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Placebo analgesia is hypothesized to involve top-down engagement of prefrontal regions that access endogenous pain inhibiting opioid pathways. Fibromyalgia (FM) patients have neuroanatomical and neurochemical alterations in pathways relevant to placebo analgesia. Thus, it remains unclear whether placebo analgesic mechanisms would differ in FM patients compared to healthy controls (HCs). Here, using placebo-analgesia-inducing paradigms that included verbal suggestions and conditioning manipulations, we examined whether behavioral and neural placebo analgesic responses differed between 32 FM patients and 46 age- and sex-matched HCs. Participants underwent a manipulation scan, where noxious high and low heat were paired with the control and placebo cream, respectively, and a placebo experimental scan with equal noxious heat temperatures. Before the experimental scan, each participant received saline or naloxone, an opioid receptor antagonist. Across all participants, the placebo condition decreased pain intensity and unpleasantness ratings, decreased activity within the right insula and bilateral secondary somatosensory cortex, and modulated the Neurologic Pain Signature. There were no differences between HCs and FM patients in pain intensity ratings or neural responses during the placebo condition. Despite the perceptual and neural effects of the placebo manipulation, prefrontal circuitry was not activated during the expectation period and the placebo analgesia was unaltered by naloxone, suggesting placebo effects were driven more by conditioning than expectation. Together, these findings suggest that placebo analgesia can occur in both HCs and chronic pain FM patients, without the involvement of opiodergic prefrontal modulatory networks.

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

Objectives The recent availability of paraesthesia/sensation free spinal cord stimulation (SCS) modalities allow the design of clinical trials of SCS using placebo/sham controls and blinding of patients, clinicians, and researchers. The aims of this study were to: 1) systematically review the current evidence base of randomized controlled trials (RCTs) of SCS placebo/sham trials and 2) to undertake a methodological critique of their methods. Based on this critique, we developed a checklist for the design and reporting of future RCTs of SCS. Materials and methods Electronic data bases were searched from inception until January 2019 for RCTs of SCS using a placebo/sham control. RCTs with only an active comparator arm were excluded. The results are presented as a narrative synthesis. Results Searches identified 12 eligible RCTs. SCS modalities included paraesthesia stimulation, subthreshold, burst, and high-frequency SCS and were mainly conducted in patients with failed back surgery syndrome, complex regional pain syndrome, and refractory angina. The quality and transparency of reporting of the methods of placebo stimulation, blinding of patients, clinicians, and researchers varied markedly across studies. Conclusions To date the methods of placebo/sham control and blinding in RCTs have been poorly reported, leading to concerns about the validity and replicability of the findings. Important aspects that need to be clearly reported in the design of placebo-/sham-controlled RCTs of SCS include the transparent reporting of stimulation programming parameters, patient position during perception threshold measurement, management of the patient handheld programmer, frequency of recharging, and assessment of the fidelity of blinding.

Sex differences exist in the prevalence, progression and treatment efficacy of a wide array of medical conditions. While the placebo and nocebo effects have become increasingly relevant in the clinical arena, little is known about the influence of biological sex on placebo and nocebo effects. This paper discusses the existing, relatively limited and sometimes conflicting evidence about how sex impacts the occurrence and magnitude of the placebo and nocebo effects, mainly focusing on pain studies. We present recent evidence that when compared to men, women suffering from chronic orofacial pain may derive greater benefit from the placebo effect for analgesia. Nonetheless, we broadly argue that the field is not currently positioned to draw definitive conclusions and propose several important factors that may explain the inconsistency in the literature and that should be taken into account in future research. These include the specific target symptom of the placebo or nocebo manipulation and whether or not the target is related to the medical condition, the placebo or nocebo induction method, the sex of the experimenter or physician, and so forth. Future research should intentionally include sex a biological variable to favor translation of placebo and nocebo mechanisms into clinical applications.

Positive and negative expectancies drive behavioral and neurobiological placebo and nocebo effects, which in turn can have profound effects on patient improvement or worsening. However, expectations of events and outcomes are often not met in daily life and clinical practice. It is currently unknown how this affects placebo and nocebo effects. We have demonstrated that the violation of expectancies, such as when there is a discrepancy between what is expected and what is actually presented, reduces both placebo and nocebo effects while causing an extinction of placebo effects. The reduction of placebo and nocebo effects was paralleled by an activation of the left inferior parietal cortex, a brain region that redirects attention when discrepancies between sensory and cognitive events occur. Our findings highlight the importance of expectancy violation in shaping placebo and nocebo effects and open up new avenues for managing positive and negative expectations in clinical trials and practices.

INTRODUCTION: Placebo effects in human clinical trials for depression treatment are robust and often comparable to drug effects. Placebo effects are traditionally difficult to study in rodents due to the slow-onset action of classical antidepressant drugs. We hypothesized that the rapid antidepressant actions of ketamine would allow modeling antidepressant placebo effects in rodents. METHODS: Male and female CD-1 mice received either ketamine or saline injections with concomitant exposure to specific environmental conditioning stimuli, for a total of three drug/conditioning sessions each 2 weeks apart. Two weeks later, during an evocation phase, mice were exposed to the drug-paired conditioning stimuli or no conditioned stimuli followed by testing for motor stimulatory actions and antidepressant-like effects using the forced swim test. Negative (no ketamine administration at any time) and positive (acute ketamine administration prior to evocation testing) control groups were included as comparators. RESULTS: Both male and female mice exhibited increased locomotor activity following ketamine administration during the conditioning phase, which was not observed following exposure to the conditioning stimuli. Exposure to the conditioning stimuli previously paired with ketamine, similar to an acute ketamine administration, reduced immobility time in the forced swim test both 1 and 24 h after administration in male, but not female, mice. CONCLUSIONS: These results represent the first evidence of antidepressant-like placebo-conditioned effects in an animal model. The developed approach can be used as a model to explore the neurobiological mechanisms of placebo effects, their possible sexually dimorphic effects, and relevance to mechanisms underlying antidepressant action.

Objective Little is known about the perceptions and attitudes of participants who volunteer in studies involving authorized deception. Thus, this cross-sectional pilot study measured, for the first time, the perceptions about participation in an authorized-deception placebo analgesia study in chronic pain patients with fibromyalgia and assessed whether their perceptions differed from healthy controls. Methods An anonymous survey with questions about trust in research and willingness to participate in future research involving deception was mailed to participants in both groups after completion of the parent study. Statistical analyses were performed using the Mann-Whitney U and chi-square tests (31 controls and 16 fibromyalgia patients were included in the analyses). Results The majority of participants expressed little or no concern about the deception, still trusted the scientific process, and found the debriefing procedure helpful and worthwhile. Group differences were found in willingness to 1) participate in the parent study had the deceptive element been disclosed in advance (controls = definitely, fibromyalgia patients = probably, U = 341.5, P = 0.01) and 2) participate in future studies (controls = definitely, fibromyalgia patients = probably, U = 373, P Conclusions Despite slightly less favorable responses of fibromyalgia patients and the relatively small size of the study, these findings suggest that attitudes and perceptions about participating in an authorized placebo study remain positive in both healthy and chronic pain populations.

Clinical research on social observational learning (SoL) as an underlying mechanism for inducing expectancy and eliciting analgesic placebo effects is lacking. This double-blinded randomized controlled clinical trial investigated the influence of SoL on medication-augmenting placebo effects in 44 patients with chronic low back pain. Our hypothesis was that observing positive drug effects on pain and mobility in another patient could increase pain reduction and functional capacity. To test this, we compared the effects of observing positive treatment outcomes in a sham patient (the social learning group [SoLG]) vs hearing the same sham patient report neutral effects (the control group). In the SoLG, the sham patient told peers about pain reduction due to amitriptyline and demonstrated his improved mobility by bending forwards and sideways while he told the control group only that he was taking amitriptyline. The primary outcome was a reduction in clinical low back pain self-ratings. The secondary outcome was perceptions of pain-related disability. The exploratory outcome was mood and coping statements. Data collection occurred before and after the intervention and 2 weeks later. After the intervention, pain decreased in both groups (F [1, 41] = 7.16, P0.05, d = 0.83), with no difference between groups. However, the SoLG showed a significantly larger decrease in perceived disability (F [1, 41] = 5, P0.05, d = 0.63). The direct observation of patient with chronic low back pain of positive treatment outcomes in the sham patient seems to have enhanced the treatment effects while indirect verbal reports of reduced pain did not.

Sex-related differences can influence outcomes of randomized clinical trials and may jeopardize the effectiveness of pain management and other therapeutics. Thus, it is essential to understand the mechanistic and translational aspects of sex differences in placebo outcomes. Recently, studies in healthy participants have shed light on how sex-related placebo effects might influence outcomes, yet no research has been conducted in a patient population. Herein, we used a tripartite approach to evaluate the interaction of prior therapeutic experience (eg, conditioning), expectations, and placebo effects in 280 chronic (orofacial) pain patients (215 women). In this cross-sectional study, we assessed sex differences in placebo effects, conditioning as a proxy of prior therapeutic effects, and expectations evaluated before and after the exposure to positive outcomes, taking into account participant-experimenter sex concordance and hormonal levels (estradiol and progesterone assessed in premenopausal women). We used mediation analysis to determine how conditioning strength and expectations impacted sex differences in placebo outcomes. Independent of gonadal hormone levels, women showed stronger placebo effects than men. We also found significant statistical sex differences in the conditioning strength and reinforced expectations whereby reinforced expectations mediated the sex-related placebo effects. In addition, the participant-experimenter sex concordance influenced conditioning strength, reinforced expectations, and placebo effects in women but not in men. Our findings suggest that women experience larger conditioning effects, expectations, and placebo effects emphasizing the need to consider sex as a biological variable when placebo components of any outcomes are part of drug development trials and in pain management.

Introduction: Clinical and laboratory studies demonstrate that placebo and nocebo effects influence various symptoms and conditions after the administration of both inert and active treatments. Objective: There is an increasing need for up-to-date recommendations on how to inform patients about placebo and nocebo effects in clinical practice and train clinicians how to disclose this information. Methods: Based on previous clinical recommendations concerning placebo and nocebo effects, a 3-step, invitation-only Delphi study was conducted among an interdisciplinary group of internationally recognized experts. The study consisted of open- and closed-ended survey questions followed by a final expert meeting. The surveys were subdivided into 3 parts: (1) informing patients about placebo effects, (2) informing patients about nocebo effects, and (3) training clinicians how to communicate this information to the patients. Results: There was consensus that communicating general information about placebo and nocebo effects to patients (e.g., explaining their role in treatment) could be beneficial, but that such information needs to be adjusted to match the specific clinical context (e.g., condition and treatment). Experts also agreed that training clinicians to communicate about placebo and nocebo effects should be a regular and integrated part of medical education that makes use of multiple formats, including face-to-face and online modalities. Conclusions: The current 3-step Delphi study provides consensus-based recommendations and practical considerations for disclosures about placebo and nocebo effects in clinical practice. Future research is needed on how to optimally tailor information to specific clinical conditions and patients’ needs, and on developing standardized disclosure training modules for clinicians.

No large-cohort studies that examine potential racial effects on placebo hypoalgesic effects exist. To fill this void, we studied placebo effects in healthy and chronic pain participants self-identified as either African American/black (AA/black) or white. We enrolled 372 study participants, 186 with a diagnosis of temporomandibular disorder (TMD) and 186 race-, sex-, and age-matched healthy participants to participate in a placebo experiment. Using a well-established paradigm of classical conditioning with verbal suggestions, each individual pain sensitivity was measured to calibrate the temperatures for high- and low-pain stimuli in the conditioning protocol. These 2 temperatures were then paired with a red and green screen, respectively, and participants were told that the analgesic intervention would activate during the green screens to reduce pain. Participants then rated the painfulness of each stimulus on a visual analog scale ranging from 0 to 100. Racial influences were tested on conditioning strength, reinforced expectations, and placebo hypoalgesia. We found that white participants reported greater conditioning effects, reinforced relief expectations, and placebo effects when compared with their AA/black counterparts. Racial effects on placebo were observed in TMD, although negligible, short-lasting, and mediated by conditioning strength. Secondary analyses on the effect of experimenter-participant race and sex concordance indicated that same experimenter-participant race induced greater placebo hypoalgesia in TMDs while different sex induced greater placebo hypoalgesia in healthy participants. This is the first and largest study to analyze racial effects on placebo hypoalgesia and has implications for both clinical research and treatment outcomes.

Placebo effects influence symptom perceptions and treatment outcomes. Placebo effects can be explored in laboratory settings controlling for natural history and expectations. Such a mechanistic approach to neurological disorders has been implemented in the domain of chronic clinical pain and other neurological disorders. This article therefore focuses on definitions and historical notes related to placebo effects and mechanisms of placebo effects in chronic pain. Knowledge on mechanisms of placebo effects could inform current clinical practice for the treatment of neurological disorders by focusing on patients (and providers) expectations for outcome optimization.

Learning through social observation is critical for humans. The present study investigates the neural processes underlying the acquisition of placebo effects through observational learning. We created a new functional magnetic resonance imaging (fMRI) paradigm where participants (n ​= ​38, healthy, both sexes) observed a demonstrator experiencing pain relief by a placebo treatment cream and experiencing pain without a treatment (control cream), and subsequently performed the same procedure themselves. Participants demonstrated placebo hypoalgesia while they performed the procedure themselves, confirming that observational learning can lead to placebo effects. During the observational learning phase, fMRI analysis showed a modulation of the amygdalae, periaqueductal grey, temporoparietal junctions (TPJ), and dorsolateral prefrontal cortex (DLPFC). Connectivity between the DLPFC and TPJ during the observational learning task was modulated by the placebo treatment and predicted subsequent placebo effects. Mediation analysis further confirmed that the DLPFC-TPJ connectivity formally mediated the effect of the observed treatment condition on subsequent placebo effects. Additionally, pre-recorded resting state connectivity between the DLPFC and TPJ also predicted observationally-learned placebo effects. Our findings provide an understanding of the neural processes during the acquisition of placebo effects through observation and indicate a critical role for DLPFC-TPJ integration processes during observational learning of therapeutic outcomes.

Background Placebo analgesia studies generally reported that the actual use of a placebo analgesic reduces pain. Yeung, Geers, and Kam found that the mere possession (without use) of a placebo analgesic also reduces pain. Purpose We investigated the relative effectiveness of using versus possessing a placebo analgesic on pain outcomes. Methods In Study 1a, 120 healthy adults were randomized to either the experimental (EXP) conditions (EXP1: used a placebo analgesic cream, EXP2: possessed a placebo analgesic cream) or control (CO) conditions (CO1: possessed a sham cream, CO2: no cream). All participants underwent a cold pressor test (CPT). Study 1b further delineated the effect of possession from the effect of use. Sixty healthy adults were randomized to either the placebo-possession condition (merely possessed a placebo analgesic cream) or the placebo-possession-use condition (possessed and used a placebo analgesic cream). All participants did a CPT. Results In Study 1a, as expected, a placebo effect was found—participants who used a placebo analgesic cream showed better pain outcomes than the two CO groups. Surprisingly, participants who merely possessed a placebo analgesic cream performed equally well as those who actually used it. In Study 1b, participants in the two conditions did not differ in most pain outcomes. Participants who possessed and used a placebo analgesic cream only showed slightly more reduction in pain intensity compared to participants who merely possessed the placebo analgesic cream. Conclusions Our results suggest that merely possessing a placebo analgesic could enhance pain outcomes similar to that of applying the placebo analgesic.

Placebo and Nocebo Effects Placebo and nocebo effects (effects of patients’ positive and negative expectations) are powerful and pervasive in clinical practice. Neurobiologic mechanisms, informatio...

The placebo (and the nocebo) effect is a powerful determinant of health outcomes in clinical disease treatment and management. Efforts to completely eradicate placebo effects have shifted dynamically, as increasingly more researchers are tuned to the potentially beneficial effects of incorporating those uncontrollable placebo effects into clinical therapeutic strategies. In this review, we highlight the major findings from placebo research, elucidating the main neurobiological systems and candidate determinants of the placebo phenomenon, and illustrate a perspective that can effectively frame future research on the topic. Finally, we issue a call for increased research on the efficacy of therapeutic strategies that incorporate placebo "tools," and argue that clinical trials of the placebo response in neuropsychiatric diseases and disorders has important and far-reaching translational and clinical relevance.

Over the last few decades, placebo, and nocebo effects in general, have been investigated at rest. This proposed study explores whether they could work even when the experience of pain occurs during a movement. Exercise itself can have a hypoalgesic effect, suggesting that placebo- and exercise-induced hypoalgesia could foster pain reduction. In the present study, we investigated the interplay of exercise, placebo and nocebo effects on pain. To this aim, we developed a machine-controlled isotonic motor task to standardize the exercise across participants and used a well-validated model of placebo and nocebo manipulations with reinforced expectations via a conditioning procedure including visual cues paired with heat painful stimulations. Participants reported expectations and pain on a trial-by-trial basis. We found that the standardized isotonic exercise elicited a reduction of pain intensity. Moreover, both exercise and placebo induced comparable hypoalgesic effects. When the exercise was added, placebo and nocebo effects were influenced by expectations but were not affected by fatigue or sex differences. Exercise-, placebo- and nocebo-induced pain modulation are likely to work through distinct mechanisms and neurophysiological research is needed to fully exploit the implications for sport, rehabilitation and pain management.

The desire to reduce high placebo response rates in clinical trials is a popular concept. However, few studies have rigorously examined the effectiveness of methods to control for placebo responses that are relevant to randomized controlled trials. The primary objective of this review was to evaluate the effect of experimental placebo manipulations in randomized controlled trials (RCTs). We critically reviewed studies designed to manipulate placebo responses including positive expectations regarding the effectiveness of the placebo treatment, manipulating the time spent with subjects, and training study staff and subjects to accurately report symptom severity. These efforts have generally resulted in reduced placebo response and improved discrimination between drug and placebo. Interventions that neutralize staff and subject expectations and improve the ability of subjects to accurately report symptom severity have shown the most promise. Reduction of the placebo response has the potential to accelerate the development of new therapeutics.

Introduction: Many clinical trials fail because of placebo responses. Prior therapeutic experiences and patients’ expectations may affect the capacity to respond to placebos in chronic disorders. Objective: The scope of this study in 763 chronic orofacial pain and healthy study participants was to compare the magnitude and prevalence of placebo effects and determine the putative role of prior therapeutic experiences vs. expectations. Methods: We tested placebo propensity in a laboratory setting by using 2 distinct levels of individually tailored painful stimulations (high pain and low pain) to reinforce expectations and provide a hypoalgesic experience (conditioning phase). Afterwards, both levels of pain were surreptitiously set at a moderate pain level to test for placebo effects (testing phase). Pain and expectation ratings were assessed as primary outcomes using visual analog scales. Results: In both chronic pain and healthy participants, placebo effects were similar in magnitude, with the larger prevalence of responders in the healthy participants. Although chronic pain participants reported higher pain relief expectations, expectations did not account for the occurrence of placebo effects. Rather, prior experience via conditioning strength mediated placebo effects in both pain and healthy participants. Conclusions: These findings indicate that participants with chronic pain conditions display robust placebo effects that are not mediated by expectations but are instead directly linked to prior therapeutic experiences. This confirms the importance of assessing the therapeutic history while raising questions about the utility of expectation ratings. Future research is needed to enhance prediction of responses to placebos, which will ultimately improve clinical trial designs.

Highlights • Placebo analgesia and nocebo hyperalgesia can be induced by classical conditioning. • Oxytocin does not enhance placebo effect or decrease nocebo effect. • Oxytocin does not influence extinction of placebo and nocebo responses., Oxytocin has been shown to increase trust, decrease anxiety, and affect learning as has been observed in conditioning paradigms. Trust, anxiety, and learning are important factors that influence placebo effects. In this study, we investigated whether oxytocin can increase placebo analgesia, decrease nocebo hyperalgesia, and influence extinction processes of both. Eighty male volunteers were assigned to a 40 IU of oxytocin nasal spray group, or to a placebo control group. Placebo analgesia and nocebo hyperalgesia were induced by a conditioning procedure in combination with verbal suggestions. The results demonstrate that the conditioning procedure successfully elicited significant placebo analgesia and nocebo hyperalgesia responses (P < .001). Furthermore, extinction was observed (P < .001), although placebo and nocebo responses did not return to baseline and remained significant. Oxytocin did not influence placebo analgesia or nocebo hyperalgesia and had no effect on extinction. This study provides support against the placebo-boosting effects of oxytocin and was the first one to demonstrate that it also did not influence nocebo effects or extinction processes, however, these results pertain to only a male sample. As managing placebo and nocebo effects has widespread clinical implications, further research should investigate other neurobiological or behavioral pathways to boost placebo and decrease nocebo effects. Perspective The present study demonstrated that placebo analgesia and nocebo hyperalgesia can be successfully induced by conditioning and verbal suggestions. We could not confirm the hypothesis that oxytocin affects either of these phenomena. Other pharmacological agents and behavioral manipulations for increasing placebo and decreasing nocebo effects should be investigated.

Genetics studies on the placebo hypoalgesic effect highlight a promising link between single nucleotide polymorphisms (SNPs) in the dopamine, opioid, and endocannabinoid genes and placebo hypoalgesia. However, epistasis and replication studies are missing. In this study, we expanded upon previous findings related to the three SNPs in the opioid receptor mu subunit (OPRM1 rs1799971), catechol-O-methyltransferase (COMT rs4680), and fatty acid amide hydrolase (FAAH rs324420) genes associated with placebo hypoalgesia and tested the effect of a three-way interaction on placebo hypoalgesia. Using two well-established placebo procedures (verbal suggestion, learning paradigm), we induced significant placebo hypoalgesic effects in 160 healthy participants. We found that individuals with OPRM1 AA combined with FAAH Pro/Pro and those carrying COMT met/met together with FAAH Pro/Pro showed significant placebo effects. Participants with COMT met/val alleles showed significant placebo effects independently of OPRM1 and FAAH allele combinations. Finally, the model that included the placebo procedure and genotypes predicted placebo responsiveness with a higher accuracy (area under the curve, AUC=0.773) as compared to the SNPs alone indicating that genetic variants can only partially explain the placebo responder status. Our results suggest that the endogenous mu-opioid system with a larger activation in response to pain in the met/val allele carriers as well as the synergism between endogenous mu-opioid system and cannabinoids might play the most relevant role in driving hypoalgesic responses. Future epistasis studies with larger sample sizes will help us to fully understand the complexity of placebo effects and explain the mechanisms that underlie placebo responsiveness.

Social cues and interpersonal interactions strongly contribute to evoke placebo effects that are pervasive in medicine and depend upon the activation of endogenous modulatory systems. Here, we explore the possibility to boost placebo effects by targeting pharmacologically the vasopressin system, characterized by a sexually dimorphic response and involved in the regulation of human and nonhuman social behaviors.We enrolled 109 healthy participants and studied the effects of intranasal administration of an arginine vasopressin 1A and 1B receptor agonist against 1) no treatment, 2) oxytocin, and 3) saline in a randomized, placebo-controlled, double-blind, parallel design trial using a well-established model of placebo analgesia while controlling for sex differences.Vasopressin agonists boosted placebo effects in women but had no effect in men. The effects of vasopressin on expectancy-induced analgesia were significantly larger than those observed in the no-treatment (p.004), oxytocin (p.001), and saline (p.015) groups. Moreover, women with lower dispositional anxiety and cortisol levels showed the largest vasopressin-induced modulation of placebo effects, suggesting a moderating interplay between pre-existing psychological factors and treatment cortisol changes.This is the first study that demonstrates that arginine vasopressin boosts placebo effects and that the effect of vasopressin depends upon a significant sex by treatment interaction. These findings are novel and might open up new avenues for clinically relevant research due to the therapeutic potentials of vasopressin as well as the possibility to systematically control for influences of placebo responses in clinical trials.

The placebo effect is a complex phenomenon that can be described from neurobiological, psychosocial, and epistemological perspectives. Different leaders in the field have proposed multiple theories and models that attempt to describe both the nature and the mechanisms of action underlying placebo effects. This article focuses on the most relevant psychological models that have been suggested for characterizing the different mechanisms underlying the placebo effect. We outline how the dynamic psychoneurobiological aspects of the placebo phenomenon can be a potential reliable and useful tool in daily clinical practice for illness and symptom management within a wide variety of specialties and health-care practices.

Pharmacological strategies for pain management have primarily focused on dampening ascending neurotransmission and on opioid receptor–mediated therapies. Little is known about the contribution of endogenous descending modulatory systems to clinical pain outcomes and why some patients are mildly affected while others suffer debilitating pain-induced dysfunctions. Placebo effects that arise from patients’ positive expectancies and the underlying endogenous modulatory mechanisms may in part account for the variability in pain experience and severity, adherence to treatment, distinct coping strategies, and chronicity. Expectancy-induced analgesia and placebo effects in general have emerged as useful models to assess individual endogenous pain modulatory systems. Different systems and mechanisms trigger placebo effects that highly impact pain processing, clinical outcomes, and sense of well-being. This review illustrates critical elements of placebo mechanisms that inform the methodology of clinical trials, the discovery of new therapeutic targets, and the advancement of personalized pain management.

Scientific research indicates that open-label and dose-extending placebos (that patients know are placebos) can elicit behavioral, biological, and clinical outcome changes. In this chapter, we present the state-of-the-art evidence and ethical considerations about open-label and dose-extending placebos, discussing the perspective of giving placebos with a rational, as dose extension of active drugs, or expectancy boosters. Previous comprehensive reviews of placebo use have considered how to harness placebo effects in medicine and the need to focus on elements of the clinical encounter as well as patient-clinician relations. Here, we illustrate the similarities and differences between standard (deceptive) placebos, open-label placebos and dose-extending placebos. We conclude that placebos without deception would override ethical barriers to their clinical use. This paves the way to future large-scale, pragmatic randomized trials that investigate the potential of ethical open-label and dose-extending placebos to improve patients' outcomes, and reduce side effects.

The investigation of placebo effects in animal pain models has received less attention than human research. This may be related to a number of difficulties, including the fact that animals lack the ability to use language and establish expectancies verbally, that animals cannot report and rate the extent to which they experience pain, and the inadequacy of current models of pain. Here, we describe the relatively small number of studies that have been published, communicating the opportunities and excitement of this research. We critically discuss pitfalls and limitations with the hope that this will advance future animal placebo-related research.

Placebo analgesia is a robust experimental and clinical phenomenon. While our understanding of the mechanisms of placebo analgesia has developed rapidly, some central questions remain unanswered. Among the important questions is how placebo analgesia interacts with active analgesic effects. It is an assumption underlying double-blind randomized placebo-controlled trials (RCTs) that the true effect of a treatment can be determined by examining the effect of the active treatment arm and subtracting the response in the placebo group (“the assumption of additivity”). However, despite the importance of this assumption for the interpretation of RCTs, it has rarely been formally examined. This article reviews the assumption of additivity in placebo analgesia by examining studies employing factorial designs manipulating both the receipt of an active analgesic and instructions about the treatment being delivered. In reviewing the literature, we identified seven studies that allowed a test of additivity. Of these, four found evidence against additivity, while the remaining three studies found results consistent with additivity. While the limited available data are somewhat mixed, the evidence suggests that at least under some conditions the assumption of additivity does not hold in placebo analgesia. The concordance between mechanisms of the active analgesic and placebo analgesia may influence whether additivity occurs or not. However, more research using factorial designs is needed to disentangle the relationship between placebo analgesia and the active effect of analgesic treatments.

The analgesic placebo effect is well documented by numerous studies. Many important influencing factors, however, are yet to be discovered. In the arena of placebo effects and clinical implications, expectancies play a central role. Expectancies are shaped by processes of classical and social learning as well as verbal instructions and are strongly related to emotional factors. Expectancies trigger a cascade of endogenous opioids and non-opioids, which alter the experience of pain. For clinical application it is important to know, that placebo research yields ethical possibilities to use placebo effects without deception and without using placebos. Since placebo effects contribute to responses to active analgesics, it is feasible to enhance patients' benefits from pain treatments by increasing the additional placebo effect. There are several possibilities to use the placebo effects via shaping and adapting information about analgesic medication and via associating medication intake with a positive context. A positive patient-clinician communication atmosphere is very important to generate clinically meaningful placebo effects in pain medicine.

The mysterious phenomenon known as the nocebo effect describes negative expectancies. This is in contrast to positive expectancies that trigger placebo effects ( 1 ). In evolutionary terms, nocebo and placebo effects coexist to favor perceptual mechanisms that anticipate threat and dangerous events (nocebo effects) and promote appetitive and safety behaviors (placebo effects). In randomized placebo-controlled clinical trials, patients that receive placebos often report side effects (nocebos) that are similar to those experienced by patients that receive the investigational treatment ( 2 ). Information provided during the informed consent process and divulgence of adverse effects contribute to nocebo effects in clinical trials ( 1 ). Nocebo (and placebo) effects engage a complex set of neural circuits in the central nervous system that modulate the perception of touch, pressure, pain, and temperature ( 1 , 3 , 4 ). Commercial features of drugs such as price and labeling influence placebos ( 5 , 6 ). On page 105 of this issue, Tinnermann et al. ( 7 ) show that price also influences nocebo effects.

Contains fulltext : 184205.pdf (Publisher’s version ) (Open Access) 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. 17 p.

1. IntroductionOver the past 15 years, research into analgesic placebo effectshas been intense, and several psychological and neurobiologicalmechanisms have been discovered [10]. Placebo analgesia occurswhen alterations in pain perception appear that exceed the specificeffect of the pain treatment, be it pharmacological, psychological,or physical. Neurobiological studies have revealed great similaritybetween the molecular basis of drug action and the related placeboresponse, suggesting that a placebo can partially replace the verumand enhance its effects as detailed in our previous review onneurobiological mechanisms [10]. Core psychological mechanismsinclude expectancy [33,39] and learning such as classical condi-tioning and social learning [6,11,32], and these processes closelyinteract [7,27] with emotions and motivations (eg, anxiety, desirefor relief), somatic focus, or cognitions (eg, attitudes toward thetreatment) [8,15,17,32,33,35,37,39]. In line with these findings,Benedetti et al. [4] suggested that the effect of analgesic medica-tion has 2 components: a pharmacological and a psychologicalcomponent. In this sense, the analgesic placebo effect can be con-sidered to be ‘‘additive,’’ supplementing pain management andenhancinganalgesic medication beyondits purely pharmacologicaleffect within ethical borders. However, placebo effects not only oc-cur in pharmacological interventions, but are part of any analgesictreatment and thus, also of psychological interventions, physicaltherapy, or alternative medicine applications.A number of meta-analyses have demonstrated the efficacy ofplacebo analgesia [37,38], however, high variance is apparent indifferent study designs [20,21,37,38]. Furthermore, long-lastingefficacy of placebos has been demonstrated for psychological treat-ments (eg, [16]) or acupuncture [19]. The modifiability of theanalgesic placebo response led to proposals to make better use ofit in clinical practice [15,26,32] to optimize treatment outcomeand to provide patients with an additional placebo-based benefit.Here we propose several approaches how to exploit placebo mech-anisms to improve pharmacological and nonpharmacological paininterventions in a more systematic manner than what naturally oc-curs in clinical settings.2. Enhancing expectancyThe placebo effect can be produced by instructions and theanticipatory expectancy of pain relief [25] in the context of theinteraction and communication between health practioners andpatients [23,29]. The strength and certainty of positive expectan-cies will influence the magnitude of the placebo effect by increas-ing self-control beliefs and attention to positive effects, which can,in turn, reduce anxiety and stress [36].Placebo effects in pain treatment can be enhanced by informingthe patients about placebo mechanisms and by explaining their ef-fects to them. Such an educational informative approach ought toexplain the placebo effect based on the models of classical condi-tioning and expectancy, but also its neurobiological bases, withoutoverstraining the patient [31] (eg, the therapist can inform aboutpharmacological and psychologicaleffects of analgesics, emphasizelearning and the fact that placebos alter neurobiological processessuch as opioid release). The analgesic placebo effect can be usefullyapplied to enhance the patient’s knowledge and self-managementcompetence. For example, if patients understand the basic princi-ples of the placebo effect, they can attempt to shape the contextof taking medication to optimize its administration (eg, takingmedication attentively with focus on taste, smell, and look of thedrug, rather than inattentively). They can examine their ownexpectancies toward the drug and seek out additional informationin order to improve their attitude to the drug. In addition, healthcare providers can shape the context in which therapeutic inter-ventions are given and can thus influence the outcome via maxi-mizing expectancy. Kaptchuk et al. [23] showed that placeboacupuncture combined with a positive therapeutic relationship

Numerous studies indicate that placebo analgesia can be established via conditioning procedures. However, these studies have exclusively involved conditioning under continuous reinforcement. Thus, it is currently unknown whether placebo analgesia can be established under partial reinforcement and how durable any such effect would be. We tested this possibility using electro-cutaneous pain in healthy volunteers. Sixty undergraduates received placebo treatment (activation of a sham electrode) under the guise of an analgesic trial. The participants were randomly allocated to different conditioning schedules, namely continuous reinforcement (CRF), partial reinforcement (PRF), or control (no conditioning). Conditioning was achieved by surreptitiously reducing pain intensity during training when the placebo was activated compared with when it was inactive. For the CRF group, the placebo was always followed by a surreptitious reduction in pain during training. For the PRF group, the placebo was followed by a reduction in pain stimulation on 62.5% of trials only. In the test phase, pain stimulation was equivalent across placebo and no placebo trials. Both continuous and partial reinforcement produced placebo analgesia, with the magnitude of initial analgesia being larger following continuous reinforcement. However, while the placebo analgesia established under continuous reinforcement extinguished during test phase, the placebo analgesia established under partial reinforcement did not. These findings indicate that partial reinforcement can induce placebo analgesia and that these effects are more resistant to extinction than those established via continuous reinforcement. Partial reinforcement may, therefore, reflect a novel way of enhancing clinical outcomes via the placebo effect.

Pain modulation by placebo mechanisms is one of the most robust and best-studied phenomena, yet almost all research investigating the mechanisms and implications of the placebo analgesia are based on adult research. After highlighting crucial aspects that need to be considered in studying pain modulation in children, this comprehensive review examines studies related to pain modulation with an emphasis on factors such as age, neural development and pain measures. We critically discuss psychological mechanisms underlying placebo effects, including (1) verbally induced expectations, (2) conditioning and learning mechanisms, and (3) child-parent-physician interactions. Taken together, research suggests that placebo mechanisms can affect therapeutic outcomes and potentially be exploited clinically to improve clinical outcomes in pediatric population. Recommendations for further investigating the mechanistic bases and harnessing placebo effects for supportive therapeutic applications are given.

This study tested the experimental placebo effect in a group of chronic pain patients. Forty-eight patients having chronic back pain participated in a randomized clinical trial that tested the efficacy of a sham opioid solution (NaCl) compared with an alleged neutral, completely inactive solution (NaCl). We shaped the placebo effect by 2 interventions: verbal instruction and conditioning. The patients were either told that the "solution reduces pain and improves physical capacity" or the "solution is neutral, a placebo." Half of each group was additionally conditioned (coupling solution with reduced experimental pain), yielding 4 subgroups with 12 participants each. Outcome measures were as follows: the patients' clinical back pain ratings and acute pain ratings (both examined by numerical rating scale 0-10) and self-rated functional capacity (0%-100%; time required for the exercise). Expected pain relief before and after solution intake was also assessed. The inactive solution (NaCl), when presented as an effective treatment (sham "opioid" solution), induced placebo analgesia as evident in lower ratings of the patients' clinical back pain (F(3.12,144.21) = 25.05, P0.001), acute pain ratings (F(1.99,87.40) = 18.12, P0.01), and time needed to complete a series of daily activities exercises (F(1,44) = 8.51, P0.01) as well as increased functional capacity (F(1,44.00) = 19.42, P0.001). The 2 manipulations (instruction and conditioning) changed pain expectations, and they were maintained in both sham opioid groups. The results suggest that it may be clinically useful to explicitly integrate placebo analgesia responses into pain management.

Negative expectations deriving from the clinical encounter can produce negative outcomes, known as nocebo effects. Specifically, research on the nocebo effect indicates that information disclosure about potential side effects can itself contribute to producing adverse effects. Neurobiological processes play a role in the nocebo effect and this paper provides a selective review of mechanistic research on the nocebo effect. Comparatively little attention has been directed to clinical studies and their implications for daily clinical practice. The nocebo response is influenced by the content and the way information is presented to patients in clinical trials in both the placebo as well as active treatment conditions. Nocebo effect adversely influences quality of life and therapy adherence, emphasizing the need for minimizing these responses to the extent possible. Evidence further indicates that the informed consent process in clinical trials may induce nocebo effects. This paper concludes with ethical directions for future patient-oriented research and routine practice.

Despite growing scientific interest in the placebo effect and increasing understanding of neurobiological mechanisms, theoretical conceptualization of the placebo effect remains poorly developed. Substantial mechanistic research on this phenomenon has proceeded with little guidance by any systematic theoretical paradigm. This review seeks to present a theoretical perspective on the formation of placebo responses. We focus on information processing, and argue that different kinds of learning along with individuals' genetic make-up evolved as the proximate cause for triggering behavioural and neural mechanisms that enable the formation of individual expectations and placebo responses. Conceptualizing the placebo effect in terms of learning offers the opportunity for facilitating scientific investigation with a significant impact on medical care.

Laboratory research recently has greatly enhanced the understanding of placebo and nocebo effects by identifying specific neuromodulators and brain areas associated with them. However, little progress has been made in translating this knowledge into improved patient care. Here, we discuss the limitations in our knowledge about placebo (and nocebo) effects and the need for translational research with the aim of guiding physicians in maximizing placebo effects and minimizing nocebo effects in their routine clinical practice. We suggest some strategies for how, when and why interventions to promote beneficial placebo responses might be administered in the clinical setting.

Conditioning procedures are used in many placebo studies because evidence suggests that conditioning-related placebo responses are usually more robust than those induced by verbal suggestions alone. However, it has not been shown whether there is a causal relation between the number of conditioning trials and the resistance to extinction of placebo and nocebo responses. Here we test the effects of either one or four sessions of conditioning on the modulation of both non-painful and painful stimuli delivered to the dorsum of the foot. Placebo and nocebo manipulations were obtained by pairing green or red light to a series of stimuli that were made lower or higher with respect to a yellow light associated with a series of control stimuli. Subjects were told that the lights would indicate a treatment that would reduce or increase non-painful and painful stimuli to the foot. They were randomly assigned to either Group 1 or 2. Group 1 underwent one session of conditioning and Group 2 received four sessions of conditioning. We found that one session of conditioning (Group 1) induced nocebo responses, but not placebo responses in no pain condition. After one session of conditioning, we observed both nocebo and placebo responses to painful stimulation. However, these effects extinguished over time. Conversely, four sessions of conditioning (Group 2) induced robust placebo and nocebo responses to both non-painful and painful stimuli that persisted over the entire experiment. These findings suggest that the strength of learning may be clinically important for producing long-lasting placebo effects.

Despite substantial progress in elucidating its neurobiological mechanisms, theoretical understanding of the placebo effect is poorly developed. Application of the semiotic theory developed by the American philosopher Charles Peirce offers a promising account of placebo effects as involving the apprehension and response to signs. The semiotic approach dovetails with the various psychological mechanisms invoked to account for placebo effects, such as conditioning and expectation, and bridges the biological and cultural dimensions of this fascinating phenomenon.

Although it has long been known that psychosocial factors play a crucial role in placebo responses, no attempt has been made to understand if social observation shapes the placebo analgesic effect. To address this question, we compared placebo analgesia induced through social observation (Group 1) with first-hand experience via a typical conditioning procedure (Group 2) and verbal suggestion alone (Group 3). In Group 1, subjects underwent painful stimuli and placebo treatment after they had observed a demonstrator (actually a simulator) showing analgesic effect when the painful stimuli were paired to a green light. In Group 2, subjects were conditioned according to previous studies, whereby a green light was associated to the surreptitious reduction of stimulus intensity, so as to make them believe that the treatment worked. In Group 3, subjects received painful stimuli and were verbally instructed to expect a benefit from a green light. Pain perception was assessed by means of a Numerical Rating Scale (NRS) ranging from 0 = no pain to 10 = maximum imaginable pain. Empathy trait and heart rate were also measured. We found that observing the beneficial effects in the demonstrator induced substantial placebo analgesic responses, which were positively correlated with empathy scores. Moreover, observational social learning produced placebo responses that were similar to those induced by directly experiencing the benefit through the conditioning procedure, whereas verbal suggestions alone produced significantly smaller effects. These findings show that placebo analgesia is finely tuned by social observation and suggest that different forms of learning take part in the placebo phenomenon.

Nocebo hyperalgesia is a phenomenon that is opposite to placebo analgesia and whereby expectation of pain increase plays a crucial role. In recent times, both the neuroanatomical and the neurochemical bases of the nocebo effect and of nocebo-related effects have begun to be explored. Here, we highlight recent advances in our understanding of the neurobiology of the nocebo hyperalgesic effect.A typical nocebo hyperalgesic response occurs following the administration of an inert substance which the subject believes to be a hyperalgesic agent (negative placebo or nocebo). It has been shown that the subject's negative expectations of pain worsening induce anticipatory anxiety about the impending pain increase and this triggers the activation of cholecystokinin that, in turn, facilitates pain transmission. Accordingly, cholecystokinin antagonists have been found to prevent this anxiety-induced hyperalgesia. Brain-imaging studies have shown that the perceived intensity of a painful stimulus following negative expectations of pain increase is higher than in the absence of negative expectations and this is associated with changes in activation of specific brain regions.Since pain appears to be amplified by anxiety through the activation of cholecystokininergic systems, new therapeutic strategies, such as new cholecystokinin antagonists, can be envisaged whenever pain has an important anxiety component.

Placebo analgesia is measured by self-report, yet current, expected, and recalled efficacy may be differentially related to brain function. Here we used a human thermal pain model to compare self-reports of expected, concurrent, and recalled efficacy of a topical placebo analgesic, and tested associations of the three measures of efficacy with changes in dopamine D2/D3 receptor availability in brain using [18F]fallypride with positron emission tomography (PET). Participants (15 healthy women) were assessed on three test days. The first test day included a laboratory visit, during which the temperature needed to evoke consistent pain was determined, placebo analgesia was induced via verbal and experience-based expectation, and the placebo response was measured. On two subsequent test days, PET scans were performed in Control and Placebo conditions, respectively, in counterbalanced order. During Visit 1, concurrent and recalled placebo efficacy were unrelated; during the Placebo PET visit, expected and recalled efficacy were highly correlated (ρ = 0.68, p = 0.005), but concurrent efficacy was unrelated to expected or recalled efficacy. Region of interest analysis revealed dopamine D2/D3 receptor availability was lower in left ventrolateral prefrontal cortex in the Placebo condition (p, Highlights • Healthy women reported on expected, concurrent, and recalled placebo analgesia. • Measures were obtained in the lab and during PET scanning with [18F]fallypride. • Dopamine D2/D3 receptor availability in PFC was associated with placebo analgesia. • This relationship was specific to recalled placebo analgesia efficacy.

Despite its initial treatment as a nuisance variable, the placebo effect is now recognized as a powerful determinant of health across many different diseases and encounters. This is in light of some remarkable findings ranging from demonstrations that the placebo effect significantly modulates the response to active treatments in conditions such as pain, anxiety, Parkinson’s disease, and some surgical procedures. Here, we review pioneering studies and recent advances in behavioural, neurobiological, and genetic influences on the placebo effect. Based on a previous developed conceptual framework, the placebo effect is presented as the product of a general expectancy learning mechanism in which verbal, conditioned, observational, and social cues are centrally integrated to change behaviours and outcomes. Examples of the integration of verbal and conditioned cues, such as instructed reversal of placebo effects are also incorporated into this model. We discuss neuroimaging studies that using well-established behavioral paradigms have identified key brain regions and modulatory mechanisms underlying placebo effects. Finally, we present a synthesis of recent genetics studies on the placebo effect, highlighting a promising link between genetic variants in the dopamine, opioid, serotonin, and endocannabinoid pathways and placebo responsiveness. Greater understanding of the behavioural, neurobiological, and genetic influences on the placebo effect is critical for evaluating medical interventions and may allow health professionals to tailor and personalize interventions in order to maximise treatment outcomes in clinical settings.