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.

[Placebo effects in analgesia : Influence of expectations on the efficacy and tolerability of analgesic treatment]. / Placeboeffekte in der Schmerztherapie : Einfluss der Erwartung auf die Wirksamkeit und Verträglichkeit schmerzmedizinischer Behandlungen.

Expectations of patients influence the perception and neuronal processing of acute and chronic pain and modulate the effectiveness of analgesic treatment. The expectation of treatment is not only the most important determinant of placebo analgesia. Expectations of treatment also influence the efficacy and tolerability of "active" pharmacological and non-pharmacological treatment of pain. Recent insights into the psychological and neurobiological mechanisms underlying the clinically relevant effects of treatment expectations enable and call for the systematic integration and modulation of treatment expectations into analgesic treatment concepts. Such a strategy promises to optimize analgesic treatment and to prevent or reduce the burden of unwanted side effects and the misuse of analgesics, particularly of opioids. This review highlights the current concepts, recent achievements and also challenges and key open research questions.

Distinct neural networks subserve placebo analgesia and nocebo hyperalgesia.

Neural networks involved in placebo analgesia and nocebo hyperalgesia processes have been widely investigated with neuroimaging methods. However, few studies have directly compared these two processes and it remains unclear whether common or distinct neural circuits are involved. To address this issue, we implemented a coordinate-based meta-analysis and compared neural representations of placebo analgesia (30 studies; 205 foci; 677 subjects) and nocebo hyperalgesia (22 studies; 301 foci; 401 subjects). Contrast analyses confirmed placebo-specific concordance in the right ventral striatum, and nocebo-specific concordance in the dorsal anterior cingulate cortex (dACC), left posterior insula and left parietal operculum during combined pain anticipation and administration stages. Importantly, no overlapping regions were found for these two processes in conjunction analyses, even when the threshold was low. Meta-analytic connectivity modeling (MACM) and resting-state functional connectivity (RSFC) analyses on key regions further confirmed the distinct brain networks underlying placebo analgesia and nocebo hyperalgesia. Together, these findings indicate that the placebo analgesia and nocebo hyperalgesia processes involve distinct neural circuits, which supports the view that the two phenomena may operate via different neuropsychological processes.

Understanding the Role of Expectancy, Anticipatory Anxiety, and Attention Bias in Nocebo Hyperalgesia: A Gaze-Contingent Attention Bias Modification Study.

Nocebo effects in pain (nocebo hyperalgesia) have been thoroughly researched, and negative expectancies have been proposed as a key factor in causing nocebo hyperalgesia. However, little is known about the psychological mechanisms by which expectations exacerbate the perception of pain. A potential mechanism that has been proposed within wider pain research is pain-related attention. The aim of the present study was thus to explore whether attention bias (AB) to pain influenced nocebo hyperalgesia. One-hundred and thirty-four healthy participants were randomized in a 2 (AB training: towards vs away from pain) × 2 (nocebo condition: nocebo vs control) design. Pain-related AB was manipulated through a novel, partially gaze-contingent dot-probe task. Participants then completed either a nocebo instruction and conditioning paradigm or a matched control condition. Primary outcomes were measures of expectancy, anticipatory anxiety, and pain intensity completed during a nocebo test phase. Results showed that the AB manipulation was unsuccessful in inducing ABs either toward or away from pain. The nocebo paradigm induced significantly greater expectancy, anticipatory anxiety, and pain intensity for the nocebo groups compared to the control groups. In a posthoc analysis of participants with correctly induced ABs, AB towards pain amplified nocebo hyperalgesia, expectancy, and anticipatory anxiety relative to AB away from pain. The results are consistent with the expectancy model of nocebo effects and additionally identify anticipatory anxiety as an additional factor. Regarding AB, research is needed to develop reliable means to change attention sample-wide to corroborate the present findings. PERSPECTIVE: This article explores the role of AB, expectancy, and anticipatory anxiety in nocebo hyperalgesia. The study shows that expectancy can trigger anticipatory anxiety that exacerbates nocebo hyperalgesia. Further, successful AB training towards pain heightens nocebo hyperalgesia. These findings identify candidate psychological factors to target in minimizing nocebo hyperalgesia.

The role of self-reported and physiological stress in nocebo hyperalgesia.

Negative expectations can increase pain sensitivity, leading to nocebo hyperalgesia. However, the physiological and psychological factors that predispose individuals to this phenomenon are still not well understood. The present study examined whether stress induced by a social stressor affects nocebo hyperalgesia, and whether this effect is mediated by self-reported and physiological stress responses. We recruited 52 healthy participants (15 men) who were randomly assigned to either the Trier Social Stress Test (TSST) or a control condition (a friendly version of the TSST). Nocebo hyperalgesia was induced using negative suggestions combined with a validated pain conditioning paradigm. We assessed self-reported (anxiety and stress) and physiological (cortisol, alpha-amylase, heart rate, and skin conductance) responses to stress. Both groups exhibited significant nocebo hyperalgesia. The stress group showed higher levels of anxiety, self-reported stress, and cortisol levels compared to the control group while no significant differences were found in other physiological markers. The stress and control groups did not differ in the magnitude of nocebo hyperalgesia, but anxiety levels partially mediated the effects of the stress test on nocebo hyperalgesia. Our findings suggest that an external social stressor does not directly affect nocebo hyperalgesia, but that increased anxiety due to the stressor enhances its magnitude. Thus, it may be worthwhile to investigate whether reducing stress-related anxiety in clinical settings would help alleviate nocebo effects.

Translating knowledge on placebo and nocebo effects into clinical practice.

Introduction: Positive and negative treatment expectations are powerful modulators of health and treatment outcomes. A substantial part of treatment success is due to contextual factors modulating patient's expectations towards a treatment. Consequently, treatment expectations should be a target of therapeutic interventions themselves. Objectives: This article highlights the neurobiological underpinnings of treatment expectations as well as strategies to modulate contextual factors to optimize treatment outcomes in daily clinical settings. Methods: This clinical update aligns with the 2022 IASP Global Year Translating Pain Knowledge into Practice and selectively reviews the best available evidence and practice. Results: The effects of treatment expectations, also known as placebo and nocebo effects, are observed in various clinical conditions and physiological systems. However, most of our knowledge comes from the field of pain, where expectation effects substantially contribute to overall analgesic treatment outcomes. Experimental placebo analgesia paradigms provide the best illustration of how analgesic effects can be attributed not only to a pharmacological or specific treatment, but instead are the result of the expectation towards the treatment. The impact of expectations on treatment outcome is highly variable between individuals, and the identification of factors predicting an individual's response has proven to be challenging. Further research is required to provide personalized treatment strategies for the daily clinical practice. Conclusion: Patient's previous experiences and expectations are powerful modulators of treatment efficacy, tolerability, and adherence. By providing a comprehensive overview of recent advances in this field, this review offers valuable insights for clinicians and researchers seeking to improve patient-clinician interaction.

Nocebo hyperalgesia and other expectancy-related factors in daily fibromyalgia pain: Combining experimental and electronic diary methods.

OBJECTIVE: Expectancies are known to shape pain experiences, but it remains unclear how different types of expectancies contribute to daily pain fluctuations in fibromyalgia. This combined experimental and diary study aims to provide insights into how experimentally-derived nocebo hyperalgesia and other, diary-derived, expectancy-related factors are associated with each other and with daily pain in fibromyalgia. METHODS: Forty-one female patients with fibromyalgia first participated in a lab procedure measuring nocebo hyperalgesia magnitude, then filled out an electronic diary 3 times a day over 3 weeks regarding the expectancy-related factors of pain expectancy, anxiety, optimism, and pain-catastrophizing thoughts, and current pain intensity. RESULTS: Our results indicate that experimentally-induced nocebo hyperalgesia was not significantly related to diary-assessed expectancy-related factors and did not predict daily fibromyalgia pain. Higher levels of the self-reported expectancy-related factors pain expectancy and pain catastrophizing, but not anxiety and optimism, predicted moment-to-moment pain increases in fibromyalgia, after controlling for current pain, moment-of-day and all other expectancy-related factors. CONCLUSION: Our exploratory research findings indicate that self-reported expectancy-related factors, particularly pain expectancy and pain catastrophizing, are potentially more relevant for predicting daily pain experience than experimentally-induced nocebo hyperalgesia. Further translation of nocebo hyperalgesia is needed from experimental to Ecological Momentary Assessment research. Our findings imply that targeting the decrease in pain expectancy and catastrophizing thoughts e.g., via Cognitive Behavioral Therapy, have potential for improving daily pain levels in fibromyalgia.

Pain Rating is Worth a Thousand Words: Nocebo Hyperalgesia Induced by Verbal Modeling Prevails Over the Effects of Symbolic Modeling and Verbal Suggestion.

This study compares the effectiveness of verbal modeling, symbolic modeling, and verbal suggestion in inducing nocebo hyperalgesia. It is the first study to examine the contribution of stress to observationally induced nocebo hyperalgesia. This study's experimental groups represented various sources of social information: a group of people participating in the study (verbal modeling), a single participant (symbolic modeling), and an experimenter (verbal suggestion). During the experiment, participants received electrocutaneous stimuli at the same intensity, some of which were applied with a nocebo (sham device). Participants in the verbal modeling group were acquainted with pain ratings that had allegedly been provided by other participants. The ratings suggested that other participants experienced more pain in the nocebo trials than in the control trials. In the symbolic modeling group, participants observed a videotaped model experiencing more pain in the nocebo than in the control trials. In the verbal suggestion group, participants received a verbal suggestion of hyperalgesia in the nocebo trials and no suggestion in the control trials. No manipulations were used in the control group. To investigate whether nocebo hyperalgesia is stable over time, an additional extinction phase was conducted. Nocebo hyperalgesia was induced by verbal modeling only and was partially mediated by expectancy. Stress was a significant moderator of the induced effect. Nocebo hyperalgesia was extinguished during the extinction phase. The obtained results provide potential implications for minimizing nocebo hyperalgesia in clinical practice by, for instance, controlling patients' expectancies and stress levels. PERSPECTIVE: The study shows the role of pain-related information derived from other people in shaping negative treatment experiences in the individual. Because information from others has a particular impact on individuals experiencing stress, both this information and the stress level of patients should be monitored in the treatment process.

The Temporal Modulation of Nocebo Hyperalgesia in a Model of Sustained Pain.

Background: The direction and the magnitude of verbal suggestions have been shown to be strong modulators of nocebo hyperalgesia, while little attention has been given to the role of their temporal content. Here, we investigate whether temporal suggestions modulate the timing of nocebo hyperalgesia in an experimental model of sustained pain. Methods: Fifty-one healthy participants were allocated to one of three groups. Participants received an inert cream and were instructed that the agent had either hyperalgesic properties setting in after 5 (Nocebo 5, N5) or 30 (Nocebo 30, N30) minutes from cream application, or hydrating properties (No Expectation Group, NE). Pain was induced by the Cold Pressure Test (CPT) which was repeated before cream application (baseline) and after 10 (Test10) and 35 (Test35) minutes. Changes in pain tolerance and in HR at each test point in respect to baseline were compared between the three groups. Results: Tolerance change at Test 10 (Δ10) was greater in N5 (MED = -36.8; IQR = 20.9) compared to NE (MED = -5.3; IQR = 22.4; p < 0.001) and N30 (MED = 0.0; IQR = 23.1; p < 0.001), showing that hyperalgesia was only present in the group that expected the effect of the cream to set in early. Tolerance change at Test 35 (Δ35) was greater in N5 (MED = -36.3; IQR = 35.3; p = 0.002) and in N30 (MED = -33.3; IQR = 34.8; p = 0.009) compared to NE, indicating delayed onset of hyperalgesia in N30, and sustained hyperalgesia in N5. No group differences were found for HR. Conclusions: Our study demonstrated that temporal expectations shift nocebo response onset in a model of sustained pain.

What is the role of placebo in neurotherapeutics?

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.

No evidence that attentional bias towards pain-related words is associated with verbally induced nocebo hyperalgesia: a dot-probe study.

INTRODUCTION: Placebo and nocebo effects in pain are well documented. One leading explanation is that instructions indicating that pain will either increase or decrease after receipt of a treatment give rise to expectations for increased or decreased pain. However, the psychological mechanisms through which expectations affect pain perception are not well understood. One possibility is that the expectation of increased pain leads to anticipatory anxiety, which in turn increases attention towards painful sensations. OBJECTIVES: The aim of this study was to test the hypothesis that attention mediates nocebo hyperalgesia. This was done by measuring attentional bias towards pain using a dot-probe task both before and after a nocebo manipulation. METHODS: Ninety-six healthy volunteers were randomized to receive one of the following: (1) an inert nasal spray with placebo instructions, (2) an inert nasal spray with nocebo instructions, or (3) no treatment. Participants completed measures of expectations, anxiety, and attention bias (dot-probe paradigm) both before and after randomization. RESULTS: Results showed that the nocebo instructions induced expectations for increased pain and resulted in nocebo hyperalgesia. Conversely, the placebo instruction failed to induce expectations for decreases in pain and did not demonstrate any placebo analgesia. Furthermore, despite the significant expectancies for pain and subsequent nocebo hyperalgesia, there were no differences between the nocebo group and either the placebo or no-treatment group for anxiety or attentional bias. CONCLUSION: The results are consistent with the expectancy model of placebo and nocebo effects. That is, changes in expectations seemed to be necessary to induce a placebo or nocebo effect. However, there was no evidence that anxiety or attention bias towards pain-related stimuli was necessary to achieve nocebo hyperalgesia.

Pre-Exposure, But Not Overshadowing, Inhibits Nocebo Hyperalgesia.

Nocebo hyperalgesia is a pervasive problem that significantly adds to the burden of pain. Conditioning is a key mechanism of nocebo hyperalgesia and recent evidence indicates that, once established, nocebo hyperalgesia is resistant to extinction. This means that preventive strategies are critical. We therefore tested whether two novel strategies - overshadowing (Experiment 1) and pre-exposure (Experiment 2) - could inhibit conditioned nocebo hyperalgesia. Overshadowing involves introducing additional cues during conditioning that should compete with and overshadow learning about the target nocebo cue. Pre-exposure involves pre-exposing the target nocebo cue in the absence of pain, which should diminish its ability to become associated with pain later. In both studies, healthy volunteers (N = 141) received exposure to a series of electrocutaneous pain stimuli with and without a sham electrode 'activated', which they were led to believe was a genuine hyperalgesic treatment. Nocebo conditioning was achieved by pairing sham activation with high pain prior to testing at equivalent pain intensity. In both studies, standard nocebo conditioning led to clear nocebo hyperalgesia relative to natural history controls. In Experiment 1, there was no evidence that overshadowing attenuated nocebo hyperalgesia. Importantly, however, Experiment 2 found that pre-exposure successfully attenuated nocebo hyperalgesia with post hoc analysis suggesting that this effect was dose-dependent. These findings provide novel evidence that pre-exposure, but not overshadowing, could be a cheap and effective way for mitigating the substantial harm caused by conditioned nocebo hyperalgesia in clinical settings. PERSPECTIVE: Nocebo hyperalgesia causes substantial patient burden with few preventive options available. Our study found novel evidence that pre-exposing treatment cues without pain, but not overshadowing them with other cues, has the capacity to inhibit conditioned nocebo hyperalgesia. Pre-exposure may therefore be an effective preventive strategy to combat nocebo hyperalgesia.

Brain Network to Placebo and Nocebo Responses in Acute Experimental Lower Back Pain: A Multivariate Granger Causality Analysis of fMRI Data.

Background and Objective: Placebo and nocebo responses are widely observed. Herein, we investigated the nocebo hyperalgesia and placebo analgesia responses in brain network in acute lower back pain (ALBP) model using multivariate Granger causality analysis (GCA). This approach analyses functional magnetic resonance imaging (fMRI) data for lagged-temporal correlation between different brain areas. Method: After completing the ALBP model, 20 healthy subjects were given two interventions, once during a placebo intervention and once during a nocebo intervention, pseudo-randomly ordered. fMRI scans were performed synchronously during each intervention, and visual analog scale (VAS) scores were collected at the end of each intervention. The fMRI data were then analyzed using multivariate GCA. Results: Our results found statistically significant differences in VAS scores from baseline (pain status) for both placebo and nocebo interventions, as well as between placebo and nocebo interventions. In placebo network, we found a negative lagged-temporal correlation between multiple brain areas, including the dorsolateral prefrontal cortex (DLPFC), secondary somatosensory cortex area, anterior cingulate cortex (ACC), and insular cortex (IC); and a positive lagged-temporal correlation between multiple brain areas, including IC, thalamus, ACC, as well as the supplementary motor area (SMA). In the nocebo network, we also found a positive lagged-temporal correlation between multiple brain areas, including the primary somatosensory cortex area, caudate, DLPFC and SMA. Conclusion: The results of this study suggest that both pain-related network and reward system are involved in placebo and nocebo responses. The placebo response mainly works by activating the reward system and inhibiting pain-related network, while the nocebo response is the opposite. Placebo network also involves the activation of opioid-mediated analgesia system (OMAS) and emotion pathway, while nocebo network involves the deactivation of emotional control. At the same time, through the construction of the GC network, we verified our hypothesis that nocebo and placebo networks share part of the same brain regions, but the two networks also have their own unique structural features.

Category-based generalization of placebo and nocebo effects.

Human beings possess the adaptive ability to apply experiential knowledge to new situations. Although this generalization capability has been demonstrated in fear and reward learning, it remains unclear whether it extends to analgesic and hyperalgesic pain responses. Here, we conducted two experiments (total n = 104) to test the generalization effects of placebo analgesia and nocebo hyperalgesia. The first experiment, using a category-based conditioning paradigm in which two categories of images were used as acquisition stimuli, assessed whether pain perception can be generalized to never-seen pictures of the same category in the generalization phase. The second experiment adopted a single stimulus for each category as CS to further examine the generalization effects after learning a single exemplar. Pain ratings showed that participants reported higher pain or lower pain when the pain was preceded by novel stimuli that were conceptually similar to the previously conditioned stimuli, suggesting a generalization of analgesic and hyperalgesic pain modulation effects. These results provide novel evidence that analgesic and hyperalgesic effects on pain perception can be generalized to conceptually similar new items.

How Does Observational Learning Produce Placebo Effects? A Model Integrating Research Findings.

There is a growing body of evidence proving that observational learning, in addition to classical conditioning and verbal suggestions, may induce both placebo analgesia and nocebo hyperalgesia. However, much less is known about the mechanisms and factors influencing placebo effects induced by observational learning. The paper critically reviews the research findings in the field in the context of Bandura's social learning theory. We apply Bandura's taxonomy of the sources of social learning (behavioral, symbolic, and verbal modeling) and discuss the results of previous studies. Critical points in the placebo effects induced by observational learning are identified. We discuss aspects of behavior presented by the model (both verbal and non-verbal) involved in the formation of placebo effects induced by observational learning as well as the role of expectancies in this process. As a result, we propose a model that integrates the existing research findings. The model shows the main ways of transmission of pain-related information from the model to the observer. It highlights the role of expectancies and the individual characteristics of the observer in formation of placebo analgesia and nocebo hyperalgesia induced by observational learning. Finally, we propose future research directions based on our model.

Autonomic Arousal as a Mechanism of the Persistence of Nocebo Hyperalgesia.

Placebo and nocebo mechanisms can lead to clinically significant modulation of pain. Although learning is considered to be the broad mechanism underlying placebo analgesia as well as nocebo hyperalgesia, critical differences have emerged in their specific mechanisms. One of the most interesting of these is that whereas placebo analgesia seems to be relatively short-lived, nocebo hyperalgesia appears more resistant to extinction, often persisting indefinitely. The current study examined why nocebo hyperalgesia persists longer than placebo analgesia. Sixty healthy volunteers were randomized to receive placebo conditioning, nocebo conditioning, or no conditioning using an experimental pain model with surreptitious decreases (placebo group) and increases (nocebo group) in pain stimulation paired with sham treatment during training. Pain was then assessed in a test phase with and without the sham treatment at equal pain stimulation. The conditioning procedure successfully induced placebo analgesia as well as nocebo hyperalgesia in the relevant groups, with nocebo hyperalgesia outlasting placebo analgesia, confirming nocebo hyperalgesia's resistance to extinction. Most interestingly, nocebo treatment led to heightened anticipatory anxiety ratings and autonomic arousal. Further, autonomic arousal completely mediated the effect of nocebo versus placebo training on extinction, suggesting that heightened autonomic arousal may be an important mechanism in the persistence of nocebo hyperalgesia. PERSPECTIVE: Heightened anticipatory anxiety in the form of elevated autonomic arousal may explain why nocebo hyperalgesia persists relative to placebo analgesia. As such, interventions that reduce anticipatory anxiety could reduce the burden of persistent nocebo hyperalgesia.

A systematic review of sex differences in the placebo and the nocebo effect.

OBJECTIVES: The present review investigated whether there are systematic sex differences in the placebo and the nocebo effect. METHODS: A literature search was conducted in multiple electronic databases. Studies were included if the study compared a group or condition where a placebo was administered to a natural history group or similar cohort. RESULTS: Eighteen studies were identified - 12 on placebo effects and 6 on nocebo effects. Chi-square tests revealed that 1) males responded more strongly to placebo treatment, and females responded more strongly to nocebo treatment, and 2) males responded with larger placebo effects induced by verbal information, and females responded with larger nocebo effects induced by conditioning procedures. CONCLUSION: This review indicates that there are sex differences in the placebo and nocebo effects, probably caused by sex differences in stress, anxiety, and the endogenous opioid system.

The sustained influence of prior experience induced by social observation on placebo and nocebo responses.

BACKGROUND: Social observation is one of the main ways to gain experience. Similar to first-person experience, observational experience affects the effectiveness of subsequent treatments. Yet, it is still undetermined whether the influence of social observation on placebo and nocebo effects to subsequent treatments remains even if related experience occurred a few days ago. METHODS: Eighty-two participants were recruited and each of them was randomly assigned to one of the four experimental groups acquiring first-person or observational experience, which was either effective or ineffective. For the first-person groups, participants were presented with pain cues paired with pain stimuli in person. In the effective condition, low pain cues were paired with low pain stimuli, and high pain cues were paired with high pain stimuli. In contrast, the associations between cues and pain stimuli were not established in the ineffective condition. Similarly, for the observational groups, participants received effective/ineffective treatment through observation. Five or six days later, all participants underwent a conditioning phase followed by a test phase composed of two tests, where participants were asked to report their perceived pain. RESULTS: Placebo and nocebo responses to subsequent treatments can be affected by prior experience gained several days ago regardless of acquisition ways, and both placebo and nocebo responses in the effective condition were significantly larger than those in the ineffective condition. Furthermore, once placebo and nocebo effects were elicited, the latter was more persistent, while the former was more likely to diminish. CONCLUSION: First-person and observational experience obtained a few days ago could affect the following treatments, which advance our understanding of the crucial and sustained influence of social observation on placebo analgesia and nocebo hyperalgesia, and provide insights into clinical applications.

Nocebo hyperalgesia and the startle response.

BACKGROUND: The literature on the effects of nocebo on pain is sparse. The present experimental study investigated whether suggestions of nocebo hyperalgesia modified the startle response and whether increased startle contributed to the nocebo hyperalgesic effect. METHODS: A design with four groups was employed; the participants were randomized into either a placebo group, a natural history group, or into two nocebo groups. The participants in the placebo and nocebo groups received suggestions of pain decrease or pain increase, together with a placebo or nocebo cream applied to the lower arm, respectively. Heat pain was induced by a PC-controlled thermode before and after the treatment. White noise was used to elicit startle responses. Startle was assessed by measuring eye blink electromyographic responses recorded from the right orbicularis oculi muscle. RESULTS: The results showed that nocebo suggestions increased reports of pain and startle responses. Increased startle was significantly associated with the nocebo hyperalgesic response. CONCLUSIONS: The results of the present study suggest that verbally induced expectations of increased pain engage cortical physiological defensive systems that in turn mediate the experience of increased pain.

Psychological Placebo and Nocebo Effects on Pain Rely on Expectation and Previous Experience.

UNLABELLED: Expectation and previous experience are both well established key mediators of placebo and nocebo effects. However, the investigation of their respective contribution to placebo and nocebo responses is rather difficult because most placebo and nocebo manipulations are contaminated by pre-existing treatment expectancies resulting from a learning history of previous medical interventions. To circumvent any resemblance to classical treatments, a purely psychological placebo-nocebo manipulation was established, namely, the "visual stripe pattern-induced modulation of pain." To this end, experience and expectation regarding the effects of different visual cues (stripe patterns) on pain were varied across 3 different groups, with either only placebo instruction (expectation), placebo conditioning (experience), or both (expectation + experience) applied. Only the combined manipulation (expectation + experience) revealed significant behavioral and physiological placebo-nocebo effects on pain. Two subsequent experiments, which, in addition to placebo and nocebo cues, included a neutral control condition further showed that especially nocebo responses were more easily induced by this psychological placebo and nocebo manipulation. The results emphasize the great effect of psychological processes on placebo and nocebo effects. Particularly, nocebo effects should be addressed more thoroughly and carefully considered in clinical practice to prevent the accidental induction of side effects. PERSPECTIVE: Even purely psychological interventions that lack any resemblance to classical pain treatments might alter subjective and physiological pain correlates. A manipulation of treatment expectation and actual treatment experience were mandatory to elicit this effect. Nocebo effects were especially induced, which indicated the necessity for prevention of accidental side effects besides exploitation of placebo responses.