Learned Nocebo Effects on Cutaneous Sensations of Pain and Itch: A Systematic Review and Meta-analysis of Experimental Behavioral Studies on Healthy Humans.

OBJECTIVE: In past decades, the field of nocebo research has focused on studying how sensory perception can be shaped by learning. Nocebo effects refer to aggravated sensory experiences or increased sensitivity to sensations such as pain and itch resulting from treatment-related negative experiences. Behavioral conditioning and verbal suggestions of a negative treatment outcome may aggravate pain and itch perception. Gaining a comprehensive view of the magnitude of nocebo effects and contributing factors will help steer nocebo research toward fruitful directions for understanding complex sensory phenomena. METHODS: We conducted a systematic review and meta-analysis of a total of 37 distinct experimental nocebo studies on healthy participants (all published in English between 2008 and 2021), with four separate meta-analyses for nocebo effects on pain or itch. We conducted subgroup analyses and meta-regression on factors such as type and intensity of sensory stimuli, and length of conditioning paradigms. RESULTS: This meta-analysis showed that, on average, effect sizes of nocebo effects were moderate to large (Hedges g between 0.26 and 0.71 for the four primary outcomes). The combination of conditioning and verbal suggestions yielded stronger nocebo responses on pain in particular. Subgroup analyses, including factors such as the type of sensory stimulation, did not explain the moderate heterogeneity in nocebo magnitudes between different studies. Risk of bias was generally low and was not related to nocebo magnitudes either. CONCLUSIONS: We discuss these results in relation to the role of conditioning and aversive learning, and we recommend more consistency in designing and reporting nocebo experiments.

Induction and generalization of nocebo effects on itch.

Nocebo effects, that is, negative treatment outcomes due to negative expectancies, can increase itch. Moreover, indirect evidence has shown that nocebo hyperknesis can generalize to another itch modality. Knowledge on response generalization can help to prevent and decrease negative effects. The aims of this study were to investigate (1) the efficacy of inducing nocebo effects on cowhage-evoked itch via verbal suggestions and (2) whether these effects can generalize to (2a) mechanically evoked touch and (2b) mechanically evoked itch. Forty-four healthy participants watched a video suggesting that a nocebo solution increases cowhage-evoked itch and that a control solution does not affect itch. Subsequently, cowhage, mechanical itch, and mechanical touch stimuli were applied. Nocebo effects were measured as the difference in both mean and peak of the outcomes itch and urge to scratch between nocebo and control trials. Main analyses revealed significant nocebo effects on mean and peak itch for all stimuli. For urge to scratch, a significant nocebo effect was only observed for mechanical touch (peak). As mechanical stimuli did not induce pure sensations as planned, posthoc sensitivity analyses were run for mechanical stimuli that individually induced either touch or itch at baseline. These analyses showed similar results for generalization to mechanical itch, but generalization to mechanical touch was non-significant. This study showed that merely verbal suggestion can induce nocebo effects on cowhage-evoked itch and that these effects can generalize to another itch modality. Future studies may examine how to prevent negative experiences from generalizing to subsequent encounters.

Can contagious itch be affected by positive and negative suggestions?

Contagious itch can be evoked by observing people scratching. Verbal suggestions about to-be-received itch can influence itch intensity, as shown by placebo research, but it is unknown whether this extends to contagious itch. The current study aimed to replicate prior findings that listening to scratching and rubbing sounds elicits contagious itch, and to investigate whether suggestions can modulate this process. Healthy participants (n = 140) received positive or negative suggestions about itch in response to the sounds (aimed to decrease or increase expected itch, respectively), or no specific suggestions as a control. Participants listened to a number of audio fragments with scratching and rubbing sounds. The amount of expected itch as well as itch sensation after each audio fragment were measured by self-report. Suggestions had no effect on the expected itch. Both rubbing and scratching sounds significantly elicited itch in all groups. Scratching sounds induced more itch than rubbing sounds exclusively in the control group. These findings indicate that short suggestions might be not effective enough to modify the expectations of people regarding contagious itch. Furthermore, suggestions modulate contagious itch to some degree, but not in the hypothesized direction. Potential similarities and differences in the neurobiological mechanisms of contagious itch and nocebo effects are discussed.

Acute Itch Induces Attentional Avoidance of Itch-related Information.

Attention is known to modulate itch intensity. In contrast, the reverse relationship, i.e. the degree to which the presence of an acute itch affects attention, is currently not well understood. The aims of this study were to investigate whether acute itch induces an attentional bias towards or away from visual itch-related stimuli, and if so, whether it occurs in the early or later stages of processing. A volunteer sample of 60 healthy individuals were subjected to a skin prick (either histamine or placebo), followed by completion of a spatial cueing paradigm using itch-related and neutral words as cues, in order to obtain reaction time estimates of attentional bias. The results suggest that experience of acute itch induces attentional avoidance of visual itch threats. This attentional avoidance occurs at a later processing stage in the form of facilitated disengagement of attention from itch and/or delayed disengagement from neutral information.

Nocebo Effects on Cowhage-evoked Itch: A Randomized Controlled Trial of Classical Conditioning and Observational Learning.

To investigate learning processes underlying nocebo effects on itch, this study measured the efficacy of classical conditioning and observational learning for inducing nocebo effects on cowhage-evoked itch and scratching behaviour. A total of 58 healthy female participants were assigned to classical conditioning, observational learning, or sham conditioning groups. In the classical conditioning group, experimenters associated the application of an inert gel with increased itch intensity themselves. In the observational learning group, a video of the conditioning paradigm was shown. Nocebo effects were measured as the difference in itch or scratching between control and nocebo test phase trials, compared between learning and control groups. Compared with sham conditioning, classical conditioning induced a significant nocebo effect on itch, while observational learning did not. No nocebo effect on scratching was detected. These results highlight the role that learning through direct experiences plays in pruritic symptoms. Future research should investigate how a patient's history of unsuccessful treatments shapes treatment outcomes.

What is new in the psychology of chronic itch?

Itch is often regarded as unpleasant or bothersome and is accompanied by symptoms of distress and impairments in daily life. The biopsychosocial model of chronic itch describes how psychological factors can contribute to the improvement or exacerbation of chronic itch and related scratching behaviour. Recent research underlines the important role of cognitive-affective information processing, such as attention, affect and expectancies. This may not only play a role for acute itch states, but may particularly apply to the process of itch chronification, for example, due to the vicious cycle in which these factors shape the experience of itch. The present paper focuses on new insights into the relation between itch and the cognitive-affective factors of attention, affect and expectancies. These factors are thought to play a possible aggravating role in itch in the long term and have received increasing attention in the recent empirical literature on maintaining and exacerbating factors for chronic physical symptoms. Possible psychophysiological and neurobiological pathways regarding these factors are discussed, as well as possible intervention methods.

Nocebo Effects and Scratching Behaviour on Itch.

Nocebo effects, i.e. reduced treatment effects due to patients' negative expectations, play a role in itch. Recent studies have shown that nocebo effects can be induced experimentally on itch and also be minimized and even turned into the opposite direction, i.e. placebo effects. It is not known whether these effects generalize to itch-associated scratching behaviour. The aim of this study was to determine whether induction and reversal of nocebo effects on itch evoked by electrical and histamine stimuli generalized to scratching. Ninety-seven healthy participants were included in the study. The manipulation was successful, as during the nocebo learning phase, increased scratching responses were found for higher intensity compared with lower intensity itch stimuli. During the testing phase of induction or reversal of the nocebo effects, however, no significant nocebo effects or reversed nocebo effects, were found in scratching. Thus, no straightforward generalization of nocebo effects from itch to scratching was found in this laboratory setting. Further investigation into possible generalization is needed in different settings and in patients with chronic itch.

Placebo Effects of Open-label Verbal Suggestions on Itch.

Placebo effects are positive outcomes that are not due to active treatment components, which may be elicited even when patients are aware of receiving an inert substance (open-label). This proof-of-principle study investigated for the first time whether open-label placebo effects on itch can be induced by verbal suggestions alone. Ninety-two healthy volunteers were randomized to experimental (open-label suggestions) or control (no suggestions) groups. Self-reported itch evoked by histamine iontophoresis was the primary study outcome. In addition, itch expectations, skin condition and affect were assessed. The experimental group expected lower itch than the control group, which was, in turn, related to less experienced itch in this group only, although no significantly different itch levels were reported between groups. The results illustrate a potential role for open-label placebo effects in itch, and suggest that further study of verbal suggestions through an extensive explanation of placebo effects might be promising for clinical practice.

There is no functional small-fibre neuropathy in prurigo nodularis despite neuroanatomical alterations.

Prurigo nodularis (PN) is a pruritic condition with altered epidermal neuroanatomy as demonstrated previously. Here we elucidated neuroimmunological mechanisms by combining functional, morphological and gene expression experiments in twelve subjects with PN and eight healthy controls. Subjects with PN showed a reduced intra-epidermal nerve fibre density (IENFD) in lesional skin. Quantitative sensory testing indicated maintenance of somatosensory function compared to controls. None of the tested molecular markers including the neuron-distracting SEMA3A and neuron-attracting NGF were altered in lesional vs non-lesional skin in PN subjects. Accordingly, we speculate that scratching may contribute to reduced IENFD rather than an authentic endogenous neuropathy.

Does stress affect the joints? Daily stressors, stress vulnerability, immune and HPA axis activity, and short-term disease and symptom fluctuations in rheumatoid arthritis.

OBJECTIVES: Both stressors and stress vulnerability factors together with immune and hypothalamus-pituitary-adrenal (HPA) axis activity components have been considered to contribute to disease fluctuations of chronic inflammatory diseases, such as rheumatoid arthritis (RA). The aim of the present study was to investigate whether daily stressors and worrying as stress vulnerability factor as well as immune and HPA axis activity markers predict short-term disease activity and symptom fluctuations in patients with RA. METHODS: In a prospective design, daily stressors, worrying, HPA axis (cortisol) and immune system (interleukin (IL)-1ß, IL-6, IL-8, interferon (IFN)-γ, tumour necrosis factor α) markers, clinical and self-reported disease activity (disease activity score in 28 joints, RA disease activity index), and physical symptoms of pain and fatigue were monitored monthly during 6 months in 80 RA patients. RESULTS: Multilevel modelling indicated that daily stressors predicted increased fatigue in the next month and that worrying predicted increased self-reported disease activity, swollen joint count and pain in the next month. In addition, specific cytokines of IL-1ß and IFN-γ predicted increased fatigue 1 month later. Overall, relationships remained relatively unchanged after controlling for medication use, disease duration and demographic variables. No evidence was found for immune and HPA axis activity markers as mediators of the stress-disease relationship. CONCLUSIONS: Daily stressors and the stress-vulnerability factor worrying predict indicators of the short-term course of RA disease activity and fatigue and pain, while specific cytokines predict short-term fluctuations of fatigue. These stress-related variables and immune markers seem to affect different aspects of disease activity or symptom fluctuations independently in RA.

Placebo and nocebo effects in itch and pain.

Physical complaints, such as pain, can be effectively altered by placebo and nocebo effects due to induction of positive or negative expectations. While verbal suggestion and conditioning are recognized as playing a key role in placebo and nocebo effects on pain, these mechanisms have barely been investigated with regard to other somatosensory sensations, such as itch. Results on contagious itch in both animals and humans suggest that itch sensations might be even more susceptible for placebo and nocebo effects than pain. Research on placebo and nocebo effects on pain and itch can further deliver insight into the common and specific mechanisms underlying these effects in different physical complaints. Work of our research group on verbal suggestions inducing nocebo effects demonstrated an important role of verbal suggestions with regard to itch, with stronger nocebo effects on itch than a comparable procedure for pain. Recent work also demonstrated that placebo and nocebo effects on itch sensations were most effectively induced by procedures that consist of both conditioning and verbal suggestion principles. This work adds to previous prospective studies showing that expectation mechanisms, such as preservative worrying about negative consequences, are relatively consistent predictors of future disease outcomes, including itch, in chronic somatic conditions. Future studies should focus on the specific psychoneurobiological mechanisms of placebo and nocebo effects in various physical sensations, to get insight into the common and specific effects and to contribute to the long-term and clinically relevant use of placebo effects in clinical practice.

Sensitivity to itch and pain in patients with psoriasis and rheumatoid arthritis.

Symptoms of itch and pain in chronic inflammatory conditions of psoriasis (PS) and rheumatoid arthritis (RA) can highly affect patients' quality of life. Studies in other patient groups indicate that sensitivity to itch and pain is altered in line with the patient's main symptom of either chronic itch or pain, as a result of sensitization processes. This study directly compared whether patients with chronic inflammatory conditions associated with chronic itch or pain display a heightened sensitivity to itch and pain, respectively. Sensitivity to itch and pain was measured by applying stimuli of quantitative sensory testing (QST) in female patients with chronic itch due to PS or chronic pain due to RA. Levels of itch and pain evoked by the QST stimuli as well as the tolerance to the stimuli were determined. Patients with PS reacted to the stimuli with a higher itch response (histamine), while the patients with RA displayed a lowered tolerance to the stimuli (cold pressor test and mechanical stimulation) in comparison with the other patient group. In line with previous studies in other patient groups with chronic itch or pain, further support was found that somatosensory stimuli are processed in line with the patients' main symptom through generic sensitization processes, also in chronic inflammatory conditions such as PS and RA.

Attentional bias in psoriasis: The role of processing time and emotional valence.

PURPOSE: The present study explored whether people with psoriasis display an attentional bias towards disease-related threat words and whether this bias occurs relatively early during the phase of stimulus disengagement, or during a later maintained attention phase dominated by controlled strategic processes. We also explored the degree to which attentional bias is dependent on the emotional valence of control words. METHODS: Individuals with psoriasis and matched controls took part in 4 online experiments. Participants completed a spatial cueing paradigm using disease-related threat words and control words as cues, in order to obtain reaction time estimates of attentional bias. RESULTS: We did not observe evidence for attentional bias when control words were matched with threat words for emotional valence, regardless of whether processing time for the cues was limited (Experiment 1: SOA = 250 ms) or extended (Experiment 2: SOA = 1050 ms). We also did not observe evidence for attentional bias when control words of positive valence were used, but processing time was limited (Experiment 3). An attentional bias was only observed (p = .012, Cohen's d = .37) when sufficient processing time was available and positively-valanced control words were used (Experiment 4). CONCLUSION: Rather than showing large and generalized AB effects as predicted by previous accounts, our results tentatively suggest that AB in psoriasis is restricted to situations where participants have ample processing time and threat words are easily distinguishable from control words on the basis of emotional valence. The pattern of results suggests that attentional bias in psoriasis is best characterized as a relatively slow strategic process.

Subliminal attentional bias modification training for itch.

Introduction: Itch is unpleasant and induces the urge to scratch. This is adaptive to remove the itch-inducing stimulus from the skin. Accordingly, itch draws attention to protect our bodily integrity. Recent studies investigated whether attention is preferentially drawn towards its location, i.e., attentional bias (AB), and also whether this bias could be changed in healthy individuals. So far, results are mixed concerning the existance of an attentional bias towards itch stimuli in healthy individuals as well as the impact of modifications. However, available studies have typically focused on conscious processing and might miss preconscious aspects of attention and potential biases at these stages. Methods: This study included 117 healthy individuals who underwent a subliminal Attentional Bias Modification (ABM)- training for itch based on a dot-probe paradigm with itch- related pictures. Participants were randomly assigned to a training towards itch group, a training away from itch group and a control group. This was done by manipulating the itch-target congruency of the dot-probe task during a training block. Pre- and post-training assessments were regular dot-probe tasks. Exploratorily, also attentional inhibition, cognitive flexibility and itch-related cognitions were assessed. Lastly, participants received an itchy stimulus on the inner forearm before and after the ABM-training to assess potential effects on itch sensitivity. Results: Results showed no AB towards itch across groups at baseline, i.e., pre-training, but an AB away from itch, hence, avoidance of itch, post-training. Further analyses showed that this effect was driven by an attentional bias away from itch in the control group, while there were no significant effects in the experimental groups. There was no effect on itch sensitivity. Conclusion: These findings are in line with recent studies on conscious ABM-training for itch and pain that also did not find significant training effects. Therefore, it is suggested that the field of AB might need to reconsider the current assessment of AB. Moreover, AB is probably a dynamic process that is highly dependent on current itch-related goals and relevance of itch in a specific situation. This suggests that processes probably differ in patients with chronic itch and that also ABM-training might work differently in these populations. Clinical trial registration: https://trialsearch.who.int/Trial2.aspx?TrialID=NTR7561, identifier NTR7561.

Placebo effects on cutaneous pain and itch: a systematic review and meta-analysis of experimental results and methodology.

ABSTRACT: Placebo effects, positive treatment outcomes that go beyond treatment processes, can alter sensations through learning mechanisms. Understanding how methodological factors contribute to the magnitude of placebo effects will help define the mechanisms by which these effects occur. We conducted a systematic review and meta-analysis of experimental placebo studies in cutaneous pain and itch in healthy samples, focused on how differences in methodology contribute to the resulting placebo effect magnitude. We conducted meta-analyses by learning mechanism and sensation, namely, for classical conditioning with verbal suggestion, verbal suggestion alone, and observational learning, separately for pain and itch. We conducted subgroup analyses and meta-regression on the type of sensory stimuli, placebo treatment, number of acquisition and evocation trials, differences in calibrated intensities for placebo and control stimuli during acquisition, age, and sex. We replicated findings showing that a combination of classical conditioning with verbal suggestion induced larger placebo effects on pain ( k = 68, g = 0 . 59) than verbal suggestion alone ( k = 39, g = 0.38) and found a smaller effect for itch with verbal suggestion alone ( k = 7, g = 0.14). Using sham electrodes as placebo treatments corresponded with larger placebo effects on pain than when topical gels were used. Other methodological and demographic factors did not significantly affect placebo magnitudes. Placebo effects on pain and itch reliably occur in experimental settings with varied methods, and conditioning with verbal suggestion produced the strongest effects. Although methods may shape the placebo effect to some extent, these effects appear robust overall, and their underlying learning mechanisms may be harnessed for applications outside the laboratory.

Do individual psychological characteristics predict induction and generalization of nocebo and placebo effects on pain and itch?

Background: Nocebo and placebo effects, i.e., adverse or beneficial treatment effects, respectively, putatively due to expectancies can modulate pain and itch. These effects can generalize within the pain or itch modality. Predicting the induction and generalization of these effects can be helpful in clinical practice. This study aims to investigate whether psychological characteristics related to the fear-avoidance model predict the induction and generalization of nocebo and placebo effects on pain and itch in young healthy participants. Methods: Data from two previous experiments were analyzed. In Experiment 1, we induced nocebo and placebo effects on heat pain and tested generalization to pressure pain and to cowhage-evoked itch (n = 33 in a nocebo group, n = 32 in a placebo group). In Experiment 2, we induced nocebo effects on cowhage-evoked itch and tested generalization to mechanical itch and to mechanical touch (n = 44). Potential predictors were anxiety- and stress symptoms, attention to pain/itch, and pain/itch catastrophizing. Multiple regression analyses were performed. Results: For nocebo effects, none of the individual psychological characteristics significantly predicted induction of nocebo effects nor their generalization. For placebo effects, only less stress symptoms, lower attention to pain, and higher pain catastrophizing weakly predicted a stronger generalization of placebo effects from heat pain to pressure pain. Conclusion: The tested psychological characteristics may not play an important role in the induction and generalization of nocebo and placebo effects in healthy individuals. However, firm conclusions cannot be drawn with the current sample. Future studies should validate findings in larger and more diverse samples.

No indications for altered EEG oscillatory activity in patients with chronic post-burn itch compared to healthy controls.

A large proportion of patients with burn injuries develop chronic itch, which impacts quality of life. The underlying pathophysiological mechanisms are poorly understood. This cross-sectional pilot study investigates whether altered cortical oscillatory processes are involved in chronic post-burn itch. Continuous electroencephalography (EEG) data were recorded during rest and stimulation of non-injured skin, inducing itch (histamine and electrical) and cold-pressor task pain for 15 adults with chronic post-burn itch and 15 matched healthy controls. Quantitative metrics comprised oscillatory power and peak frequencies in theta, alpha, and beta bands. No statistical differences between patients and healthy controls were found in oscillatory activity during rest or stimulation, with Bayesian analysis suggesting equivocal evidence. However, post-traumatic stress symptoms and duration of chronic itch may be associated with changes in oscillatory activity. A lack of differences in cortical oscillatory processing and itch levels at non-injured sites, suggests that itch symptoms have a localised character in this sample of patients with post-burn itch. For future studies, a biopsychological approach with integration of peripheral and central nervous system techniques, linear and non-linear EEG analysis, injured and non-injured stimulation sites, and incorporation of individual characteristics is recommended. Insight into pathophysiological mechanisms underlying chronic post-burn itch could improve diagnostics and treatments.

Can placebo and nocebo effects generalize within pain modalities and across somatosensory sensations?

Pain and other somatosensory sensations, such as itch, can be effectively decreased by placebo effects and increased by nocebo effects. There are indications that placebo effects on pain generalize to other sensations and that nocebo effects generalize within itch modalities. However, it has not yet been investigated whether learned effects can generalize within pain stimulus modalities or from pain to itch. Our aims were to test whether placebo and nocebo effects can generalize within pain modalities, ie, from heat pain to pressure pain, and across somatosensory sensations with psychophysiological similarities, ie, from heat pain to cowhage-evoked itch. For this purpose, 65 healthy participants were randomized to either a placebo or nocebo group. All participants first underwent a conditioning and verbal suggestion procedure with heat pain stimuli. Subsequently, responses to heat pain, pressure pain, and cowhage-evoked itch stimuli were tested. Results showed altered levels of heat and pressure pain with the conditioned cue in both placebo and nocebo groups in the expected directions, but no significant difference in itch in both groups. In conclusion, placebo and nocebo effects on pain may generalize within but not across stimulus modalities. This study provides a novel perspective on the role that response generalization plays in physical symptoms.

No preconscious attentional bias towards itch in healthy individuals.

Rapidly attending towards potentially harmful stimuli to prevent possible damage to the body is a critical component of adaptive behavior. Research suggests that individuals display an attentional bias, i.e., preferential allocation of attention, for consciously perceived bodily sensations that signal potential threat, like itch or pain. Evidence is not yet clear whether an attentional bias also exists for stimuli that have been presented for such a short duration that they do not enter the stream of consciousness. This study investigated whether a preconscious attentional bias towards itch-related pictures exists in 127 healthy participants and whether this can be influenced by priming with mild itch-related stimuli compared to control stimuli. Mild itch was induced with von Frey monofilaments and scratching sounds, while control stimuli where of matched modalities but neutral. Attentional bias was measured with a subliminal pictorial dot-probe task. Moreover, we investigated how attentional inhibition of irrelevant information and the ability to switch between different tasks, i.e., cognitive flexibility, contribute to the emergence of an attentional bias. Attentional inhibition was measured with a Flanker paradigm and cognitive flexibility was measured with a cued-switching paradigm. Contrary to our expectations, results showed that participants attention was not biased towards the itch-related pictures, in facts, attention was significantly drawn towards the neutral pictures. In addition, no effect of the itch-related priming was observed. Finally, this effect was not influenced by participants' attentional inhibition and cognitive flexibility. Therefore, we have no evidence for a preconscious attentional bias towards itch stimuli. The role of preconscious attentional bias in patients with chronic itch should be investigated in future studies.

Temporal structure of brain oscillations predicts learned nocebo responses to pain.

This study aimed to identify electrophysiological correlates of nocebo-augmented pain. Nocebo hyperalgesia (i.e., increases in perceived pain resulting from negative expectations) has been found to impact how healthy and patient populations experience pain and is a phenomenon that could be better understood in terms of its neurophysiological underpinnings. In this study, nocebo hyperalgesia was induced in 36 healthy participants through classical conditioning and negative suggestions. Electroencephalography was recorded during rest (pre- and post-acquisition) and during pain stimulation (baseline, acquisition, evocation) First, participants received baseline high thermal pain stimulations. During nocebo acquisition, participants learned to associate an inert gel applied to their forearm with administered high pain stimuli, relative to moderate intensity control stimuli administered without gel. During evocation, all stimuli were accompanied by moderate pain, to measure nocebo responses to the inert gel. Pre- to post-acquisition beta-band alterations in long-range temporal correlations (LRTC) were negatively associated with nocebo magnitudes. Individuals with strong resting LRTC showed larger nocebo responses than those with weaker LRTC. Nocebo acquisition trials showed reduced alpha power. Alpha power was higher while LRTC were lower during nocebo-augmented pain, compared to baseline. These findings support nocebo learning theories and highlight a role of nocebo-induced cognitive processing.