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.

Uncertainty of treatment efficacy moderates placebo effects on reinforcement learning.

The placebo-reward hypothesis postulates that positive effects of treatment expectations on health (i.e., placebo effects) and reward processing share common neural underpinnings. Moreover, experiments in humans and animals indicate that reward uncertainty increases striatal dopamine, which is presumably involved in placebo responses and reward learning. Therefore, treatment uncertainty analogously to reward uncertainty may affect updating from rewards after placebo treatment. Here, we address whether different degrees of uncertainty regarding the efficacy of a sham treatment affect reward sensitivity. In an online between-subjects experiment with N = 141 participants, we systematically varied the provided efficacy instructions before participants first received a sham treatment that consisted of listening to binaural beats and then performed a probabilistic reinforcement learning task. We fitted a Q-learning model including two different learning rates for positive (gain) and negative (loss) reward prediction errors and an inverse gain parameter to behavioral decision data in the reinforcement learning task. Our results yielded an inverted-U-relationship between provided treatment efficacy probability and learning rates for gain, such that higher levels of treatment uncertainty, rather than of expected net efficacy, affect presumably dopamine-related reward learning. These findings support the placebo-reward hypothesis and suggest harnessing uncertainty in placebo treatment for recovering reward learning capabilities.

¿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)

Placebo Effect of Caffeine on Physiological Parameters and Physical Performance.

This study aimed to analyse the placebo effect associated with a high dose of caffeine (9 mg/kg) on heart rate and its variability and on strength tests. METHODS: 18 participants experienced in strength training (19.7 ± 2.3 years; 72.2 ± 15.0 kg; 169.6 ± 9.0 cm) performed two days of trials (caffeine-informed/placebo-ingested (placebo) and non-ingested (control)). Firstly, heart rate and its variability were measured while participants lay down for 15 min. After that, bench press and squat tests were performed at 3 different loads (50%, 75% and 90% of 1RM). Perception of performance, effort and side effects were also evaluated. RESULTS: no differences were found in the vast majority of strength variables analysed. Resting heart rate decreased in the placebo trial (60.39 ± 10.18 bpm control vs. 57.56 ± 9.50 bpm placebo, p = 0.040), and mean RR increased (1020.1 ± 172.9 ms control vs. 1071.5 ± 185.7 ms placebo, p = 0.032). Heart rate variability and perception of performance and effort were similar between conditions (p > 0.05 in all cases). Side effects such as activeness and nervousness were reported while consuming the placebo. CONCLUSIONS: the placebo effect did not modify performance in the majority of the strength test variables, HRV and perception of performance and effort. However, resting heart rate was reduced, mean RR increased, and some side effects appeared in the placebo trial.

Patient information leaflets for placebo-controlled surgical trials: a review of current practice and recommendations for developers.

INTRODUCTION: Informed consent for participation in an RCT is an important ethical and legal requirement. In placebo surgical trials, further issues are raised, and to date, this has not been explored. Patient information leaflets (PILs) are a core component of the informed consent process. This study aimed to investigate the key content of PILs for recently completed placebo-controlled trials of invasive procedures, including surgery, to highlight areas of good practice, identify gaps in information provision for trials of this type and provide recommendations for practice. METHODS: PILs were sought from trials included in a recent systematic review of placebo-controlled trials of invasive procedures, including surgery. Trial characteristics and data on surgical and placebo interventions under evaluation were extracted. Directed content analysis was applied, informed by published regulatory and good practice guidance on PIL content and existing research on placebo-controlled surgical trials. Results were analysed using descriptive statistics and presented as a narrative summary. RESULTS: Of the 62 eligible RCTs, authors of 59 trials were contactable and 14 PILs were received for analysis. At least 50% of all PILs included content on general trial design. Explanations of how the placebo differs or is similar to the surgical intervention (i.e. fidelity) were reported in 6 (43%) of the included PILs. Over half (57%) of the PILs included information on the potential therapeutic benefits of the surgical intervention. One (7%) included information on potential indirect therapeutic benefits from invasive components of the placebo. Five (36%) presented the known risks of the placebo intervention, whilst 8 (57%) presented information on the known risks of the surgical intervention. A range of terms was used across the PILs to describe the placebo component, including 'control', 'mock' and 'sham'. CONCLUSION: Developers of PILs for placebo-controlled surgical trials should carefully consider the use of language (e.g. sham, mock), be explicit about how the placebo differs (or is similar) to the surgical intervention and provide balanced presentations of potential benefits and risks of the surgical intervention separately from the placebo. Further research is required to determine optimal approaches to design and deliver this information for these trials.

Caffeine Expectancy Does Not Influence the Physical Working Capacity at the Fatigue Threshold.

ABSTRACT: Ambrozy, CA, Hawes, NE, Hayden, OL, Sortzi, I, and Malek, MH. Caffeine expectancy does not influence the physical working capacity at the fatigue threshold. J Strength Cond Res 38(6): 1056-1062, 2024-The placebo effect occurs when a desired outcome is experienced due to the belief that a treatment is effective, even in the absence of an active ingredient. One explanation for this effect is based on a person's expectations of a drug or supplement. Although caffeine's effects on sports performance have been studied, little is known about how expectations of caffeine affect neuromuscular fatigue during continuous muscle action. The physical working capacity at the fatigue threshold (PWCFT) can be used to assess neuromuscular fatigue noninvasively using surface electromyography. Thus, the purpose of this study was to investigate whether caffeine expectancy influences PWCFT. We hypothesized that regardless of expectancy, caffeine consumption would delay neuromuscular fatigue. The study involved 8 healthy college-aged men (mean ± SEM: age, 25.6 ± 1.0 years) who visited the laboratory on 4 occasions, each separated by 7 days. The subjects completed 4 experimental conditions, in random order, where they were told that they were consuming caffeine or placebo and either received caffeine or placebo. After consuming the drink, the subjects remained in the laboratory for an hour and then performed an incremental exercise test. The results showed that the condition where subjects were told that they were consuming caffeine and received caffeine had significantly higher mean values for maximal power output (F(3, 21) = 11.75; p < 0.001), PWCFT (F(3, 21) = 12.28; p < 0.001), PWCFT (%maximal power output; F(3, 21) = 8.75; p < 0.001), and heart rate at end exercise (%predicted; F(3, 21) = 3.83; p = 0.025) compared with the 2 conditions where placebo was received. However, no statistically significant mean differences were found from the condition where subjects were told that they were consuming placebo but consuming caffeine. This suggests that a person's expectancy and potential somatic response may serve as a cue for how an ergogenic aid or placebo could affect subsequent performance.

Re-evaluating the placebo response in recent canine dietary epilepsy trials.

The placebo response is a common phenomenon. Limited evidence is available about its magnitude in canine epilepsy trials, even though it can significantly influence the efficacy evaluation of new treatments. It was hypothesised that the placebo response is diminished when epilepsy trials are conducted in a prospective crossover design. Seizure data spanning six months from three previous multicenter epilepsy studies were analysed. The monthly seizure frequency of 60 dogs diagnosed with idiopathic epilepsy was calculated, comparing baseline data with placebo treatment. Furthermore, differentiation was made between dogs randomised to the placebo group early (Phase 1: first 3 months) or later during the study (Phase 2: second 3 months).The analysis did not reveal any placebo response in terms of monthly seizure frequency. Instead, an increase was noted during the placebo treatment period, with a mean of 2.95 seizures per month compared to 2.30 seizures per month before study entry (p = 0.0378). Additionally, a notable phase effect was observed. Dogs receiving the placebo in the second study phase exhibited a significant increase in monthly seizure frequency compared to baseline (p = 0.0036). Conversely, no significant difference from baseline was observed for dogs receiving the placebo in the first study phase. These findings underscore the considerable variability in placebo responses observed in trials for canine epilepsy, contrasting with previous limited data. The identified phase effect should be carefully considered in the design and evaluation of canine epilepsy trials to ensure a more accurate assessment of efficacy for new treatments.

Peripheral blood transcriptomic profiling of molecular mechanisms commonly regulated by binge drinking and placebo effects.

Molecular responses to alcohol consumption are dynamic, context-dependent, and arise from a complex interplay of biological and external factors. While many have studied genetic risk associated with drinking patterns, comprehensive studies identifying dynamic responses to pharmacologic and psychological/placebo effects underlying binge drinking are lacking. We investigated transcriptome-wide response to binge, medium, and placebo alcohol consumption by 17 healthy heavy social drinkers enrolled in a controlled, in-house, longitudinal study of up to 12 days. Using RNA-seq, we identified 251 and 13 differentially expressed genes (DEGs) in response to binge drinking and placebo, respectively. Eleven protein-coding DEGs had very large effect sizes in response to binge drinking (Cohen's d > 1). Furthermore, binge dose significantly impacted the Cytokine-cytokine receptor interaction pathway (KEGG: hsa04060) across all experimental sequences. Placebo also impacted hsa04060, but only when administered following regular alcohol drinking sessions. Similarly, medium-dose and placebo commonly impacted KEGG pathways of Systemic lupus erythematosus, Neutrophil extracellular trap formation, and Alcoholism based on the sequence of drinking sessions. These findings together indicate the "dose-extending effects" of placebo at a molecular level. Furthermore, besides supporting alcohol dose-specific molecular changes, results suggest that the placebo effects may induce molecular responses within the same pathways regulated by alcohol.

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.

Evidence and sources of placebo effects in transcranial direct current stimulation during a single session of visuospatial working memory practice.

Transcranial direct current stimulation (tDCS) can be used to non-invasively augment cognitive training. However, the benefits of tDCS may be due in part to placebo effects, which have not been well-characterized. The purpose of this study was to determine whether tDCS can have a measurable placebo effect on cognitive training and to identify potential sources of this effect. Eighty-three right-handed adults were randomly assigned to one of three groups: control (no exposure to tDCS), sham tDCS, or active tDCS. The sham and active tDCS groups were double-blinded. Each group performed 20 min of an adapted Corsi Block Tapping Task (CBTT), a visuospatial working memory task. Anodal or sham tDCS was applied during CBTT training in a right parietal-left supraorbital montage. After training, active and sham tDCS groups were surveyed on expectations about tDCS efficacy. Linear mixed effects models showed that the tDCS groups (active and sham combined) improved more on the CBTT with training than the control group, suggesting a placebo effect of tDCS. Participants' tDCS expectations were significantly related to the placebo effect, as was the belief of receiving active stimulation. This placebo effect shows that the benefits of tDCS on cognitive training can occur even in absence of active stimulation. Future tDCS studies should consider how treatment expectations may be a source of the placebo effect in tDCS research, and identify ways to potentially leverage them to maximize treatment benefit.

Placebo Effects Are Small on Average in the 7.5% CO2 Inhalational Model of Generalized Anxiety.

BACKGROUND: Anxiety disorders are highly prevalent and socio-economically costly. Novel pharmacological treatments for these disorders are needed because many patients do not respond to current agents or experience unwanted side effects. However, a barrier to treatment development is the variable and large placebo response rate seen in trials of novel anxiolytics. Despite this, the mechanisms that drive placebo responses in anxiety disorders have been little investigated, possibly due to low availability of convenient experimental paradigms. We aimed to develop and test a novel protocol for inducing placebo anxiolysis in the 7.5% CO2 inhalational model of generalized anxiety in healthy volunteers. METHODS: Following a baseline 20-minute CO2 challenge, 32 healthy volunteers were administered a placebo intranasal spray labelled as either the anxiolytic "lorazepam" or "saline." Following this, participants surreptitiously underwent a 20-minute inhalation of normal air. Post-conditioning, a second dose of the placebo was administered, after which participants completed another CO2 challenge. RESULTS: Participants administered sham "lorazepam" reported significant positive expectations of reduced anxiety (P = .001), but there was no group-level placebo effect on anxiety following CO2 challenge post-conditioning (Ps > .350). Surprisingly, we found many participants exhibited unexpected worsening of anxiety, despite positive expectations. CONCLUSIONS: Contrary to our hypothesis, our novel paradigm did not induce a placebo response, on average. It is possible that effects of 7.5% CO2 inhalation on prefrontal cortex function or behavior in line with a Bayesian predictive coding framework attenuated the effect of expectations on subsequent placebo response. Future studies are needed to explore these possibilities.

Placebo response in patients with Dravet syndrome: Post-hoc analysis of two clinical trials.

OBJECTIVE: Dravet syndrome is a rare, early childhood-onset epileptic and developmental encephalopathy. Responses to placebo in clinical trials for epilepsy therapies range widely, but factors influencing placebo response remain poorly understood. This study explored placebo response and its effects on safety, efficacy, and quality of life outcomes in patients with Dravet syndrome. METHODS: We performed exploratory post-hoc analyses of pooled data from placebo-treated patients from the GWPCARE 1B and GWPCARE 2 randomized controlled phase III trials, comparing cannabidiol and matched placebo in 2-18 year old Dravet syndrome patients. All patients had ≥4 convulsive seizures during a baseline period of 4 weeks. RESULTS: 124 Dravet syndrome-treated patients were included in the analysis (2-5 years: n = 35; 6-12 years: n = 52; 13-18 years: n = 37). Convulsive seizures were experienced by all placebo group patients at all timepoints, with decreased median convulsive seizure frequency during the treatment period versus baseline; the number of convulsive seizure-free days was similar to baseline. Convulsive seizure frequency had a nominally significant positive correlation with age and a nominally significant negative correlation with body mass index. Most placebo-treated patients experienced a treatment-emergent adverse event; however, most resolved quickly, and serious adverse events were infrequent. Placebo treatment had very little effect on reported Caregiver Global Impression of Change outcomes versus baseline. INTERPRETATION: Placebo had little impact on convulsive seizure-free days and Caregiver Global Impression of Change versus baseline, suggesting that these metrics may help differentiate placebo and active treatment effects in future studies. However, future research should further assess placebo responses to confirm these results.

Open-label placebos enhance test performance and reduce anxiety in learner drivers: a randomized controlled trial.

Passing the driving school test can be very challenging, especially in big cities, where up to 52% of all students fail this test. Consequently, many learner drivers experience stress and anxiety. For some learner drivers these feelings can be extreme and negatively affect the performance in the driving test. Different strategies to face anxiety and stress are known, including, for example, psychological or pharmacological approaches and even placebo pills. Recent intriguing findings have also demonstrated that placebos without deception, so-called open-label placebos, successfully reduce anxiety. Here we aimed to test effects of this novel treatment for learner drivers. We investigated whether open-label placebos affect test performance and feelings of anxiety in learner drivers. Sixty-eight healthy participants (mean age 21.94 years, 26 females) were randomized into two groups. The open-label placebo group received placebo pills two weeks before the driving test (two pills each day). The control group received no treatment. Results revealed that the open-label placebo group experienced significantly less anxiety than the control group before the test (measured with the State-Trait-Anxiety-Inventory, STAI-S, and the German Test Anxiety Inventory, PAF). Moreover, in the open-label placebo group less learner drivers failed the driving test (29.41% vs. 52.95%). The results suggest that open-label placebos may provide an ethical unproblematic way to experience less anxiety and might also enhance the probability to pass the driving test. We discuss possible mechanisms of open-label placebos and limitations of our findings.

The pill you don't have to take that is still effective: neural correlates of imaginary placebo intake for regulating disgust.

A commonly established protocol for the administration of open-label placebos (OLPs)-placebos honestly prescribed-emphasizes the necessity of ingesting the pill for the placebo effect to manifest. The current functional magnetic resonance imaging study used a novel approach to OLP administration: the imaginary intake of an OLP pill for regulating disgust. A total of 99 females were randomly allocated to one of three groups that either swallowed a placebo pill (OLP Pill), imagined the intake of a placebo pill (Imaginary Pill) or passively viewed (PV) repulsive and neutral images. The imaginary pill reduced reported disgust more effectively than the OLP pill and was also perceived as a more plausible method to reduce emotional distress. Relative to the OLP pill, the imaginary pill lowered neural activity in a region of interest involved in disgust processing: the pallidum. No significant differences in brain activation were found when comparing the OLP pill with PV. These findings highlight that imagining the intake of an OLP emerged as a superior method for regulating feelings of disgust compared to the actual ingestion of a placebo pill. The study's innovative approach sheds new light on the potential of placebo interventions in emotion regulation.

A Fictionalist Account of Open-Label Placebo.

The placebo effect is now generally defined widely as an individual's response to the psychosocial context of a clinical treatment, as distinct from the treatment's characteristic physiological effects. Some researchers, however, argue that such a wide definition leads to confusion and misleading implications. In response, they propose a narrow definition restricted to the therapeutic effects of deliberate placebo treatments. Within the framework of modern medicine, such a scope currently leaves one viable placebo treatment paradigm: the non-deceptive and non-concealed administration of "placebo pills" or open-label placebo (OLP) treatment. In this paper, I consider how the placebo effect occurs in OLP. I argue that a traditional, belief-based account of OLP is paradoxical. Instead, I propose an account based on the non-doxastic attitude of pretence, understood within a fictionalist framework.

The Social Epistemology of Clinical Placebos.

Many extant theories of placebo focus on their causal structure wherein placebo effects are those that originate from select features of the therapy (e.g., client expectations or "incidental" features like size and shape). Although such accounts can distinguish placebos from standard medical treatments, they cannot distinguish placebos from everyday occurrences, for example, when positive feedback improves our performance on a task. Providing a social-epistemological account of a treatment context can rule out such occurrences, and furthermore reveal a new way to distinguish clinical placebos from standard medical treatments.

Warm-up plus verbal communications administered as placebo procedure during the training session improves running performance.

The aim of this study was to investigate the effects on running performance of a within-session placebo procedure consisting of a conditioning treatment plus verbal communications. Twenty-six subjects were assigned to PLACEBO and CONTROL groups. Participants performed three sessions: Session 1-Cooper Test, Session 2-Baseline session and Session 3-Experimental session. During Session 2, participants performed a sprint-interval-training (SIT)-until-exhaustion preceded by a general warm-up, while in Session3 the SIT was preceded by a conditioning treatment (FIFA11+ warm-up), known to be effective in preventing injuries but not improving performance. Moreover, in Session3, only the PLACEBO group received verbal suggestions (before the warm-up) to influence participants' expectations about FIFA11+ effectiveness in improving performance, and deceptive feedback (during each SIT recovery bout) to increase the conditioning effect. To evaluate performance improvements, Running Time was chosen as a main outcome while to ensure participants reached exhaustion, physiological and metabolic responses were monitored. Total running distance (TRD) was also measured. Results showed that, Running Time and TRD significantly increased in the PLACEBO group whilst no differences in the CONTROL group were observed thus, suggesting the effectiveness of the within-session-placebo procedure in improving running performance. These findings shed a new light on the interaction between cognitive domain and performance, thus encouraging coaches to adopt this innovative method during the training protocol to enhance athletes' performance. Moreover, this placebo procedure, not requiring additional time, tools or resources, could represent a more ecological approach that can be easily adopted in the field.