimental and in clinical settings. The lack of systematic evaluation of subjective expectations and beliefs before and after stimulation could represent a caveat that overshadows the potential contribution of placebo and nocebo effects in the outcome of NIBS trials.

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.

Nocebo effects in the treatment of endometriosis

The current approach to treating endometriosis is often inadequate or intolerable for many patients. Until more effective therapies are available, we should aim to maximize the effectiveness of our current options. Optimization may be possible by reducing nocebo effects, which are the negative therapeutic effects not directly caused by a treatment. Awareness of these effects, how they arise, and the factors influencing them, is invaluable if we aim to limit their magnitude. The unique nature of endometriosis diagnosis and management is especially prone to nocebo effects due to multiple factors, including diagnostic delays, feelings of invalidation, social transmission of expectations, and persistent symptoms despite numerous treatments. This commentary discusses the origins of these effects in people with endometriosis, methods of limiting nocebo effects, and future research directions.

Thirty Years of Neuroscientific Investigation of Placebo and Nocebo: The Interesting, the Good, and the Bad

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. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.