Pain memory in children: a systematic review and meta-analysis with a meta-regression.

ABSTRACT: The aim of this systematic review and meta-analysis was to analyze the accuracy of memory of pain and the variables that may influence it in children with acute, experimental, and chronic pain. We conducted a search in electronic databases from inception to February 11, 2022. Twelve observational studies and 3 randomized controlled studies were included in the study. The main outcome measure was the accuracy of the memory of the pain intensity (experienced/recalled). To compare the outcomes reported by the studies, we calculated the standardized mean difference (SMD) over time for the continuous variables. The overall meta-analysis showed a small effect size in favor of an overestimation of experienced pain intensity (SMD = 0.28). Subanalyzing per pain context, there was a small effect size in favor of overestimation in the clinical context (SMD = 0.33), but there was no evidence of any change in the accuracy of memory of pain in the experimental context (SMD = 0.07). The mean age of the participants and the proportion of girls significantly predicted the accuracy of the memory of pain. The period since the experienced pain measurement, the intensity of expected and recalled fear, trait anxiety, and anxiety sensitivity did not significantly predict the accuracy of the memory of pain. Children showed an overestimation in pain memory between the experienced and recalled intensity of acute pain, especially in a clinical context. Furthermore, only gender and age were predictors of the accuracy of pain memory. These results highlight the relevance of pain memory to medical practice and future research.

Placebo Hypoalgesia and Nocebo Hyperalgesia Induced by Observational Learning May Be Difficult to Disentangle in a Laboratory Setting.

Observational learning (OBL) (seeing pain/pain treatment in others) can evoke placebo hypoalgesia and nocebo hyperalgesia. Data that compare these effects and illuminates the role of expectations and empathy are scarce. Healthy participants (n = 105) were randomized to: 1) placebo OBL, 2) nocebo OBL, or 3) no-observation control group. OBL consisted of a model simulating pain relief or increase after a sham ointment was applied to one arm. Pain was evoked with thermal stimuli on both arms (ointment, contralateral) at baseline and postobservation. Expectations, pain ratings, and physiological data (eg, skin conductance level) were collected. A 3 × 2 × 2 (Group × Arm × Phase) mixed analyses of variance revealed a 3-way interaction that confirmed that OBL modulates pain: F(2, 93) = 6.08, P = .003, ηp2 = .12. Significant baseline-to-post-observation pain increases were shown in the nocebo OBL group, with a bigger increase for the arm with ointment (both P ≤ .007). In the placebo OBL group, pain was higher for the contralateral relative to the ointment arm (P < .001). Baseline-to-post-observation pain increase was significant for the contralateral arm (P < .001). Expectation mediated these effects. Skin conductance level decreased over time during ointment trials in the nocebo OBL group, suggesting reduced physiological arousal. The findings illustrate that OBL modulates pain through expectations. In the placebo OBL group, the pain did not decrease for the ointment but increased for the contralateral stimuli, which may reflect nocebo learning. Experimental OBL paradigms typically examine relative differences between ointment and contralateral cues. This can complicate disentangling placebo hypoalgesia and nocebo hyperalgesia in laboratory settings. Implications for existing theories are discussed. PERSPECTIVE: Data that systematically compare placebo hypoalgesia and nocebo hyperalgesia induced by OBL are scarce. The current work illustrates that these effects may be more difficult to disentangle than previously assumed, which could have implications for existing theories on OBL and placebo effects and their translation to clinical practice.

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

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

Learning pain from others: a systematic review and meta-analysis of studies on placebo hypoalgesia and nocebo hyperalgesia induced by observational learning.

ABSTRACT: Observing someone experience pain relief or exacerbation after an intervention may induce placebo hypoalgesia or nocebo hyperalgesia. Understanding the factors that contribute to these effects could help in the development of strategies for optimizing treatment of chronic pain conditions. We systematically reviewed and meta-analyzed the literature on placebo hypoalgesia and nocebo hyperalgesia induced by observational learning (OL). A systematic literature search was conducted in the databases PubMed, PsycINFO, Web of Science, ScienceDirect, PsycARTICLES, Scopus, and Academic Search Ultimate. Twenty-one studies were included in the systematic review, 17 of which were suitable for meta-analysis (18 experiments; n = 764 healthy individuals). The primary end point was the standardized mean difference (SMD) for pain following placebo cues associated during OL with low vs high pain. Observational learning had a small-to-medium effect on pain ratings (SMD 0.44; 95% confidence interval [CI] 0.21-0.68; P < 0.01) and a large effect on pain expectancy (SMD 1.11; 95% CI 0.49-2.04; P < 0.01). The type of observation (in-person vs videotaped) modulated the magnitude of placebo hypoalgesia/nocebo hyperalgesia ( P < 0.01), whereas placebo type did not ( P = 0.23). Finally, OL was more effective when observers' empathic concern (but no other empathy-related factors) was higher ( r = 0.14; 95% CI 0.01-0.27; P = 0.03). Overall, the meta-analysis demonstrates that OL can shape placebo hypoalgesia and nocebo hyperalgesia. More research is needed to identify predictors of these effects and to study them in clinical populations. In the future, OL could be an important tool to help maximize placebo hypoalgesia in clinical settings.

From past pain to future pain through the pain of others: Information about other people's pain ratings can alleviate our subsequent pain.

BACKGROUND: Previous studies have shown that pain memories have a profound impact on subsequent pain experiences. This study investigated whether pain ratings derived from other people can modify an individual's memory of past pain. This study also examined whether pain memory modified by others' pain ratings determines subsequent pain experiences. METHODS: Participants were divided into two groups: an experimental group and a control group. Participants in both groups were exposed to pain stimulation; then, they recalled its intensity twice over a period of time; after a break, they were again exposed to pain stimulation of the same intensity. The final sample consisted of 53 participants. The only difference between the experimental group and the control group was that in the former the pain ratings of other alleged participants were presented between the two consecutive pain recalls. These ratings suggested that other people experienced the same pain as less intense. RESULTS: The pain ratings derived from other people did not alter the pain memory; nevertheless, they affected an individual's next pain experience even for a certain period of time after their presentation. This type of pain-related information shaped participants' subsequent pain experiences regardless of their empathy, conformity, and susceptibility to social influence. CONCLUSIONS: Information on pain derived from other people not only shapes the response to a novel stimulation but also substantially modifies the subsequent experience of that stimulation. SIGNIFICANCE: The study demonstrates the importance of social information on pain and provides evidence that this type of information substantially modifies the subsequent experience of the same pain. These results suggest that social information on pain can be used to alleviate pain associated with recurring medical procedures and thus increase patients' willingness to continue treatment.

Development and cross-national investigation of a model explaining participation in WHO-recommended and placebo behaviours to prevent COVID-19 infection.

To protect themselves from COVID-19, people follow the recommendations of the authorities, but they also resort to placebos. To stop the virus, it is important to understand the factors underlying both types of preventive behaviour. This study examined whether our model (developed based on the Health Belief Model and the Transactional Model of Stress) can explain participation in WHO-recommended and placebo actions during the pandemic. Model was tested on a sample of 3346 participants from Italy, Japan, Poland, Korea, Sweden, and the US. It was broadly supported: objective risk and cues to action showed both direct and indirect (through perceived threat) associations with preventive behaviours. Moreover, locus of control, decision balance, health anxiety and preventive coping moderated these relationships. Numerous differences were also found between countries. We conclude that beliefs about control over health and perceived benefits of actions are critical to the development of interventions to improve adherence to recommendations.

The Effects of Pain Expectancy and Desire for Pain Relief on the Memory of Pain in Half Trail Marathon Runners.

PURPOSE: It has been shown that the memory of pain induced by running might be underestimated. Our previous study showed the contribution of emotional factors to this process. This study aimed to investigate the cognitive factors that might influence the memory of this type of pain, ie expectancy of pain intensity, expectancy of pain unpleasantness, and desire for pain relief. PARTICIPANTS AND METHODS: A total of 49 half-marathon runners rated the intensity and unpleasantness of pain immediately after completing a run and one month later. Participants rated the expected intensity and unpleasantness of the upcoming pain before starting the run, as well as the desire for pain relief after its completion. Those who also participated in the previous edition of the half marathon were asked to recall the pain experienced due to that run. RESULTS: Participants underestimated remembered pain intensity and unpleasantness. The desire for pain relief mediated the memory of pain intensity (p < 0.05), while expectancy of pain intensity influenced memory of pain intensity (a × b) through its effect on the experienced pain (bootstrapped point estimate = 0.08; 95% CI: 0.02-0.32). The remembered intensity of pain experienced during the previous half marathon affected the current pain experience directly (p < 0.05) or indirectly (a × b) by generating pain-related expectancy (bootstrapped point estimate = 0.11; 95% CI: 0.01-0.46). The cognitive variables did not influence the memory of pain unpleasantness. CONCLUSION: The memory of pain induced by sports activity may change due to cognitive factors; however, further research is needed to investigate their role in shaping the memory of the sensory and affective dimensions of pain.

The Lighter Side of Pain: Do Positive Affective States Predict Memory of Pain Induced by Running a Marathon?

BACKGROUND: Memory and in turn, memory of pain is a reconstructive process. This study considers the relationship between time, memory, affective states, and pain induced by running a marathon by investigating the influence of these factors on a participant's memory of pain experienced after a marathon. The following two hypotheses were formulated: 1) participants' recalled-pain of marathon experience is underestimated; and 2) the underestimation of recalled pain would be greater for participants experiencing higher positive affect. METHODS: A longitudinal design was employed to check pain intensities of marathon participants a) at the finish line and b) 6 months following its completion. The sample size was based on a power analysis, and 108 marathonists rated their pain intensities and positive and negative affects at the finish line. From this sample, 58 participants recalled their pain experience of running the marathon 6 months later. Linear models, including computer-based data-mining algorithms, were used. RESULTS: The experienced pain was higher than their recalled pain (t(55) = 3.412, p < 0.01, d = 0.45), supporting the first hypothesis. The memory of pain faded similarly in all participants, which did not directly support the second hypothesis. Further exploratory analysis suggested that negative and positive affective states were related to participants' pain memory; positive affective states appeared to be inversely related to the recall (ß = -0.289, p = 0.039). DISCUSSION: This study shows that time has a significant effect on memory recall and that emotions may also influence the memory of pain. This is the first study that preliminarily showcased the effect of positive affective states on the memory of pain induced by physical exercise.

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.

One of us or one of them? The effects of the model's and observer's characteristics on placebo analgesia induced by observational learning.

Previous studies have proved that observational learning can induce placebo analgesia, but the factors that influence observationally induced placebo analgesia have not yet been extensively examined. The primary goal of this study was to investigate the effect of information about the role that the observed person (model) plays in the experiment on the magnitude of the observationally induced placebo effect. This study also examined the contribution of the observer's empathy, conformity and fear of pain to the placebo analgesia induced by observational learning. The effects induced in two experimental groups and one control group were compared. Participants in the experimental groups observed a model introduced as either another participant taking part in the study or a coworker of the experimenter. The model rated the intensity of pain induced by electrocutaneous stimuli preceded by color stimuli. One-half of all participants watched a model rating pain stimuli preceded by the color orange as higher than stimuli preceded by the color blue; for the other half, the ratings were the opposite. There was no observation in the control group. Subsequently, all participants received pain stimuli of the same intensity preceded by orange and blue stimuli and rated the intensity of the experienced pain. Placebo analgesia was found in both experimental groups. However, the way the observed model was introduced to participants did not affect the magnitude of placebo analgesia. Thus, the study showed that the role played by the model is not crucial for observationally induced placebo analgesia. The examined observer's individual characteristics did not predict the magnitude of placebo effect.

Nocebo hyperalgesia can be induced by classical conditioning without involvement of expectancy.

Influential theoretical accounts take the position that classical conditioning can induce placebo effects through conscious expectancies. In the current study two different conditioning procedures (hidden and open) were used to separate expectancy from conditioning in order to reveal the role of expectancy in the formation of nocebo hyperalgesia. Eighty-seven healthy females were randomly assigned to three groups (hidden conditioning, open conditioning, and control). Participants were selected according to the Fear of Pain Questionnaire scores and assigned to two subgroups: high and low level of fear of pain (trait). They received electrocutaneous pain stimuli preceded by either an orange or blue color. During the conditioning phase, one color was paired with pain stimuli of moderate intensity (control stimuli) and the other color was paired with pain stimuli of high intensity (nocebo stimuli) in both hidden and open conditioning groups. Only participants in the open conditioning group were informed about this association, however just before the testing phase the expectancy of hyperalgesia induced in this way was withdrawn. In the control group, both colors were followed by control pain stimuli. During the testing phase all participants received a series of stimuli of the same intensity, regardless of the preceding color. Participants rated pain intensity, expectancy of pain intensity and fear (state). We found that nocebo hyperalgesia was induced by hidden rather than open conditioning. The hidden conditioning procedure did not produce conscious expectancies related to pain. Nocebo hyperalgesia was induced in participants with low and high fear of pain and there was no difference in the magnitude of the nocebo effect between both groups. Nocebo hyperalgesia was not predicted by the fear of upcoming painful stimuli.

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.

Memory of pain in adults: a protocol for systematic review and meta-analysis.

BACKGROUND: The way pain is remembered and reported can affect medical decisions taken by patients and health-care professionals. Memory of pain has been investigated extensively for the past few decades; however, the results of previous studies are highly variable, indicating that the recollection of pain can be accurate, overestimated or underestimated. It is therefore difficult to conclude how well pain is remembered. The aim of this systematic review and meta-analysis is to summarize research findings on memory of pain in healthy adults and patients suffering from acute and chronic pain. METHODS: The systematic review will be performed by searching for articles indexed in the following databases: PubMed, MEDLINE, PsycINFO, Web of Science, ScienceDirect, PsycARTICLES, Scopus and Academic Search Complete. Studies will be included if (1) they investigated healthy adults or patients with any acute or chronic pain condition and if (2) they assessed experienced pain (pain intensity and/or pain unpleasantness) and its recollection. No restrictions related to the date of publication and recall delay will be applied. Studies will be screened for eligibility and risk of bias by two independent assessors. The risk of bias will be assessed by a modified Downs and Black checklist. A narrative synthesis will be performed in the first stage; in the second stage, the results of studies with comparable designs will be pooled in meta-analytical syntheses. DISCUSSION: The question of whether pain is remembered accurately is crucial for valid pain diagnosis, effective treatment and prognosis. So far, a number of studies on memory of pain have been conducted; however, a definitive conclusion on whether memory of pain is accurate is still lacking. In this systematic review and meta-analysis, available data will be pooled together to further inform research and clinical practice. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018093523.

Rewarded placebo analgesia: A new mechanism of placebo effects based on operant conditioning.

BACKGROUND: Placebo analgesia is explained by two learning processes: classical conditioning and observational learning. A third learning process, operant conditioning, has not previously been investigated as a mechanism of placebo effects. We aimed to induce placebo analgesia by operant conditioning. METHODS: Three groups of participants received electrocutaneous pain stimuli of the same intensity, preceded by either an orange or blue stimulus. In the conditioning phase of the study, participants from the experimental group were rewarded for low pain responses following one of the colour stimuli (placebo) and for high pain responses following the other colour stimuli (non-placebo). Moreover, they were punished when their pain responses were high following placebo stimuli and low following non-placebo stimuli. To investigate the role of contingency, that is dependent relation between rewards/punishers and pain responses, the random-control group received rewards and punishers in a non-contingent manner. The colour-control group did not receive any rewards or punishers to control for nonassociative learning. Pain intensity ratings were used as an outcome measure, and verbal feedback on pain ratings was used as rewards/punishers. RESULTS: When rewarding and punishment were stopped, only participants from the experimental group experienced less pain following the placebo than following the non-placebo stimuli; that is, placebo analgesia was found in this group. This effect was not extinguished during the study. CONCLUSIONS: Placebo analgesia can be induced by operant conditioning, which should be considered a third mechanism for producing placebo effects. Moreover, the contingency between pain responses and rewards/punishers is crucial to induce placebo analgesia through operant conditioning. SIGNIFICANCE: According to the current placebo literature, placebo analgesia can be explained by two learning processes: classical conditioning and observational learning. A third learning process, operant conditioning, has not previously been investigated as a mechanism of placebo effects. Our study reveals that patients can learn placebo analgesia as a result of operant conditioning, suggesting that randomized controlled trials could be improved by controlling the reinforcement that might occur spontaneously when patients interact with, for example, medical personnel.

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

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

How Classical Conditioning Shapes Placebo Analgesia: Hidden versus Open Conditioning.

Objective: To investigate the influence of expectancy of pain intensity, fear of pain (trait), and fear (state) on the effectiveness of hidden and open conditioning to produce placebo analgesia. Methods: A total of 90 healthy female volunteers were randomly assigned to three groups (hidden conditioning, open conditioning, and control) that received electrical stimuli preceded by either orange or blue lights. One color was paired with painful stimuli (control stimuli) and the other color was paired with nonpainful stimuli (conditioned stimuli) in both the hidden and open conditioning groups. Only participants in the open conditioning group were informed about this association. In the control group, both color lights were followed by control stimuli. In the testing phase, both colored lights were followed by identical control stimuli. Participants rated pain intensity, expectancy of pain intensity, fear, and fear of pain. Results: A significant analgesic effect was found only in the hidden conditioning group, where no explicit verbal suggestions were provided. Hidden conditioning had an effect on expectancy and fear-participants in the hidden conditioning group expected less pain and experienced less fear in relation to conditioned stimuli. Fear was the only predictor of placebo analgesia in the hidden conditioning group. Neither expectancy of pain intensity nor fear of pain predicted placebo analgesia. Conclusions: Fear seems to be a more important factor than expectancy in producing placebo analgesia induced by hidden conditioning.

Classical conditioning without verbal suggestions elicits placebo analgesia and nocebo hyperalgesia.

The aim of this study was to examine the relationships among classical conditioning, expectancy, and fear in placebo analgesia and nocebo hyperalgesia. A total of 42 healthy volunteers were randomly assigned to three groups: placebo, nocebo, and control. They received 96 electrical stimuli, preceded by either orange or blue lights. A hidden conditioning procedure, in which participants were not informed about the meaning of coloured lights, was performed in the placebo and nocebo groups. Light of one colour was paired with pain stimuli of moderate intensity (control stimuli), and light of the other colour was paired with either nonpainful stimuli (in the placebo group) or painful stimuli of high intensity (in the nocebo group). In the control group, both colour lights were followed by control stimuli of moderate intensity without any conditioning procedure. Participants rated pain intensity, expectancy of pain intensity, and fear. In the testing phase, when both of the coloured lights were followed by identical moderate pain stimuli, we found a significant analgesic effect in the placebo group, and a significant hyperalgesic effect in the nocebo group. Neither expectancy nor fear ratings predicted placebo analgesia or nocebo hyperalgesia. It appears that a hidden conditioning procedure, without any explicit verbal suggestions, elicits placebo and nocebo effects, however we found no evidence that these effects are predicted by either expectancy or fear. These results suggest that classical conditioning may be a distinct mechanism for placebo and nocebo effects.