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The Nocebo Effect: A Review of Contemporary Experimental Research

Abstract

Background

Nocebo effect, the occurrence of adverse symptoms fallowing an inactive treatment, is much less understood than its opposite, placebo effect. This systematic review of contemporary studies exploring the nocebo effect focuses on (1) the mechanisms underlying the nocebo effect, (2) the characteristics of participants exhibiting a more intensive nocebo response, and (3) the circumstances that might reduce or prevent the nocebo effect.

Method

We included experimental nocebo studies published in English that examined the occurrence of nocebo in various domains (i.e., types of sensations and symptoms) and different levels of nocebo response (e.g., performance, self-assessment) and in different populations of participants (healthy and clinical). Using Web of Science, PsycInfo and PubMed, we identified 25 papers (35 studies) that met our criteria with a total of N = 2614 participants, mostly healthy volunteers.

Results

Nocebo was invoked by manipulating expectations, conditioning or both. A narrative content synthesis was conducted. Nocebo was successfully invoked in a range of domains (e.g., pain, nausea, itch, skin dryness) and levels (sensory, affective, psychological, and behavioral). Various characteristics of the conditioning procedure and participants’ emotions, expectations, and dispositions are found to be related to the nocebo response, which sheds insight into the possible mechanisms of the nocebo effect. Strategies successful and unsuccessful in diminishing the nocebo response are identified. Limitations of this review include a small sample of studies.

Conclusion

These findings point to the universality of nocebo as well as to the importance of participant characteristics and experimental circumstances in invoking the nocebo effect. Further research should examine the nocebo effect in clinical populations.

Introduction

Nocebo can be defined as the onset of a symptom, worsening of a symptom, or lack of improvement as a result of an inactive treatment, substance, device, or procedure [1]. The same phenomena can occur following an active treatment [2]. Nocebo is the opposite of the more highly recognized placebo effect, which involves improvement after receiving an inactive treatment. The effects of placebo and nocebo treatments are attributed to the psychosocial context in which they occur [3] and can be explained by learning, expectations, and social cognitions [4].

Compared to the placebo effect, the nocebo effect is less understood [5]. The limited amount of research might be attributed to the fact that invoking a nocebo effect involves deceiving participants but also inducing unpleasant symptoms. Experimentally, it is invoked by manipulating expectations or through conditioning. In the case of the former, participants are informed about the negative consequences of an inactive treatment (e.g., that an inactive spray will intensify pain). The experience of pain caused by a method such as electrical stimulation is then recorded with and without the application of the inactive treatment. In a conditioning-type experiment, participants are exposed to high intensity pain (unconditional stimulus) in the presence of the inactive treatment, e.g., spray (conditioned stimulus), and to less intensive pain without treatment. This is called the conditioning phase. They are then exposed to pain stimuli of constant intensity with and without the application of the spray, and estimates of pain intensity are recorded. This is called the testing phase. In both paradigms, the nocebo effect is confirmed if pain is perceived as stronger when it is applied in conjunction with the application of the inactive treatment, despite the fact that it is of an objectively constant intensity.

Although the placebo and nocebo effects share a number of common characteristics, research has indicated that only placebo occurs in some circumstances while in others, only nocebo will occur and that these effects will also sometimes vary in their intensity [e.g., 6]. In addition, placebo and nocebo responses differ at a neural level [7]. Therefore, simply concluding that the findings established for the placebo effect are also valid for nocebo is not justified. Indeed, nocebo research has a potential to illuminate the mechanisms underlying this phenomenon and to contribute to the understanding of human functioning. Such research also has practical value in that it might offer insight into how the nocebo effect might be reduced or prevented in everyday life. For example, such research might inform the development of protocols on how to convey information to a patient about risks of a given treatment, while minimizing the potential for a nocebo effect. Such research can also help prevent modern-day nocebo effects, such as nocebo caused by reading information about the side effects of certain drugs online [8] or by attributing non-specific somatic symptoms to various contemporary phenomena, such as wind turbines or Wi-Fi radiation, despite the fact that existing research confirms these responses to be the result of a nocebo effect [9, 10].

To date, several review papers examining the nocebo effect have been published. These papers have focused on the neurobiology of the nocebo effect [5, 11, 12], factors related to nocebo [13], gender differences in the nocebo effect [14, 15], nocebo in the field of pain [16, 17], and nocebo with non-specific drug side effects [18]. In this review, we have applied a slightly broader focus in order to gain an overview of a wider area of nocebo research and to allow comparisons of findings from different domains. Specifically, we have included a review of experimental research examining the occurrence of nocebo in various domains (i.e., types of sensations and symptoms), different levels of nocebo research (e.g., neurobiology, performance, self-assessment), research involving both active and inactive substances and treatments, and different populations of participants (healthy and clinical).

As such, the aim of this paper is to present a review of contemporary experimental research examining the nocebo effect, with particular emphasis on (1) the mechanisms underlying the nocebo effect, (2) the characteristics of participants exhibiting a more intensive nocebo response, and (3) the circumstances that might reduce or prevent the nocebo effect.

Method

PRISMA guidelines [19] were followed in conducting and reporting on this review, when applicable. In order to identify relevant articles examining the nocebo effect, the following databases were searched: Web of Science, PsycInfo and PubMed. In each database, the English key terms “nocebo” and “experiment” were entered. The search was conducted in November, 2019. Papers were included in the review if they were research papers examining the nocebo effect (or both nocebo and placebo), addressed at least one of the research questions posed, applied an experimental or quasi-experimental design, and were written in English.

The course of article selection is presented in Fig. 1. A search of all three databases identified a total of 107 results. Based on a review of titles and abstracts, 24 papers that did not meet the criteria for type of article were excluded. After removing duplicate papers, 42 unique articles remained. After reviewing the full text of these papers, a further 15 papers that did not meet the criteria for content were excluded. Finally, two studies were excluded due to high risk of bias. Following this selection process, a total of 25 papers containing 35 studies were included in the review.

Fig. 1
figure 1

Course of selection of relevant papers examining the nocebo effect

In order to organize, synthesize, and analyze the findings arising from the articles included in this review, a narrative content synthesis was conducted in accordance with the guidelines provided by Popay and colleagues [20]. First, data from all included articles were entered into a table that contained the following data for each article: authors and year of publication, number of participants and the population to which they belong, summary of study design and procedure, the method and domain in which nocebo was invoked, and the main findings relevant to the aims of this review. This was followed by a thematic analysis in order to conduct a preliminary content analysis. On the basis of their content, articles were first grouped into three categories consistent with the objectives of this review: underlying mechanisms of nocebo, characteristics of participants demonstrating a stronger nocebo response, and nocebo reduction/prevention. Articles could be included in more than one category. Narrower common themes or similarities were then identified in each category (Table 1). Using a process of research triangulation [20], studies with similar themes or methodological elements were compared with respect to their findings. As a result, possible common theoretical explanations or, in cases where inconsistencies arose in findings across studies, alternative explanations were proposed. The analysis was conducted by BLINDED and BLINDED, and potential disagreements were resolved by BLINDED.

Table 1 Categories and themes

Brief Description of Included Papers

Participants. A total of 2614 participants participated in the included studies. In general, samples consisted of both men and women, while in two studies only women participated and two studies included only men. Electronic Supplementary Material 1 presents further details regarding the samples in each study. Participants were predominantly young adults. In 34 studies, participants were healthy individuals, while one study included women with breast cancer. In a few studies, participants were further selected based on specific criteria: two studies involved participants considered to be sensitive to electromagnetic radiation, one study included participants who had exhibited stronger nocebo or placebo responses in a previous experiment, and a further two studies selected participants based on previous experience with nausea.

Methods. Together, the papers included in this review presented 25 experimental and 10 quasi-experimental studies. The nocebo effect was most often invoked in the domain of pain sensation (15 studies) and less frequently in the domain of nausea (4 studies), various non-specific symptoms (4 studies), cognitive ability (3 studies), dry skin (2 studies), touch (2 studies), dizziness (1 study), headache (1 study), itching (1 study), satiety (1 study), and cardiorespiratory function (1 study). In 20 studies, nocebo was invoked by manipulating expectations, while another 5 studies used conditioning and 12 studies used both procedures. The nocebo treatments applied varied across studies and included a nasal spray that allegedly reduces arousal, breath freshening strips that allegedly heighten nausea, inactive electrodes or creams that allegedly induce pain, an alleged transcranial magnetic stimulation device (actually an impressive-looking head massager!), false electromagnetic radiation implied via lighting and testing room set-up, alleged results of genetic analysis, and various visual stimuli that allegedly intensify pain. While in most cases, only an inactive treatment was applied, in some cases both active and inactive treatments were used [21] or only an active treatment [22, 23] but with different instructions given to participants in different conditions.

Relevant Variables. Across all studies, the contribution of a number of different variables to the nocebo effect was investigated. These included gender, personality, anxiety, depression, fear of pain, somatosensory amplification, perceived sensitivity to electromagnetic radiation, beliefs about medications, and characteristics of memories, and expectations related to symptoms.

Results and Discussion

A summary of key information from all papers is presented in Electronic Supplementary Material 1, whereas key categories and corresponding identified themes and subthemes are presented in Table 1.

Domains of Nocebo Effect

Across all studies, the nocebo effect was successfully invoked in the domains of pain sensation [6, 24,25,26,27,28,29,30,31,32], nausea [33, 34], non-specific symptoms [21, 35, 36], perception of cognitive abilities [1, 37, 38], skin dryness [22], touch [6, 39], itching [40], headache [41], and cardiorespiratory function [42]. The nocebo effect was not observed in the satiety [42] and dizziness [23] domains. In two studies (one in the area of pain [27] and another in the area of nausea [33]), a nocebo response was not confirmed at the level of the whole sample, but rather was observed among participants exhibiting certain characteristics only. It should also be noted that, across studies, not only was the nocebo effect invoked in different domains but also used in different procedures. As such, these findings point to the universality of nocebo as well as to the importance of participant characteristics and experimental circumstances in invoking the nocebo effect.

Underlying Mechanisms

Conditioning. Research examining the role of conditioning in the onset of nocebo has identified the conditions under which the nocebo effect can be invoked as well as those that contribute to its severity. Several studies [25, 28, 29, 31] demonstrated that nocebo can be invoked using psychological stimuli alone (e.g., abstract visual stimuli) as opposed to pharmacological stimuli (e.g., a placebo ointment). In cases of a pharmacologically induced nocebo effect, such as inactive creams or sprays, it is not possible to completely rule out the influence of previous learning (i.e., expectations regarding these substances). In contrast, the nocebo effect was also invoked in these studies using stimuli for which participants did not have any associations with unpleasant symptoms, such as horizontal or vertical stripes [31], light of a certain color [40], or a human face [28] displayed on a screen.

The findings of the studies included in this review confirm that a number of general conditioning laws can be applied to the nocebo effect. For example, a longer conditioning process produces a more robust nocebo effect and one that is more resistant to extinction [6]. This finding can be explained by the increased predictability of events under this condition and has also been observed for the placebo effect [6]. Interestingly, the role of conditioning duration was more important for non-painful tactile stimuli than for painful stimuli, a finding that perhaps points to the importance of rapid learning about stimuli associated with pain or physiological discomfort. In addition, two studies within a same paper demonstrated that the nocebo effect can be generalized to similar stimuli [29], where the expression of nocebo for the original stimuli for which conditioning was performed (e.g., pictures of animals) and new stimuli that fall into the same conceptual category (a second group of pictures of animals) practically does not differ [29]. Such generalization was more pronounced if the magnitude of the original nocebo response was greater. This is consistent with the assumption that generalization is an active cognitive process that requires explicit learning [43]. Conversely, one study demonstrated that nocebo can be invoked even without the participants’ consciousness using implicit conditioning [25]. In this study, painful and non-painful stimuli were administered after the presentation of a series of different visual stimuli (abstract black characters on a white background with red lines in the foreground that served as distractors). All visual stimuli that preceded painful stimulation were different from each other, but shared one difficult-to-notice characteristic (symmetry of black characters) that distinguished them from the visual stimuli that preceded painless stimulation (in which all were characterized by asymmetry of black characters — counterbalanced). Although the participants could not report the difference between these two groups of visual stimuli upon request, the nocebo effect was nevertheless evident. Two additional studies further demonstrated that the nocebo effect can also be activated subliminally. After conditioning with a supraliminal stimulus (presentation of a male face), nocebo was observed during later subliminal presentation of the same conditioned stimulus, but not for a control stimulus (another male face) [28].

Together, the findings of these studies have a number of implications for people experiencing chronic pain. Firstly, we might assume that repeated conditioning of the contextual stimuli that accompany chronic pain, results in nocebo pain which is stronger and more resistant to extinction. In addition, as a result of generalization, implicit and subliminal conditioning processes, pain can also be activated or intensified by stimuli that were not present during experienced pain or that were not consciously registered. As such, the onset of pain may seem very unpredictable and uncontrollable, thus contributing to feelings of helplessness and stress [25].

Manipulation of Expectations. Research in which nocebo was invoked by manipulating expectations emphasizes the importance of emotions in the onset of the nocebo effect. Specifically, it has demonstrated that people exposed to nocebo treatment report greater levels of anxiety [21], worry [42], arousal and a lower sense of dominance [1], and a general worsening of mood [9]. Similarly, a larger nocebo effect was found among individuals with a more pronounced fear of pain, but this relationship was mediated by increased stress in these individuals [24]. Negative emotions are assumed to provoke increased attention to bodily symptoms [41], which makes it more likely that such symptoms will be noticed and, in turn, attributed to a given treatment. In contrast, induction of a positive mood appears to preclude the later onset of the nocebo effect [41], perhaps by diverting attention from symptoms or changing expectations about the likelihood that negative symptoms will occur [41].

In an attempt to shed further insight into the role of expectations, a number of studies directly measured participants’ expectations regarding the nocebo effect. In one study, nocebo instruction influenced not only participants’ expectations but also their performance and subjective experience [42]. In a second study, nausea expectations predicted the experience of nausea [34]. In two studies, nocebo instruction had no effect on expectations or on symptom experience or performance [38, 43]. In one of these studies [38], however, a moderate correlation was found between expectations about task performance and subsequent perception of changes in performance following treatment (where no difference in objective performance measures was observed). Thus, expectations play an important role in the emergence of the nocebo effect, regardless of whether they stem from experimental manipulation or not. In one interesting study [30], an objective electrophysiological measure whose early phase is associated with anticipation — contingent negative variation (CNV) — was used as a measure of pain expectation. This study demonstrated that the nocebo cue produced a high amplitude CNV potential while the placebo sign produced a low amplitude potential. A similar and more recent study investigated the impact of the specificity and valence of memory and symptom-related expectations on placebo and nocebo [40]. Although individuals with higher memory specificity and more positive expectations regarding the future onset of itching exhibited a stronger placebo response, no such patterns were found for nocebo, a finding that was attributed to the robustness of the nocebo effect.

On the whole, there is evidence of the importance of expectations in the occurrence of nocebo, both when expectations are measured by participant report and using electrophysiological measures. However, further research is needed to better understand the specific characteristics of expectations that predict a stronger nocebo effect. For example, the nocebo response may be the result of the interaction between general expectations about the action of pharmacological or psychological treatments gained from previous experiences and specific expectations about symptoms and symptom intensity that are acquired during the experimental procedure. This question certainly deserves further research attention.

Comparison of Conditioning and Expectation Manipulation. In studies comparing conditioning and expectation manipulation procedures, the nocebo response was more pronounced when both procedures were used when compared to only one [30, 31], suggesting the presence of an additive effect.

Levels of Nocebo Response. Analysis of results across a number of studies offer the interesting possibility to compare the occurrence of nocebo at various levels, including sensory, affective, physiological and behavioral levels. For example, perception of more severe pain (the sensory component of nocebo) was found in studies where conditioning was performed explicitly [30, 31], but not when it was conducted implicitly [25]. In contrast, greater perceived discomfort with pain (affective component) was evident with both explicit [25, 31] and implicit conditioning [25]. Studies measuring the physiological component of the nocebo response found higher skin conductivity following presentation of the nocebo cue compared to that measured following the placebo sign [25, 31]. Interestingly, extinction occurred very quickly in the case of explicit conditioning [31], while the physiological component of nocebo was resistant to extinction in the case of implicit conditioning [25]. Another study found that cortisol was increased in the nocebo group when compared with a control group (physiological level), but there were no differences in subjective pain ratings between the two groups (sensory level) [32]. Research involving behavioral measures produced inconsistent results. Namely, while the nocebo effect was not evident in a study that measured reaction time required to terminate a painful stimulus [30], another study demonstrated that men had shorter reaction times when terminating a nausea-inducing rotation stimulus after receiving a nocebo instruction [33]. It should be noted, however, that participants in the first study were instructed to terminate the stimulus as soon as possible (reaction time), while in the second study, they were told to terminate the rotation when they could no longer endure it (tolerance time). Finally, in a somewhat atypical study, the nocebo effect was evident in physiological and behavioral levels [42]. In this study, half of the participants were told that they had a genetic risk for reduced exercise capacity [42], while the other half were told they had a protective gene. This nocebo information had a negative effect on both cardiovascular measures (physiology) and running endurance (behavior). It should be noted, however that, in this study, each participant was given “personalized nocebo information” (i.e., that tests indicated that he or she was at increased genetic risk for reduced exercise capacity) in contrast to receiving information that most people experience side effects following specific treatment. Secondly, no concrete treatment was applied in this study and, as such, does not speak to the nocebo effect in the narrower sense. This onset of symptom exacerbation following the expectation of such exacerbation without any special treatment has been called a nocebo-related effect [44]. In another study by the same authors [42] in which participants were told that they had either a risk or protective gene for ​​satiety, a placebo effect was evident, but the nocebo effect was not observed.

Manipulation of participants, expectations about task performance allows for a comparison of nocebo response using both subjective and objective measures. The studies included in this review suggest that such manipulation mainly affects subjective measures, while the situation is less clear for objective performance measures. In a study in which participants were told that a nasal spray increases or decreases arousal [38], group differences were evident in participants’ assessments of their performance on attention and working memory tasks, while no differences on objective task performance measures were observed. Similarly, in another study [1], participants receiving the instruction that transcranial magnetic stimulation causes a left-sided attention deficit reported concentration difficulties during a visual search task following false stimulation. In contrast, the opposite effect was observed on objective measures of left-sided attention, where the nocebo group exhibited improved performance. The authors attribute this latter result to the greater effort exerted by the nocebo group, while the placebo group may have expected “help” from the treatment. Conversely, in a previously mentioned “genetic risk” study [42], nocebo information affected participants’ performance (running endurance) but not subjective impression (running duration before reporting fatigue and feeling hot). Obviously, not all types of performance can be equally affected by effort and participants are not equally familiar with all types of performance deterioration (e.g., left-sided attention deficit [1]). Also, for performances more affected by emotions, it may be more easy to produce the nocebo effect. Additional research measuring the occurrence of nocebo using various measures and across differing levels and domains would contribute to a better understanding of the mechanisms underlying the nocebo effect and the conditions necessary for its occurrence.

Nocebo Risk Factors

The question of whether some people are more prone to placebo and nocebo effects than others is one that has long interested researchers, but one for which there is not yet a clear answer. The papers included in this review, albeit representing only a small number of studies, demonstrated that a number of individual characteristics are associated with a more pronounced nocebo response. In one study, participants who believed they were sensitive to radiation reported more symptoms and symptoms of higher intensity when they believed radiation had been activated [10]. People with more pronounced somatosensory amplification reported a higher intensity of tactile stimulation when a false Wi-Fi signal was applied, but only if they had viewed a video about the harmfulness of this signal [39]. Anxiety and depression also appear to be associated with a more pronounced nocebo response for painful stimuli [6], but this was the case only in shorter conditioning, whereas the effect of personality diminished in a longer conditioning. Finally, individuals with greater fear of medical pain reported more severe pain after applying a nocebo cream [24]. Because this result was not observed for any of the five-factor-model personality traits nor for fear of other types of pain, the authors of this study concluded that arousal by trait relevant situational cue is necessary for expression of that trait.

Surprisingly, none of the studies included in this review examined the nocebo effect among health-anxious individuals. Health anxiety is a consequence of the belief that normal bodily sensations or changes are a sign of serious illness [45]. Highly anxious people are prone to heightened attention to their body and bodily sensations and could therefore be more prone to the nocebo effect. There are sporadic findings that people with high health anxiety are more likely to report drug side effects [46], but more studies are necessary. Another characteristic that might be relevant to nocebo is anxiety sensitivity — a fear of anxiety itself because of the belief that anxiety can have detrimental physical, mental, and social consequences [47]. Among anxiety-sensitive individuals, the expectation of unpleasant symptoms and a consequent increase in anxiety might further heighten fear and related bodily sensations, thus leading to a stronger nocebo response. While some preliminary findings have suggested that anxiety sensitivity is associated with the nocebo effect [48], further research examining this topic is certainly needed.

In some studies, gender differences in nocebo response were observed. In general, research demonstrated that women report more pain after the nocebo treatment [24, 26, 27]. For example, when participants were taught to associate three different scenarios presented through virtual reality (e.g., an office) with pain, vibration or lack of stimulation, a nocebo response was observed among women only [27]. In this study, women reported a higher pain experience for the stimuli applied in the earlier pain-related scenario than for the control scenario, while there was no difference between the pain-related and vibration-related scenarios. In another study reporting the nocebo effect among women only [26], women reported more severe pain when they had been told that a short sound stimulus preceding painful stimuli (prepulse) would intensify the pain experience. Interestingly, this increase occurred for all stimuli following nocebo instruction, regardless of whether a prepulse was present or not. Again, this finding is indicative of the role of anxiety, which likely increased following instruction, in the onset of a nocebo response [26]. In another study examining gender differences, conditioning proved to be more effective in inducing nocebo for nausea among women, while manipulation of expectations was more effective among men [33]. A similar finding has been demonstrated elsewhere and is similarly true for the placebo effect [14]. The authors argue that this result reflects gender differences in learning capacities [33]. Furthermore, although the men participating in this study had previously terminated nausea-induced rotation following nocebo instructions, they did not report a greater number of symptoms, perhaps suggesting that some of the observed gender differences stem from a socially conditioned willingness to acknowledge symptoms [33]. Another proposed explanation for the more frequent occurrence of nocebo among women is that women have more stable negative expectations, worry more, and are more problem-oriented than men [19].

The only study examining nocebo in a clinical sample points to some unique aspects of this population. In this study, women with cancer reported more cognitive impairment when they had been told that chemotherapy could result in such impairment, but only if they exhibited heightened awareness of the stigma associated with their disease [37]. This finding indicates the importance of social cognition in this population. However, this finding pertains to the reporting of symptoms that appeared before the nocebo instruction was given and, as such, is perhaps a result of a change in the interpretation of previous events or even event recall in accordance with the instructions provided. Arguably, if participants had been asked to assess their own performance on a cognitive task within an experiment, the effect might have been even more pronounced. In any case, there is certainly a lack of research examining the nocebo effect in clinical samples, including those with both somatic and mental illnesses.

How Is the Nocebo Effect Reduced or Prevented?

A number of studies demonstrated that various procedures performed prior to invoking nocebo were effective in its prevention. In one study, invoking a nocebo response through conditioning was more difficult following latent inhibition [34]. This involved the presentation of a conditioned stimulus prior to the conditioning process without an appropriate unconditioned stimulus. In this study, participants were first exposed to false stimulation that allegedly causes nausea, followed by real stimulation that caused nausea and then again to the false stimulation [34]. At the latter false stimulation, participants reported nausea of the same intensity as the control group, who received false stimulation only (no nocebo induction). In contrast, a nocebo response was evident in a third group that underwent the classic nocebo conditioning procedure (actual simulation, followed by false stimulation). The authors argue that the efficacy of latent inhibition in preventing the nocebo effect is a result of reduced attention to the conditioned stimulus because of its decreased novelty [34]. Interestingly, the outcome following latent inhibition was the same even when participants were told that this procedure would be performed and for what purpose [34]. In another study, the aforementioned induction of positive mood was demonstrated to prevent a nocebo response [41]. Finally, findings of one study indicated that invoking a placebo response may also diminish the subsequent nocebo effect [35]. However, the reverse is not true, where evoking a nocebo response did not reduce the subsequent occurrence of a placebo response [35].

Conversely, some strategies did not prove to be effective in reducing or preventing a nocebo response. Specifically, studies that aimed to reduce the nocebo response by differently formulating or re-framing information given to participants regarding side effects did not produce impressive results [23, 49]. For example, in one study [23], one group of participants were given information regarding drug side effects in the standard manner, while a second group were told that side effects were a sign that the drug was working. All participants were administered the real medication. Although no differences were found between groups, there were indications that such a procedure would be useful in the prevention of nocebo among people with negative beliefs regarding certain drugs [23]. Another strategy that has not been demonstrated to be effective in reducing the nocebo effect is reducing the price of a given medication. In fact, marketing research has shown that a lower price for a medicinal cream resulted in a stronger nocebo response among participants who had previously been exposed to information about the side effects of such creams, as compared to a higher price [22]. In light of the readily available information about side effects that is included in medications’ instructions for use, this finding suggests that the frequency and number of side effects could increase when a given medication goes on sale. Indeed, price itself appears to act as a placebo or nocebo by creating certain expectations about a given product [22].

Critical Appraisal of the Included Studies

The findings arising from the studies described in this review should be considered alongside a number of limitations. First, two studies did not include a no-treatment control situation, but instead only nocebo and placebo conditions [30, 34]. In the case of any observed difference between these two conditions, it remains unclear whether both effects actually occurred, only one effect occurred or one effect was of much greater intensity. A similar problem was evident in a study that included only two nocebo groups [49]. A second limitation was the absence of so-called booster sessions (i.e., additional conditioning sessions during the test phase) [31]. Without such sessions, the nocebo effect can be quickly extinguished or even masked. A third problem arises in research measuring the behavioral aspect of nocebo using methods such as terminating an unpleasant stimulus over repeated trials [30, 33], where individuals more sensitive to a particular symptom would be experimentally exposed to the stimulus for a shorter period of time because they will consistently terminate the stimulus earlier. A problem arises, for example, when under this condition, habituation becomes more difficult.

Furthermore, the conditioning studies reviewed here have generally used the same type of conditioned stimuli (e.g., colors). Future studies should investigate differences in nocebo response with respect to the type of conditioned stimulus. For example, it might be easier to condition hyperalgesia or nausea using alternative stimuli (e.g., snakes or insects) that have been shown to more readily condition fear due to evolutionary readiness [50, 51]. In addition, the context in which unpleasant symptoms occur in everyday life is significantly more complex than the conditioned stimuli presented in laboratories, a factor that should be taken into consideration when interpreting the results of experimental studies.

The finding that the nocebo effect can be invoked using a number of different procedures raises the question of the similarity of mechanisms underlying such different types of nocebo. One can use conditioning or instruction, give instructions that treatment may cause a certain symptom or intensify a symptom that is experimentally induced, induce either a specific or non-specific nocebo response. In the case of a specific nocebo response, a specific side effect is expected (e.g., nausea or increased pain intensity), whereas with a non-specific response, there is only a vague idea of the symptoms that may occur [52], such as in the case of the effects of electromagnetic radiation. When non-specific symptoms are involved, it is possible that an individual will start to notice symptoms that were present from before [53]. The robustness of the nocebo response invoked using these varying procedures should certainly be further examined in future research.

A final limitation present in the studies included in this review arises from the fact that participants were almost exclusively healthy individuals. Arguably, invoking and generalizing a nocebo response might be easier among persons with some form of chronic somatic or psychological problem. Similarly, preventing a nocebo response using the previously described procedures might be more difficult in these groups. Here, the “conditioning procedure” is much longer and more complex (e.g., long-term medication use and the appearance of increasingly pronounced side effects). Persons with a history of somatic or mental illness have differing experiences with medication (e.g., beliefs that treatment that is more effective has stronger side effects or greater exposure to information regarding drug side effects). As such, it is reasonable to presume that their expectations regarding a given treatment will be different. When considering clinical groups, it is also important to recognize the differences between the doctor–patient relationship and the participant–experimenter relationship in terms of factors such as level of trust and need for help, as well as the potential effects of these factors on the intensity of the nocebo response.

Critical Appraisal of the Systematic Review

On a methodological level, this review offers a number of advantages. First, the systematic selection of articles according to predetermined criteria and use of a systematic method for analyzing qualitative data according to previously published guidelines allows for greater objectivity. Furthermore, the inclusion of studies that examine the nocebo effect in different domains and using differing methods for invoking and registering the nocebo response has enabled a comparison across studies and for broader conclusions regarding the nocebo effect to be drawn.

However, a number of limitations should also be considered when evaluating the conclusions presented in this review. One of the main limitations arising from this review is the inclusion of a relatively small number of studies, which is likely a result of the narrowly selected keywords. The inconsistent use of terminology in the area of nocebo research [13] raises the possibility that some papers examining this topic have been omitted. Also, there are likely many experimental studies of nocebo that do not explicitly use the word “experiment” in the paper. Indeed, wording has a strong effect on papers identified in databases. A related issue is the inclusion of only papers that were written in English. Another limitation to this review is the underrepresentation of certain domains of the nocebo effect, where most of the studies in this review have examined nocebo in the area of pain. For this reason, certain conclusions arising from this review cannot be generalized to other domains. Finally, despite the inclusion of specific research questions and the application of existing guidelines for conducting qualitative reviews, a certain level of subjectivity cannot be avoided. Namely, the authors choose which studies to include, how studies will be analyzed, which aspects of the findings from a particular study will be highlighted, how different studies will be more or less heavily weighted in the results and discussion and which conclusions will be drawn. For this reason, all conclusions made in this paper should be considered with these limitations in mind.

It is important to note that, although the strict distinction between conditioning and expectation manipulation used in this study is very common in the placebo and nocebo literature, recent publications [e.g., 54] argue that expectation can be instantiated in various ways including via verbal information, prior treatment experience or observational learning. Therefore, conditioning can also be considered a way to manipulate expectation.

Conclusion

This review of contemporary experimental research examining the nocebo effect presents empirical findings indicating that the appearance and severity of a nocebo response depend on learning circumstances, participant expectations, emotional state and, most likely, participant characteristics. Furthermore, findings demonstrate that there are a number of methods through which the nocebo effect can be reduced or prevented, including latent inhibition, positive mood induction, or a previous placebo induction. Future research should focus on examining the emergence of the nocebo effect in wider and more diverse areas of human experience and behavior as well as on an exploration of the expectation characteristics that are particularly important in predicting a nocebo response. Finally, further research should examine the nocebo effect among persons with somatic and psychological problems. Ongoing research into the nocebo effect can assist in the identification of individuals more susceptible to a nocebo response as well as the situational characteristics that favor its occurrence. Such understanding will, in turn, contribute to efforts in nocebo prevention. This is an important endeavor when one takes into consideration that, even if a given symptom is “only” caused by learning and expectations, the suffering that results from these experienced symptoms is certainly real.

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Correspondence to Branka Bagarić.

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Bagarić, B., Jokić-Begić, N. & Sangster Jokić, C. The Nocebo Effect: A Review of Contemporary Experimental Research. Int.J. Behav. Med. 29, 255–265 (2022). https://doi-org.libproxy.viko.lt/10.1007/s12529-021-10016-y

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Keywords

  • Nocebo
  • Systematic review
  • Nocebo mechanisms
  • Nocebo risk factors
  • Reducing and preventing nocebo