Effects of deep brain stimulation and verbal suggestions on pain in Parkinson's disease.

BACKGROUND AND OBJECTIVES: In Parkinson's disease (PD) patients, verbal suggestions have been shown to modulate motor and clinical outcomes in treatment with subthalamic deep brain stimulation (DBS). Furthermore, DBS may alleviate pain in PD. However, it is unknown if verbal suggestions influence DBS' effects on pain. METHODS: Twenty-four people with PD and DBS had stimulation downregulated (80-60 to 20%) and upregulated (from 20-60 to 80%) in a blinded manner on randomized test days: (1) with negative and positive suggestions of pain for down- and upregulation, respectively, and (2) with no suggestions to effect (control). Effects of DBS and verbal suggestions were assessed on ongoing and evoked pain (hypertonic saline injections) via 0-10 numerical rating scales along with motor symptoms, expectations, and blinding. RESULTS: Stimulation did not influence ongoing and evoked pain but influenced motor symptoms in the expected direction. Baseline and experimental pain measures showed no patterns in degree of pain. There was a trend toward negative suggestions increasing pain and positive suggestions decreasing pain. Results show significant differences in identical stimulation with negative vs positive suggestions (60% conditions AUC 38.75 vs 23.32, t(13) = 3.10, p < 0.001). Expectations to pain had small to moderate effects on evoked pain. Patients estimated stimulation level correctly within 10 points. CONCLUSION: Stimulation does not seem to influence ongoing and evoked pain, but verbal suggestions may influence pain levels. Patients appear to be unblinded to stimulation level which is an important consideration for future studies testing DBS in an attempted blind fashion.

An international consensus definition for contextual factors: findings from a nominal group technique.

Objective: Emerging literature suggests contextual factors are important components of therapeutic encounters and may substantially influence clinical outcomes of a treatment intervention. At present, a single consensus definition of contextual factors, which is universal across all health-related conditions is lacking. The objective of this study was to create a consensus definition of contextual factors to better refine this concept for clinicians and researchers. Design: The study used a multi-stage virtual Nominal Group Technique (vNGT) to create and rank contextual factor definitions. Nominal group techniques are a form of consensus-based research, and are beneficial for identifying problems, exploring solutions and establishing priorities. Setting: International. Main outcome measures: The initial stages of the vNGT resulted in the creation of 14 independent contextual factor definitions. After a prolonged discussion period, the initial definitions were heavily modified, and 12 final definitions were rank ordered by the vNGT participants from first to last. Participants: The 10 international vNGT participants had a variety of clinical backgrounds and research specializations and were all specialists in contextual factors research. Results: A sixth round was used to identify a final consensus, which reflected the complexity of contextual factors and included three primary domains: (1) an overall definition; (2) qualifiers that serve as examples of the key areas of the definition; and (3) how contextual factors may influence clinical outcomes. Conclusion: Our consensus definition of contextual factors seeks to improve the understanding and communication between clinicians and researchers. These are especially important in recognizing their potential role in moderating and/or mediating clinical outcomes.

The Biology of Placebo and Nocebo Effects on Experimental and Chronic Pain: State of the Art.

(1) Background: In recent years, placebo and nocebo effects have been extensively documented in different medical conditions, including pain. The scientific literature has provided strong evidence of how the psychosocial context accompanying the treatment administration can influence the therapeutic outcome positively (placebo effects) or negatively (nocebo effects). (2) Methods: This state-of-the-art paper aims to provide an updated overview of placebo and nocebo effects on pain. (3) Results: The most common study designs, the psychological mechanisms, and neurobiological/genetic determinants of these phenomena are discussed, focusing on the differences between positive and negative context effects on pain in experimental settings on healthy volunteers and in clinical settings on chronic pain patients. Finally, the last section describes the implications for clinical and research practice to maximize the medical and scientific routine and correctly interpret the results of research studies on placebo and nocebo effects. (4) Conclusions: While studies on healthy participants seem consistent and provide a clear picture of how the brain reacts to the context, there are no unique results of the occurrence and magnitude of placebo and nocebo effects in chronic pain patients, mainly due to the heterogeneity of pain. This opens up the need for future studies on the topic.

The Temporal Modulation of Nocebo Hyperalgesia in a Model of Sustained Pain.

Background: The direction and the magnitude of verbal suggestions have been shown to be strong modulators of nocebo hyperalgesia, while little attention has been given to the role of their temporal content. Here, we investigate whether temporal suggestions modulate the timing of nocebo hyperalgesia in an experimental model of sustained pain. Methods: Fifty-one healthy participants were allocated to one of three groups. Participants received an inert cream and were instructed that the agent had either hyperalgesic properties setting in after 5 (Nocebo 5, N5) or 30 (Nocebo 30, N30) minutes from cream application, or hydrating properties (No Expectation Group, NE). Pain was induced by the Cold Pressure Test (CPT) which was repeated before cream application (baseline) and after 10 (Test10) and 35 (Test35) minutes. Changes in pain tolerance and in HR at each test point in respect to baseline were compared between the three groups. Results: Tolerance change at Test 10 (Δ10) was greater in N5 (MED = -36.8; IQR = 20.9) compared to NE (MED = -5.3; IQR = 22.4; p < 0.001) and N30 (MED = 0.0; IQR = 23.1; p < 0.001), showing that hyperalgesia was only present in the group that expected the effect of the cream to set in early. Tolerance change at Test 35 (Δ35) was greater in N5 (MED = -36.3; IQR = 35.3; p = 0.002) and in N30 (MED = -33.3; IQR = 34.8; p = 0.009) compared to NE, indicating delayed onset of hyperalgesia in N30, and sustained hyperalgesia in N5. No group differences were found for HR. Conclusions: Our study demonstrated that temporal expectations shift nocebo response onset in a model of sustained pain.

Unraveling Negative Expectations and Nocebo-Related Effects in Musculoskeletal Pain.

This Perspective adapts the ViolEx Model, a framework validated in several clinical conditions, to better understand the role of expectations in the recovery and/or maintenance of musculoskeletal (MSK) pain. Here, particular attention is given to the condition in which dysfunctional expectations are maintained despite no longer being supported by confirmatory evidence (i.e., belief-lifting the arm leads to permanent tendon damage; evidence-after the patient lifts the arm no tendon damage occurs). While the ViolEx Model suggests that cognitive immunization strategies are responsible for the maintenance of dysfunctional expectations, we suggest that such phenomenon can also be understood from a Bayesian Brain perspective, according to which the level of precision of the priors (i.e., expectations) is the determinant factor accounting for the extent of priors' updating (i.e., we merge the two frameworks, suggesting that highly precise prior can lead to cognitive immunization responses). Importantly, this Perspective translates the theory behind these two frameworks into clinical suggestions. Precisely, it is argued that different strategies should be implemented when treating MSK pain patients, depending on the nature of their expectations (i.e., positive or negative and the level of their precision).

Pain expectation and avoidance in the social context: an electrophysiological study.

Contingent negative variation (CNV) is an informative electrophysiological measure of pain anticipation showing higher amplitudes when highly painful stimulation is expected while presenting lower amplitudes when low painful stimulation is expected. Two groups of participants were recruited: one group expected and received an electrical stimulation of different intensities while being alone in the room (i.e. without social context), while a second group performed the same experiment with an observer in the room (i.e. with social context). Lower pain ratings and slower reaction times were observed in the group with social context and these results were accompanied in this group by a lower amplitude in the early component of the CNV as well as a lower amplitude of the later component of the wave. These results show that CNV can be considered a precise measure of central elaboration of pain anticipation explaining both its perceptual and motor components.

'External timing' of placebo analgesia in an experimental model of sustained pain.

BACKGROUND: Research on placebo analgesia commonly focuses on the impact of information about direction (i.e., increase or decrease of pain) and magnitude of the expected analgesic effect, whereas temporal aspects of expectations have received little attention so far. In a recent study, using short-lasting, low-intensity stimuli, we demonstrated that placebo analgesia onset is influenced by temporal information. Here, we investigate whether the same effect of temporal suggestions can be found in longer lasting, high-intensity pain in a Cold Pressor Test (CPT). METHODS: Fifty-three healthy volunteers were allocated to one of three groups. Participants were informed that the application of an (inert-)cream would reduce pain after 5 min (P5) or 30 min (P30). The third group was informed that the cream only had hydrating properties (NE). All participants completed the CPT at baseline and 10 (Test 10) and 35 min (Test 35) following cream application. Percentage change in exposure time (pain tolerance) from baseline to Test 10 (Δ10) and to Test 35 (Δ35) and changes in heart rate (HR) during CPT were compared between the three groups. RESULTS: Δ10 was greater in P5 than in NE and P30, indicating that analgesia was only present in the group that was expecting an early onset of analgesia. Δ35 was greater in P5 and P30 compared to NE, reflecting a delayed onset of analgesia in P30 and maintained analgesia in P5. HR differences between groups were not significant. CONCLUSIONS: Our data suggest that 'externally timing' of placebo analgesia may be possible for prolonged types of pain. SIGNIFICANCE: Research on placebo effects mainly focuses on the influence of information about direction (i.e., increase or decrease of pain) and magnitude (i.e., strong or weak) of the expected effect but ignores temporal aspects of expectations. In our study in healthy volunteers, the reported onset of placebo analgesia followed the temporal information provided. Such 'external timing' effects could not only aid the clinical use of placebo treatment (e.g., in open-label placebos) but also support the efficacy of active drugs.

The Effect of Temporal Information on Placebo Analgesia and Nocebo Hyperalgesia.

OBJECTIVE: Expectations are known to be key determinants of placebo and nocebo phenomena. In previous studies, verbal suggestions to induce such expectations have mainly focused on the direction and magnitude of the effect, whereas little is known about the influence of temporal information. METHODS: Using an experimental placebo and nocebo design, we investigated whether information about the expected onset of a treatment effect modulates the start and time course of analgesic and hyperalgesic responses. Healthy volunteers (n = 166) in three placebo and three nocebo groups were informed that the application of an (inert) cream would reduce (placebo groups) or amplify pain (nocebo groups) after 5, 15, or 30 minutes. Two control groups were also included (natural history and no expectations). Participants' pain intensity rating of electrical stimuli administered before and 10, 20, and 35 minutes after cream application was obtained. RESULTS: Mixed-method analysis of variance showed a significant interaction between group and time (F(12,262) = 18.172, p < .001, pη2 = 0.454), suggesting that pain variations differed across time points and between groups. Post hoc comparisons revealed that the placebo and nocebo groups began to show a significantly larger change in perceived pain intensity than the no-expectancy control group at the expected time point (p < .05) but not earlier (p > .05). Once triggered, the analgesic effect remained constant over the course of the experiment, whereas the hyperalgesic effect increased over time. CONCLUSIONS: Our results indicate that temporal suggestions can shape expectancy-related treatment effects, which, if used systematically, could open up new ways to optimize treatment outcome.

The placebo effect in breath holding: a preliminary behavioral investigation.

PURPOSE: This study seeks to evaluate effects of expectations and conditioning on dry breath holding. METHODS: Sixty healthy volunteers were subdivided into 3 groups and were tested across 4 breath holding trials. Participants of the Control group (C) did not undergo any manipulation. Participants of the placebo (P) and nocebo (N) groups were told that they would inhale O2 (actually sham O2) or CO2 (actually sham CO2) along with opposite information that this would enhance or worsen their breath holding time, respectively. Opposite conditioning paradigms based on false visual feedback were employed to reinforce participants' positive (placebo) and negative (nocebo) beliefs. RESULTS: The P group showed the greater increase in breath holding time from baseline to the last trial (p = 0.0001) and the longest breath holding time in the last trial compared to the C group (p = 0.02) and the N group (p = 0.0001). Additionally, in the last trial the P group showed a greater decrease in peripheral oxygen saturation (SpO2) as compared to the C group (p = 0.04) and the N group (p = 0.001). Heart rate (HR) was accelerated in the N group during breath holding (in comparison to the P group [p = 0.04] and C group [p = 0.04]). CONCLUSIONS: Psychological components can affect behavioral and physiological parameters in breath holding. This study may inform future research about the role of placebo and nocebo effects for conditions in which critical functions are at play.

European Headache Federation recommendations for placebo and nocebo terminology.

BACKGROUND AND AIM: Despite recent publications, practitioners remain unfamiliar with the current terminology related to the placebo and nocebo phenomena observed in clinical trials and practice, nor with the factors that modulate them. To cover the gap, the European Headache Federation appointed a panel of experts to clarify the terms associated with the use of placebo in clinical trials. METHODS: The working group identified relevant questions and agreed upon recommendations. Because no data were required to answer the questions, the GRADE approach was not applicable, and thus only expert opinion was provided according to an amended Delphi method. The initial 12 topics for discussion were revised in the opinion of the majority of the panelists, and after a total of 6 rounds of negotiations, the final agreement is presented. RESULTS/RECOMMENDATIONS: Two primary and mechanism-based recommendations are provided for the results of clinical trials: [1] to distinguish the placebo or nocebo response from the placebo or nocebo effect; and [2] for any favorable outcome observed after placebo administration, the term "placebo response" should be used, and for any unfavorable outcome recorded after placebo administration, the term "nocebo response" should be used (12 out of 17 panelists agreed, 70.6% agreement). The placebo or nocebo responses are attributed to a set of factors including those that are related to the medical condition (e.g. natural history, random comorbidities, etc.), along with idiosyncratic ones, in which the placebo or nocebo effects are attributed to idiosyncratic, or nonspecific mechanisms, exclusively (e.g. expectation, conditioning, observational learning etc.). To help investigators and practitioners, the panel summarized a list of environmental factors and idiosyncratic dynamics modulating placebo and nocebo effects. Some of them are modifiable, and investigators or physicians need to know about them in order to modify these factors appropriately to improve treatment. One secondary recommendation addresses the use of the terms "placebo" and "nocebo" ("placebos" and "nocebos" in plural), which refer to the triggers of the placebo/nocebo effects or responses, respectively, and which are inert agents or interventions that should not be confused with the placebo/nocebo responses or effects themselves (all panelists agreed, 100% agreement). CONCLUSION: The working group recommends distinguishing the term response from effect to describe health changes from before to after placebo application and to distinguish the terms placebo(s) or nocebo(s) from the health consequences that they cause (placebo/nocebo responses or effects).

I expect what you expect: An electrophysiological study on social expectation of pain.

Expectations and motor reactions related to pain are mainly acquired through personal experiences. Contingent negative variation (CNV) has been shown to be an informative electrophysiological measure of this pain anticipation. Expectations can also arise while observing others in painful conditions. However, it still remains unclear what are the neural correlates of this phenomenon and how the observation of others in pain can subsequently change our personal pain perception as well as our motor reaction to pain. Using CNV as a measure of expectation, this study aims to assess whether expectations formed through observation change the observer's own experience of pain and reaction to pain. A new cooperative task was designed where one participant, the model, received an electrical stimulation while another, the observer, watched the experiment and both were asked to stop the stimulation as fast as possible. Crucially, in a successive session, participants inverted their roles so that models became observers and vice versa. CNV was recorded in both participants simultaneously by means of two synchronized electroencephalograms. Results showed that CNV area did not differ between models and observers and reaction times were significantly faster in observers compared to models. Moreover, observers' pain perception was correlated to models' pain perception as well as to observers' empathy scores. These data show how expectations, perceptions as well as reactions related to pain are crucially affected not only by observation but by personal attitudes toward others and all these changes can be clearly described through CNV.

Context matters: the psychoneurobiological determinants of placebo, nocebo and context-related effects in physiotherapy.

BACKGROUND: Placebo and nocebo effects embody psychoneurobiological phenomena where behavioural, neurophysiological, perceptive and cognitive changes occur during the therapeutic encounter in the healthcare context. Placebo effects are produced by a positive healthcare context; while nocebo effects are consequences of negative healthcare context. Historically, placebo, nocebo and context-related effects were considered as confounding elements for clinicians and researchers. In the last two decades this attitude started to change, and the understanding of the value of these effects has increased. Despite the growing interest, the knowledge and the awareness of using the healthcare context to trigger placebo and nocebo effects is currently limited and heterogeneous among physiotherapists, reducing their translational value in the physiotherapy field. OBJECTIVES: To introduce the placebo, nocebo and context-related effects by: (1) presenting their psychological models; (2) describing their neurophysiological mechanisms; (3) underlining their impact for the physiotherapy profession; and (4) tracing lines for future researches. CONCLUSION: Several psychological mechanisms are involved in placebo, nocebo and context-related effects; including expectation, learning processes (classical conditioning and observational learning), reinforced expectations, mindset and personality traits. The neurophysiological mechanisms mainly include the endogenous opioid, the endocannabinoid and the dopaminergic systems. Neuroimaging studies have identified different brain regions involved such as the dorsolateral prefrontal cortex, the rostral anterior cingulate cortex, the periaqueductal gray and the dorsal horn of spine. From a clinical perspective, the manipulation of the healthcare context with the best evidence-based therapy represents an opportunity to trigger placebo effects and to avoid nocebo effects respecting the ethical code of conduct. From a managerial perspective, stakeholders, organizations and governments should encourage the assessment of the healthcare context aimed to improve the quality of physiotherapy services. From an educational perspective, placebo and nocebo effects are professional topics that should be integrated in the university program of health and medical professions. From a research perspective, the control of placebo, nocebo and context-related effects offers to the scientific community the chance to better measure the impact of physiotherapy on different outcomes and in different conditions through primary studies.

Placebo analgesia effects across central nervous system diseases: what do we know and where do we need to go?

Placebo effects are well established in healthy participants experiencing experimental or acute pain. Yet, little is known about the mechanisms of placebo analgesia effects in patients with chronic pain and even less is known in patients suffering from central nervous system (CNS) diseases where pain is prevalent, difficult to manage, and often undertreated. This article briefly reviews the current knowledge of placebo analgesia effects in healthy participants with the aim of discussing how the mechanisms in placebo analgesia differ between healthy participants and patients. The focus will be on placebo analgesia effects in chronic pain conditions as well as in 2 CNS diseases: Alzheimer disease and Parkinson disease. Finally, strengths and weaknesses of the current knowledge will be discussed and it will be demonstrated how insights from the placebo literature may point to new ways of improving treatments among patients experiencing pain in relation to CNS diseases.

Verbal communication about drug dosage balances drug reduction in Parkinson's disease: Behavioral and electrophysiological evidences.

INTRODUCTION: Changing drug dosage is common in clinical practice. Recent evidence showed that psychological factors may affect the therapeutic outcome. The aim of this study is to test whether verbal communication about drug dosage changes motor performance and fatigue in Parkinson's Disease (PD) patients. METHODS: We performed clinical (Unified PD Rating Scale), motor (number of finger flexions and perceived fatigue), and electrophysiological measurements (readiness potential, RP) in PD patients during medication-off and medication-on conditions in three groups. The first group got a full dose of l-dopa and was told it was a full dose. The second group got half dose and was told it was half dose. The third group got half dose, but it was told it was a full standard dose. RESULTS: We found that overt half dose was less effective than the full dose for clinical improvement, motor performance, and readiness potential. However, if half dose was given along with verbal instructions that it was a full dose, clinical improvement, motor performance and readiness potential were not significantly different from the full dose. CONCLUSIONS: Our findings indicate that verbal communication about dose reduction is as effective as the 50% dose reduction itself, demonstrating that deceptive information about the dose may have an important impact on the therapeutic outcome. Moreover, the supplementary motor area, source of the RP, seems to be involved in this psychological effect.

Can knowledge of Placebo and Nocebo Mechanisms Help Improve Randomized Clinical Trials?

Over the last decade, there has been a substantial increase in negative results from randomized controlled trials (RCTs), which may be due to an increasing placebo response among other factors. Currently, identification and exclusion of placebo responders from trials are attempted to overcome this problem, but so far the success of these approaches has been limited. At the same time, the placebo-mechanism literature has highlighted how contextual factors, such as patients' expectations, interfere with the effect of drug administration, leading to a certain degree of uncertainty in RCTs. In this chapter, we review the current challenges of RCTs including the uncertainties of the active arm, the placebo arm, the additivity assumption, and the double-blind procedure. We use the placebo-mechanism literature to debate the strengths and weaknesses of attempts to identify and exclude placebo responders from trials. Finally, we illustrate how insights from the placebo-mechanism literature may point to new ways of improving RCTs.

Clinical relevance of contextual factors as triggers of placebo and nocebo effects in musculoskeletal pain.

Placebo and nocebo effects are embodied psycho-neurobiological responses capable of modulating pain and producing changes at different neurobiological, body at perceptual and cognitive levels. These modifications are triggered by different contextual factors (CFs) presented in the therapeutic encounter between patient and healthcare providers, such as healing rituals and signs. The CFs directly impact on the quality of the therapeutic outcome: a positive context, that is a context characterized by the presence of positive CFs, can reduce pain by producing placebo effects, while a negative context, characterized by the presence of negative CFs, can aggravate pain by creating nocebo effects. Despite the increasing interest about this topic; the detailed study of CFs as triggers of placebo and nocebo effects is still lacked in the management of musculoskeletal pain.Increasing evidence suggest a relevant role of CFs in musculoskeletal pain management. CFs are a complex sets of internal, external or relational elements encompassing: patient's expectation, history, baseline characteristics; clinician's behavior, belief, verbal suggestions and therapeutic touch; positive therapeutic encounter, patient-centered approach and social learning; overt therapy, posology of intervention, modality of treatment administration; marketing features of treatment and health care setting. Different explanatory models such as classical conditioning and expectancy can explain how CFs trigger placebo and nocebo effects. CFs act through specific neural networks and neurotransmitters that were described as mediators of placebo and nocebo effects.Available findings suggest a relevant clinical role and impact of CFs. They should be integrated in the clinical reasoning to increase the number of treatment solutions, boosts their efficacy and improve the quality of the decision-making. From a clinical perspective, the mindful manipulation of CFs represents a useful opportunity to enrich a well-established therapy in therapeutic setting within the ethical border. From a translational perspective, there is a strong need of research studies on CFs close to routine and real-world clinical practice in order to underline the uncertainty of therapy action and help clinicians to implement knowledge in daily practice.

The placebo effect on bradykinesia in Parkinson's disease with and without prior drug conditioning.

BACKGROUND: Placebo effects represent a major drawback in clinical trials, and their magnitude hampers the development of new treatments. Previous research showed that prior exposure to active treatments increases the placebo response for muscle rigidity in Parkinson's disease. METHODS: We investigated the effects of prior exposure to apomorphine on the placebo response of another cardinal symptom of Parkinson's disease, bradykinesia, by a movement time analyzer. RESULTS: We found no placebo response if the placebo was given for the first time, whereas the placebo response was substantial after prior pharmacological conditioning with apomorphine. CONCLUSIONS: These findings indicate that prior exposure to drugs is a critical factor in the occurrence and magnitude of placebo effects. These learning effects should be carefully assessed in clinical trials in which patients receive the active treatment first and then are randomized. Indeed, this sequence may generate high placebo responders. © 2017 International Parkinson and Movement Disorder Society.

Placebo effects: From pain to motor performance.

The placebo effect can be elicited by two main mechanisms: via classical conditioning and cognitive expectations. These two mechanisms have been traditionally investigated in one single domain. The aim of the present study is to investigate how a placebo effect obtained in one modality (pain tolerance) can be transferred to another modality (motor endurance) and which mechanisms (i.e. reinforced expectation/conditioning or expectations alone) are more responsible for this placebo transferability. Participants were tested in a pain tolerance task and in a motor task in two different experiments: after a conditioning procedure on pain tolerance in which they were made to believe in the effectiveness of an analgesic treatment procedure (experiment 1) or without a previous conditioning procedure (experiment 2). In both experiments, objective (pain tolerance and number of finger flexions) and subjective (pain and fatigue perception) measures were recorded. In experiment 1 subjects experienced an increase of pain tolerance and a reduction of pain perception as well as an increased number of flexions and a reduction of reported fatigue. Conversely, in experiment 2 subjects experienced only a reduction of pain and fatigue perception with no significant increase of objective measures. Our results point out that it is possible to transfer the positive effects observed on pain to a motor task but only if verbally induced expectations are reinforced by previous experiences. This result could represent an important step to apply placebo procedures in pathological conditions such as chronic fatigue or Parkinson's disease.