Impairment of Hypnosis by Nocebo Response and Related Neurovegetative Changes: A Case Report in Oral Surgery.

This article presents the third molar removal in a highly hypnotizable patient, who had been successfully submitted to oral surgery with hypnosis as stand-alone anesthesia in previous sessions. Unexpectedly, hypnosis initially failed, as a result of a nocebo response due to a previous dentist's bad communication; two complaints made by the patient were associated with increased sympathetic activity (as defined by increased heart rate and electrodermal activity and decreased heart rate variability). After deepening of hypnosis, the patient achieved a full hypnotic analgesia allowing for a successful conclusion of the intervention, an event associated with decreased heart rate, electrodermal activity, and increased heart rate variability. Hence, the initial failure was paralleled by a decreased parasympathetic activity and increased sympathetic activity, while hypnotic analgesia was associated with the opposite pattern. The patient's postoperative report indicated that the initial failure of hypnosis depended on a strong nocebo effect because of a previous dentist distrusting hypnosis and persuading her that it was not enough to face a third molar removal.

Diet, gym, supplements, or maybe it is all in your mind? A systematic review and meta-analysis of studies on placebo and nocebo effects in weight loss in adults.

INTRODUCTION: There is evidence that placebo and nocebo effects are significant for many conditions, but their impact on weight loss has not yet been well described. MATERIAL AND METHODS: A systematic review of studies indexed on PubMed, Cochrane, PsycINFO, PsycARTICLES, TripDatabase, and Embase was carried out. Studies (1) with at least two study groups - placebo and a corresponding control group; (2) published in English; and (3) focusing on adults participating in weight loss programs or on placebo/nocebo effects in weight loss were included. Synthesis and meta-analysis of the results of studies with comparable research plans were performed. RESULTS: Some preliminary trends suggesting placebo and nocebo effects in weight loss were found. Placebo effects manifested in trends towards a slightly greater reduction of Body Mass Index (BMI) and body fat ratio in the placebo compared with the control groups. On the other hand, in one study, it was found that the expectancy effects of taking oral weight-loss agents might be disadvantageous (i.e., because they elicit a nocebo effect on weight loss). CONCLUSION: The findings suggest a possibility that the nocebo effect may occur when an intervention has a medical context. In contrast, the placebo effect can be observed in cases where the intervention is of a different nature. However, considering the low number of studies analyzing the use of placebos in weight loss, new primary research is needed.

Avoiding nocebo and other undesirable effects in chiropractic, osteopathy and physiotherapy: An invitation to reflect.

INTRODUCTION: While the placebo effect is increasingly recognised as a contributor to treatment effects in clinical practice, the nocebo and other undesirable effects are less well explored and likely underestimated. In the chiropractic, osteopathy and physiotherapy professions, some aspects of historical models of care may arguably increase the risk of nocebo effects. PURPOSE: In this masterclass article, clinicians, researchers, and educators are invited to reflect on such possibilities, in an attempt to stimulate research and raise awareness for the mitigation of such undesirable effects. IMPLICATIONS: This masterclass briefly introduces the nocebo effect and its underlying mechanisms. It then traces the historical development of chiropractic, osteopathy, and physiotherapy, arguing that there was and continues to be an excessive focus on the patient's body. Next, aspects of clinical practice, including communication, the therapeutic relationship, clinical rituals, and the wider social and economic context of practice are examined for their potential to generate nocebo and other undesirable effects. To aid reflection, a model to reflect on clinical practice and individual professions through the 'prism' of nocebo and other undesirable effects is introduced and illustrated. Finally, steps are proposed for how researchers, educators, and practitioners can maximise positive and minimise negative clinical context.

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.

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 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.

Order does matter: the combined effects of classical conditioning and verbal suggestions on placebo hypoalgesia and nocebo hyperalgesia.

ABSTRACT: In most experimental studies in which verbal suggestion and classical conditioning are implemented together to induce placebo effects, the former precedes the latter. In naturally occurring situations, however, the information concerning pain does not always precede but often follows the pain experience. Moreover, this information is not always congruent with experience. This study investigates whether the chronology of verbal suggestion and conditioning, as well as their congruence, affects placebo hypoalgesia and nocebo hyperalgesia. The effects induced in 15 groups were compared. The participants in 8 experimental groups were presented with verbal suggestions that were either congruent or incongruent with classical conditioning. The verbal suggestions were provided either before or after conditioning. In 2 other experimental groups, placebo conditioning or nocebo conditioning was implemented without any verbal suggestion; in 2 groups, verbal suggestion of hypoalgesia or hyperalgesia without conditioning was applied. The control groups without any suggestions or conditioning were also included. Placebo hypoalgesia induced by congruent procedures was significantly stronger when the suggestion of hypoalgesia preceded rather than followed conditioning. The order of the congruent procedures did not affect the magnitude of nocebo hyperalgesia. In the groups in which incongruent procedures were implemented, placebo hypoalgesia or nocebo hyperalgesia was in line with the direction of the last-used procedure, regardless of whether it was conditioning or verbal suggestion. The results show that not the type of the procedure (verbal suggestion or conditioning), but the direction of the last-used procedure shapes pain-related expectancies and determines placebo effects.

The subthalamic nucleus and the placebo effect in Parkinson's disease.

The study of the placebo effect, or response, is related to the investigation of the psychologic component of different therapeutic rituals. The high rate of placebo responses in Parkinson's disease clinical trials provided the impetus for investigating the underlying mechanisms. Ruling out spontaneous remission and regression to the mean through the appropriate experimental designs, genuine psychologic placebo effects have been identified, in which both patients' expectations of therapeutic benefit and learning processes are involved. Specifically, placebo effects are associated with dopamine release in the striatum and changes in neuronal activity in the subthalamic nucleus, substantia nigra pars reticulata, and motor thalamus in Parkinson's disease, as assessed through positron emission tomography and single-neuron recording during deep brain stimulation, respectively. Conversely, verbal suggestions of clinical worsening or drug dose reduction induce nocebo responses in Parkinson's disease, which have been detected at both behavioral and electrophysiologic level. Important implications and applications emerge from this new knowledge. These include better clinical trial designs, whereby patients' expectations should always be assessed, as well as better drug dosage in order to reduce drug intake.

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.

Open- and Closed-Label Placebo and Nocebo Suggestions About a Sham Transdermal Patch.

OBJECTIVE: Placebo effects may occur when it is known that an inert substance is given (i.e., open-label placebo). It is not yet clear whether these effects are similar to concealed (i.e., closed-label) placebo effects for itch or whether nocebo effects can be induced under open-label conditions. METHODS: Healthy volunteers (n = 112) were randomized to an open-label (I) or closed-label (II) positive suggestions group, or an open-label (III) or closed-label (IV) negative suggestions group. Participants were told, as cover story, that a transdermal caffeine patch would be applied that positively influences cognitive abilities and, as a side effect, positively or negatively (depending on group allocation) influences itch. Participants in the open-label groups were given a rationale explaining placebo and nocebo effect mechanisms. Itch (the primary outcome) was induced at baseline and postsuggestions by histamine iontophoresis. RESULTS: Analyses of variance revealed significantly lower itch in the positive compared with the negative suggestions groups for both open- and closed-label contexts (all, p ≤ .008, Cohen d ≥ 0.47). Self-rated skin response was less severe after positive versus negative suggestions (all, p ≤ .017, Cohen d ≥ 0.33), but no effects on physical skin response were found (all, p ≥ .23, Cohen d ≤ 0.30). CONCLUSIONS: Itch can be reduced by positive compared with negative suggestions under both open- and closed-label conditions. These findings indicate that open-label suggestions may potentially be a tool to use placebo effects for self-reported outcomes in clinical practice, for example, by explaining the role of expectancy in treatment. It needs to be investigated further under which circumstances an open-label rationale may impact placebo and nocebo effects.Trial Registration:www.trialregister.nl; NTR7174.

Ethnic Differences in Experimental Pain Responses Following a Paired Verbal Suggestion With Saline Infusion: A Quasiexperimental Study.

BACKGROUND: Ethnic differences in placebo and nocebo responses are an important, yet underresearched, patient factor that might contribute to treatment disparities. PURPOSE: The purpose of this study was to examine ethnic differences in pain trajectories following a verbal suggestion paired with a masked, inert substance (i.e., saline). METHODS: Using a quasiexperimental design, we examined differences between 21 non-Hispanic Black (NHB) participants and 20 non-Hispanic White (NHW) participants in capsaicin-related pain rating trajectories following a nondirectional verbal suggestion + saline infusion. All participants were told that the substance would "either increase pain sensation, decrease it, or leave it unchanged." A spline mixed model was used to quantify the interaction of ethnicity and time on ratings. RESULTS: There was a significant Ethnicity × Time interaction effect (ß = -0.28, p = .002); NHB individuals reported significantly greater increases in pain following, but not before, the verbal suggestion + saline infusion. Sensitivity analyses showed no change in primary results based on differences in education level, general pain sensitivity, or condition order. CONCLUSIONS: The present results showed ethnic differences in pain response trajectories following a verbal suggestion + saline infusion and suggest that future research rigorously examining possible ethnic differences in placebo/nocebo responses is warranted.

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.

Can insights from placebo and nocebo mechanisms studies improve the randomized controlled trial?

Background and aims The randomized controlled trial (RCT) is currently facing several challenges, one of these being that the placebo response appears to be increasing in RCTs, thereby making it difficult to demonstrate an effect of potentially new treatments over placebo. This problem has primarily been approached by predicting the magnitude of the placebo response via stable factors, such as demographic variables, and/or by developing complex designs aimed at reducing the placebo response in the hope that it will improve the test of the active treatment. Yet, the success of this approach has so far been limited. Methods A new approach toward improving the RCT is put forward based on placebo and nocebo mechanism studies, i.e. studies that investigate the mechanisms underlying placebo analgesia and nocebo hyperalgesia. In a series of meta-analyses the magnitude of placebo and nocebo effects were determined. Experimental studies across nociplastic and neuropathic pain conditions and across pharmacological and acupuncture treatments investigated psychological and neurobiological mechanisms underlying these effects. The obtained results were used to make approximations of expectations to see if that could predict the placebo response in RCTs and function as a new way of tapping into the placebo component of treatment effects. Results The magnitude of placebo and nocebo effects is large and highly variable. Placebo effects exist across chronic pain conditions with varying degrees of known etiology as well as across pharmacological and non-pharmacological treatments. Patients' perception of the treatment, the verbal suggestions given for pain relief, and the patients' expectations toward pain relief contribute to the magnitude of the placebo effect and to pain relief following placebo interventions. Also, unintentional unblinding and patients' perception of a treatment markedly influence the treatment outcome. By making approximations of expectations toward treatment effects it was possible to predict the magnitude of the placebo response in RCTs. Conclusions and implications The new approach of tapping into or directly asking patients about their perception and expectations toward a treatment, along with the account of the natural history of pain, has the potential to improve the information that can be obtained from RCTs. Thus, by interfacing insights from placebo and nocebo mechanism studies, it may be possible to enhance the information that can be obtained from RCTs and to account for a large part of the variability in the placebo component of the overall treatment effect. This approach has the potential to improve the scientific evaluation of treatments, as well as to illustrate how the effect of treatments can be optimized in clinical practice, which is the crux of evidence-based medicine.

Placebo and nocebo effects for itch and itch-related immune outcomes: A systematic review of animal and human studies.

Placebo and nocebo effects can influence somatic symptoms such as pain. For itch and other dermatological symptoms these effects have been far less investigated. This review systematically integrates evidence from both animal (mainly rodents) and human trials on placebo and nocebo effects in itch, itch-related symptoms and conditions of the skin and mucous membranes, and related immune outcomes (e.g., histamine). Thirty-one animal studies, and fifty-five human studies (k = 21 healthy participants, k = 34 patients) were included. Overall, studies consistently show that placebo and nocebo effects can be induced by various methods (e.g., suggestions, conditioning and social cues), despite high heterogeneity across studies. Effects of suggestions were found consistently across subjective and behavioral parameters (e.g., itch and scratching in humans), whereas conditioning was likely to impact physiological parameters under certain conditions (e.g., conditioning of histamine levels in stressed rodents). Brain areas responsible for itch processing were associated with nocebo effects. Future research may investigate how variations in methods impact placebo and nocebo effects, and whether all symptoms and conditions can be influenced equally.

The Placebo and Nocebo effect on sports performance: A systematic review.

The aim of this review was to determine the magnitude of the placebo and nocebo effect on sport performance. Articles published before March 2019 were located using Medline, Web of Science, PubMed, EBSCO, Science Direct, and Scopus. Studies that examined placebo and nocebo effects of an objective dependent variable on sports performance, which included a control or baseline condition, were included in the analysis. Studies were classified into two categories of ergogenic aids: (1) nutritional and (2) mechanical. Cohen's d effect sizes were calculated from 32 studies involving 1513 participants. Small to moderate placebo effects were found for both placebo (d = 0.36) and nocebo (d = 0.37) effects and when separated by nutritional (d = 0.35) and mechanical (d = 0.47) ergogenic aids. The pooled effect size revealed a small to moderate effect size across all studies (d = 0.38). Results suggest that placebo and nocebo effects can exert a small to moderate effect on sports performance.

To Experience or to Be Informed? Classical Conditioning Induces Nocebo Hyperalgesia even when Placebo Analgesia Is Verbally Suggested-Results of a Preliminary Study.

OBJECTIVE: To investigate whether direct experience (i.e., classical conditioning) or verbal suggestion is more important in inducing nocebo hyperalgesia, five groups (total sample size, N = 99) were studied: conditioning, congruent conditioning, incongruent conditioning, verbal suggestion, and control. METHODS: Participants in groups with conditioning experienced more intensive pain stimuli after presentation of a white circle. In the congruent conditioning group, suggestion that the circle would precede more intensive pain stimuli was additionally provided, whereas in the incongruent conditioning group, the opposite suggestion was used. Control and verbal suggestion groups received pain stimuli of one intensity; however, the latter received suggestion that a circle would precede pain stimuli of higher intensity. RESULTS: The nocebo effect was observed in all conditioning groups, regardless of the verbal suggestions used. Moreover, the experience of hyperalgesia was able to nullify the effect of the verbal suggestion of analgesia. Incongruence between verbal suggestion and pain experience produced expectancies that affected nocebo hyperalgesia. CONCLUSIONS: The results of this preliminary study suggest that direct experience seems to be more important than verbal suggestion in inducing nocebo hyperalgesia.

Nocebo/Placebo Effects in Dental Practice: Two Key Protagonists / Efectos Nocebo/Placebo en la práctica dental: Dos protagonistas clave

ABSTRACT Understanding the possible effects that a patient's psycho-neurobiological processes (such as the nocebo effect) may have on the every-day dental treatments, could assist the clinicians in preventing the onset of adverse events not related directly with the clinical procedure. At the same time, employing pathways to trigger plausible placebo effects could aid the clinician to enhance the outcome of ordinary clinical procedures and the patient's perspective. Identified factors, which could lead both to positive or negative effects, may be present in different ways. Prior personal experiences, second-hand information, alternative medicine, catastrophizing or patient motivation; all could have an indirect effect in the treatment outcome. A well-informed clinician should use such factors to individualize each patient treatment.

RESUMEN Comprender los posibles efectos que los procesos psico-neurobiológicos de un paciente (como el efecto nocebo) pueden tener en los tratamientos dentales diarios, podría ayudar a los clínicos a prevenir la aparición de eventos adversos que no estén relacionados directamente con el procedimiento clínico. Al mismo tiempo, el uso de vías para favorecer posibles efectos placebo podría ayudar al clínico a mejorar el resultado de sus procedimientos rutinarios y la perspectiva del paciente. Los factores identificados, ya sean positivos o negativos, pueden estar presentes de diferentes maneras. Experiencias personales anteriores, información de segunda mano, medicina alternativa, actitud catastrófica o motivación del paciente; todos podrían tener un efecto indirecto en el resultado del tratamiento. Un médico bien informado debe usar dichos factores para individualizar el tratamiento de cada paciente.

The neurobiological underpinnings of placebo and nocebo effects.

The placebo effect, once considered only a nuisance in clinical research, is today a target of scientific inquiry that allows us understand how words, rituals and, more in general, the whole psychosocial context around the patient, affect the response to a treatment and the course of a disease. Today we are in a good position to study all these complex psychological factors by using a physiological and neuroscientific approach that uses modern neurobiological tools to probe different brain functions. Since a placebo is represented by the whole ritual of the therapeutic act, the main concept that has emerged today is that words and rituals may modulate the same biochemical pathways that are modulated by drugs. Most of our knowledge about these mechanisms comes from the field of pain, and represents a biomedical, psychological and philosophical enterprise that is changing the way we approach and interpret medicine, psychology and human biology. If on the one hand we know some of the mechanisms of drug action in the central nervous system, on the other we can now understand how the clinician-patient interaction may affect different physiological functions. In fact, the placebo effect and the therapist-patient relationship can be approached by using the same biochemical, cellular and physiological tools of the materia medica. This represents an epochal transition, in which the distinction between drugs and words is progressively getting thinner, and which helps us overcome the old dichotomy between psychology and biology.

When words hurt: Verbal suggestion prevails over conditioning in inducing the motor nocebo effect.

Perception and behavior are strongly influenced by the verbal information conveyed by other individuals (e.g., verbal suggestion) and by learning (e.g., conditioning). This influence is well represented by the placebo and nocebo effects, in which positive verbal suggestion associated with positive conditioning induces beneficial outcomes (placebo effect), while the opposite is true for the negative counterpart (nocebo effect). It is still unclear whether verbal suggestion and conditioning exert distinctive roles in influencing perception, behavior and motor system activity when they occur in opposite directions. To this purpose, fifty-three healthy volunteers were assigned to four groups characterized by either congruent or incongruent verbal suggestion and conditioning. Participants were asked to perform a force motor task by pressing a piston as strongly as possible. Transcranial magnetic stimulation over the primary motor cortex was used to record motor evoked potentials (MEP) and cortical silent period (CSP) from the muscle involved in the task. We found that negative verbal suggestion counteracted positive conditioning and induced sense of weakness, effort, and force decrements. MEP amplitude was stable, whereas the CSP duration shortened in all the groups throughout the procedure, indicating the involvement of cortical inhibitory circuits, independently of the type of verbal suggestion or conditioning. Our findings highlight a prevalent role of verbal suggestion over conditioning in determining a worsening (nocebo effect) but not an improvement (placebo effect) of motor performance. These results suggest that words associated with treatments should be chosen carefully to avoid negative outcomes, especially in sports and clinical settings.