Optimizing placebo and minimizing nocebo effects through communication: e-learning and virtual reality training development.

BACKGROUND: The effects of many treatments in healthcare are determined by factors other than the treatment itself. Patients' expectations and the relationship with their healthcare provider can significantly affect treatment outcomes and thereby play a major role in eliciting placebo and nocebo effects. We aim to develop and evaluate an innovative communication training, consisting of an e-learning and virtual reality (VR) training, for healthcare providers across all disciplines, to optimize placebo and minimize nocebo effects through healthcare provider-patient communication. The current paper describes the development, mid-term evaluation, optimization, and final evaluation of the communication training, conducted in The Netherlands. METHODS: The development of both the e-learning and the VR training consisted of four phases: 1) content and technical development, 2) mid-term evaluation by healthcare providers and placebo/communication researchers, 3) optimization of the training, and 4) final evaluation by healthcare providers. To ensure the success, applicability, authenticity, and user-friendliness of the communication training, there was ongoing structural collaboration with healthcare providers as future end users, experts in the field of placebo/communication research, and educational experts in all phases. RESULTS: Placebo/communication researchers and healthcare providers evaluated the e-learning positively (overall 7.9 on 0-10 scale) and the content was perceived as useful, accessible, and interesting. The VR training was assessed with an overall 6.9 (0-10 scale) and was evaluated as user-friendly and a safe method for practicing communication skills. Although there were some concerns regarding the authenticity of the VR training (i.e. to what extent the virtual patient reacts like a real patient), placebo and communication researchers, as well as healthcare providers, recognized the significant potential of the VR training for the future. CONCLUSIONS: We have developed an innovative and user-friendly communication training, consisting of an e-learning and VR training (2D and 3D), that can be used to teach healthcare providers how to optimize placebo effects and minimize nocebo effects through healthcare provider-patient communication. Future studies can work on improved authenticity, translate the training into other languages and cultures, expand with additional VR cases, and measure the expected effects on providers communication skills and subsequently patient outcomes.

Placebo and Nocebo Effects on Sports and Exercise Performance: A Systematic Literature Review Update.

Sports performance could be affected by placebo and nocebo effects. The last literature review on placebo and nocebo effects on sports and exercise performance was published in 2019. In the past five years, several new studies have been published. This review aimed to update the previous synthesis and evaluate the results of new studies focusing on placebo or nocebo interventions in sports and exercise by determining the form and magnitude of their effect. Hence, we searched for empirical studies published from 2019 until the end of May 2024 indexed in PubMed, Medline, Web of Science, EBSCO, and Google Scholar databases. The search yielded 20 eligible studies with control or baseline-control conditions, focusing on nutritional, mechanical, and other mixed ergogenic aids. They yielded small to large placebo effects (Cohen's d) for nutritional (d = 0.86), mechanical (d = 0.38), cream and gel (d = 0.05), and open-label placebo (d = 0.16) interventions. The pooled effect size for placebo effects was moderate to large (d = 0.67), larger than in the earlier review, suggesting that placebo effects can improve motor performance even more than previously reported. However, based on five measures from three studies, the nocebo effects were almost twice as large (d = 1.20). Accordingly, the current findings support and expand the last review in the field by yielding additional support for placebo and nocebo effects in sports and exercise.

The Roles of Endogenous Opioids in Placebo and Nocebo Effects: From Pain to Performance to Prozac.

Placebo and nocebo effects have been well documented for nearly two centuries. However, research has only relatively recently begun to explicate the neurobiological underpinnings of these phenomena. Similarly, research on the broader social implications of placebo/nocebo effects, especially within healthcare delivery settings, is in a nascent stage. Biological and psychosocial outcomes of placebo/nocebo effects are of equal relevance. A common pathway for such outcomes is the endogenous opioid system. This chapter describes the history of placebo/nocebo in medicine; delineates the current state of the literature related to placebo/nocebo in relation to pain modulation; summarizes research findings related to human performance in sports and exercise; discusses the implications of placebo/nocebo effects among diverse patient populations; and describes placebo/nocebo influences in research related to psychopharmacology, including the relevance of endogenous opioids to new lines of research on antidepressant pharmacotherapies.

¿Influye la comunicación con el paciente sobre la kinesiofobia? Una revisión sistemática / Does patient communication influence kinesiophobia? A systematic review

El objetivo de la presente revisión sistemática consistió en determinar el efecto de la comunicación en el ámbito sanitario sobre la kinesiofobia. Para ello, se realizó una búsqueda bibliográfica en siete bases de datos entre noviembre de 2022 y febrero de 2023. La revisión se efectuó acorde a la declaración Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) y para el análisis de la calidad metodológica se utilizaron: la escala Physiotherapy Evidence Database (PEDro), los criterios de Van Tulder y el análisis del riesgo de sesgo de la Colaboración Cochrane. Se incluyeron un total de 13 artículos que presentaron una calidad metodológica media de 7,1 sobre 10. Se obtuvieron resultados significativos para al menos una variable (kinesiofobia, discapacidad o nivel de actividad física) en 12 trabajos. Existe evidencia sólida de que la comunicación puede influir sobre la kinesiofobia del sujeto. Es más probable que esta influencia ocurra en un sentido negativo o discapacitante, pero también puede actuar en sentido positivo disminuyendo la misma. (AU)

The aim of the present systematic review was to determine the effect of communication in the health care setting on kinesiophobia. To this end, a literature search was conducted in seven databases between November 2022 and February 2023. The review was carried out following the PRISMA statement and for the analysis of methodological quality we used: PEDro Scale, Van Tulder criteria and risk of bias analysis of the Cochrane Collaboration. A total of 13 articles were included with a mean methodological quality of 7.1 out of 10. Significant results were obtained for at least one variable (kinesiophobia, disability or level of physical activity) in 12 articles. There is strong evidence that communication can influence a subject's kinesiophobia. This influence is most likely to be in a negative or disabling sense, but it can also act in a positive sense by decreasing it. (AU)

Nocebo expectations rather than placebo expectations affect topical pain relief: A randomized clinical trial.

Patients' expectations and beliefs regarding the potential benefits and harms of medical interventions may induce placebo and nocebo effects, and affect the response to pain therapies. In a randomized clinical trial, we examined the effect of placebo and nocebo expectations on pain relief and adverse events (AEs) in association with a topical treatment among 65 cancer survivors experiencing chronic musculoskeletal pain. Participants received either a 1% camphor-based topical pain patch or a placebo treatment for 14 days. We measured pain severity with the worst pain item of the Brief Pain Inventory (BPI) at baseline and 14 days and treatment expectations at baseline with validated expectation questionnaires. We found that high vs. low nocebo expectations decreased pain severity improvements by 2.5 points (95% confidence interval [CI] -3.8 to -1.2; p<0.001) on a 0-10 numeric rating scale of the BPI and pain response rate by 42.7% (95% CI 0.2-0.6; p<0.001) at day 14, irrespective of placebo expectation status or treatment arms. Patients with high vs. low nocebo expectations in the true arm reported 22.4% more unwanted AEs. High nocebo expectations were associated with increased AEs by 39.5% (odds ratio: 12.0, 95% CI 1.2, 145.5; p=0.029) and decreased pain response in the true arm vs. placebo. Our study demonstrated that nocebo expectations, rather than placebo expectations, elevate the risk of AEs and compromise the effect of topical pain interventions. The findings raise the possibility that nocebo expectations may worsen somatic symptoms through heightening central pain amplification and should be further investigated.

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

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

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

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

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.

Vague sensations. About the background and consequences of discordance between actual and perceived physiological changes.

Empirical evidence consistently shows that discordance, also called dissociation or discrepancy, between actual physiological (mainly visceral) events and their perceived counterparts is substantial. On the one hand, we typically do not perceive actual visceral events occurring in our bodies; on the other hand, sometimes we do perceive bodily changes that do not really take place. This narrative review presents the available empirical findings on the discordance, and summarizes possible explanations that approach the phenomenon from the viewpoint of evolution, cognitive development, and predictive processing. Also, the role of top-down factors, such as expectations and experiences is discussed. Finally, practically relevant consequences of the discordance are presented using the examples of mind-body practices, the placebo and nocebo phenomenon, and medically unexplained symptoms. It is concluded that the discordance between actual and perceived body changes can have a negative impact on health, mainly through issues with adherence and other behavioral factors. The existence of actual-perceived discordance should be taught and demonstrated in the elementary and high school, as well as in many areas of higher education.

Confirmation of COVID-19 infection status and reporting of Long COVID symptoms in a population-based birth cohort: No evidence of a nocebo effect.

Some patients with COVID-19 develop symptoms after the acute infection, known as 'Long COVID'. We examined whether or not confirmation of COVID-19 infection status could act as a nocebo, using data from questionnaires distributed to the Avon Longitudinal Study of Parents and Children cohort. We examined associations between confirmation of COVID-19 infection status (confirmed by a positive test vs unconfirmed) and reporting of Long COVID symptoms. We explored the roles of sex and anxiety as potential moderators. There was no clear evidence of a strong association between confirmation of COVID-19 infection status and the Long COVID composite score, physical or psychological symptoms or duration of symptoms. There was no clear evidence of moderation by sex or anxiety. We therefore found no evidence of a nocebo effect. Our data suggest that this psychological mechanism does not play a role in the medical symptomatology experienced by patients with Long COVID.

Placebo and Nocebo Responses in Pharmacological Trials of Tic Disorders: A Meta-Analysis.

BACKGROUND: Clinical trials of new drugs for tic disorders (TD) often fail to yield positive results. Placebo and nocebo responses play a vital role in interpreting the outcomes of randomized controlled trials (RCTs), yet these responses in RCTs of TD remain unexplored. OBJECTIVE: The aim was to assess the magnitude of placebo and nocebo responses in RCTs of pharmacological interventions for TD and identify influencing factors. METHODS: A systematic search of the Embase, Medline, Cochrane Central Register of Controlled Trials, and PsycINFO databases was conducted. Eligible studies were RCTs that compared active pharmacological agents with placebos. Placebo response was defined as the change from baseline in TD symptom severity in the placebo group, and nocebo response as the proportion experiencing adverse events (AEs) in this group. Subgroup analysis and meta-regression were performed to explore modifying factors. RESULTS: Twenty-four trials involving 2222 participants were included in this study. A substantial placebo response in TD symptom severity was identified, with a pooled effect size of -0.79 (95% confidence interval [CI] -0.99 to -0.59; I2 = 67%). Forty-four percent (95% CI 27% to 63%; I2 = 92%) of patients experienced AEs while taking inert pills. Sample size, study design, and randomization ratio were correlated with changes in placebo and nocebo responses. CONCLUSION: There were considerable placebo and nocebo responses in TD clinical trials. These results are of great relevance for the design of future trials and for clinical practice in TD. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration ID CRD42023388397. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Reporting of auditory symptoms over time: (in)consistencies, expectations and the nocebo effect.

Objective: Consistent symptom reporting for conditions like tinnitus that do not have an associated sign is critical for evaluating severity and intervention effectiveness, and for interpreting research findings. There is little research examining reporting of tinnitus and hearing difficulty over time. We address this here by comparing reported hearing difficulty and tinnitus at two time-points.Design: A cross-sectional study comparing symptom reporting in March 2019 and August/September 2021 using data from two online surveys of the same cohort. Although each survey was designed to address a different question, both asked about symptoms of tinnitus and hearing difficulties and enabled this exploratory analysis.Study sample: 6881 members of the UK general public aged 18+ years.Results: Inconsistent reporting was evident - many participants who reported experiencing tinnitus and/or hearing difficulties in 2019, said in 2021 that they had never had such symptoms before. Additionally, reports of new tinnitus/hearing difficulties in 2021 were unexpectedly high, equating to 18-month incidence rates of 13.6% and 11.7%, respectively.Conclusions: Psychosocial factors, expectations and context impact symptom reporting. This should be considered when treating patients and interpreting research findings. Using real-time data collection methods could thus provide a better understanding of experiences of tinnitus and hearing.

Investigation of treatment continuity, usefulness, and nocebo effect in switching from the original etanercept to its biosimilar in patients with rheumatoid arthritis: A JET observational study in Japanese clinical practice.

OBJECTIVES: To assess the usefulness and onset of nocebo effects after switching from the original etanercept (ETN) to a biosimilar (BS) in routine clinical practice at rheumatology clinics in Japan (13 sites). METHODS: A total of 165 patients (87.0% women, age = 57.88 ± 15.07 years, and disease duration = 10.32 ± 7.71 years), whose low disease activity was maintained with the original ETN for ≥12 weeks, and who agreed to switch treatment to its BS, were included. The end-points were disease activity score 28 (DAS28)-C-reactive protein and DAS28-erythrocyte sedimentation rate. RESULTS: No significant difference was observed between the changes in DAS28-C-reactive protein and DAS28-erythrocyte sedimentation rate >12 weeks before switching and >12 weeks after switching (P = 0.132 and 0.334, respectively). The treatment continuation rate during the 52 weeks after switching to BS was 97.3%. During this period, BS was discontinued in only four patients, and no nocebo effects were suspected in these four patients. CONCLUSION: Switching from ETN to BS was effective even in routine clinical practice at rheumatology clinics in Japan, and no nocebo effects were observed. Sufficient explanations to patients by rheumatologists and the additional payment for drug costs between patients at hospital visits effectively improved the continuation rate without any nocebo effect.

Nocebo effects and influencing factors in the randomized clinical trials of chronic constipation: A systematic review and meta-analysis.

BACKGROUND: Nocebo effects are unavoidable in randomized clinical trials. We aimed to assess the magnitude of nocebo effects and explore the influencing factors in chronic constipation. METHODS: We searched the PubMed, Embase, and Cochrane Library databases up to July 2022. Randomized, placebo-controlled trials investigating interventions in chronic constipation were included. We conducted a random effects meta-analysis of the proportion of adverse events (AEs) in placebo-treated participants and evaluated the effect of trial characteristics on nocebo effects. KEY RESULTS: We identified 20,204 studies from the databases, of which 61 were included in the final analysis. The pooled placebo AE rate was 30.41%, and AE-related withdrawal rate was 1.53%. The most commonly reported AEs were headache (5.67%), diarrhea (4.45%), abdominal pain (3.98%), nasopharyngitis (3.39%), nausea (3.36%), and flatulence (2.95%). The placebo AE rate was lower in trials conducted in Asia compared to those in Europe, North America, and international trials. It was also lower in trials diagnosed by Rome III compared to clinician's opinion and Rome II. Additionally, the placebo AE rate was lower in single-center trials compared to multicenter trials, lower in 5-8 weeks therapy compared to 9-12 weeks therapy, lower in participants with FC compared to those with IBS-C and CC, lower in trials with 2 arms compared to 3 arms, and higher in trials with prokinetic drugs compared to secretagogues and laxatives. CONCLUSIONS & INFERENCES: The placebo AE rate was 30.41% in patients with chronic constipation. Based on our findings, we recommend that researchers take the nocebo effects into consideration when designing and conducting clinical trials and adopt specific measures to mitigate the negative influence of nocebo effects.

Placebo analgesia and nocebo hyperalgesia in patients with Alzheimer disease and healthy participants.

ABSTRACT: The role of placebo analgesia and nocebo hyperalgesia in patients with Alzheimer disease (AD) is largely unknown, with only few studies in the area. Therefore, this study aims to investigate to which extent placebo analgesia and nocebo hyperalgesia effects are present in patients experiencing mild-to-moderate AD. Twenty-one patients with AD (test population) and 26 healthy participants (HP; design validation) were exposed to thermal pain stimulation on 3 test days: Lidocaine condition (open/hidden lidocaine administration), capsaicin condition (open/hidden capsaicin administration), and natural history (no treatment), in a randomized, within-subject design. Open lidocaine and open capsaicin were accompanied by verbal suggestions for pain relief and pain increase, respectively. Expected pain and actual pain intensity were measured on a numerical rating scale (0-10). Placebo and nocebo effects were calculated as pain differences in open-hidden lidocaine and capsaicin, respectively, controlled for no treatment. Healthy participants obtained a placebo effect ( P = 0.01) and a trend for a nocebo effect ( P = 0.07). Patients with AD did not obtain a placebo effect ( P = 0.44) nor a significant nocebo effect ( P = 0.86). Healthy participants expected lower and higher pain with open vs hidden lidocaine and capsaicin, respectively ( P < 0.001). The same expectation effects were seen in patients with AD (open vs hidden lidocaine, P = 0.008; open vs hidden capsaicin, P < 0.001). With a well-controlled experimental setting, this study suggests that patients with AD may not experience placebo analgesia effects. Nocebo hyperalgesia effects in patients with AD needs further research. These findings may have implications for the conduction of clinical trials and the treatment of patients with AD in clinical practice.

Mind games in dentistry: confounded evidence suggests a substantial nocebo response in dental impaction pain model.

DESIGN: A systematic review and metaanalysis of randomized clinical trials (RCTs). DATA SOURCES: Electronic search was conducted in PubMed, Embase, Scopus, Web of Science and the Cochrane Central Register of Controlled Trials (CENTRAL), on 22 May 2021. SELECTION CRITERIA: Eligibility criteria included parallel-group placebo-controlled RCTs assessing analgesics after third molar (M3) surgery in healthy patients, reporting the number of patients with at least one drug-related adverse event (AE), and being published in English. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently screened all identified articles against the eligibility criteria, and performed quality assessment and data extraction. Any disagreements were resolved by discussion involving a third reviewer. The primary outcome was the pooled rate of drug-related AEs in placebo and active arms of RCTs assessing analgesic treatment following M3 surgery. Secondary outcome was the drug-related dropout rates in the same setting. RESULTS: A total of 50 RCTs in 47 articles were included in the analyses. The pooled rates of patients with AE ≥ 1 in the placebo and active arms were 22.8% and 20.6%, respectively. The pooled drug-related dropout rates in the placebo and active arms were 0.24% and 0.08%, respectively. There were no significant risk differences in patients with AE ≥ 1 and drug-related dropouts (p = 0.61 and p = 0.94; respectively). High statistical heterogeneity was found for the proportion of patients with AE ≥ 1 (I2 = 79.7%, p < 0.001), but not for drug-related dropout rates (I2 = 0%, p = 1.00). CONCLUSION: Patients in the placebo arm reported AEs at a similar frequency as patients receiving active treatment, suggesting that most analgesic-related AEs after M3 surgery may be attributed to the nocebo phenomenon.

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

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

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.